AIDS was first recognized in the United States in the summer of 1981, when the U.S. Centers for Disease Control and Prevention (CDC) reported the unexplained occurrence of Pneumocystis jirovecii (formerly P. carinii) pneumonia in five previously healthy homosexual men in Los Angeles and of Kaposi’s sarcoma (KS) with or without P. jirovecii pneumonia and other opportunistic infections in 26 previously healthy homosexual men in New York, San Francisco, and Los Angeles. The disease was soon recognized in male and female injection drug users; in hemophiliacs and blood transfusion recipients; among female sexual partners of men with AIDS; and among infants born to mothers with AIDS. In 1983, human immunodeficiency virus (HIV) was isolated from a patient with lymphadenopathy, and by 1984 it was demonstrated clearly to be the causative agent of AIDS. In 1985, a sensitive enzyme-linked immunosorbent assay (ELISA) was developed; this led to an appreciation of the scope and evolution of the HIV epidemic at first in the United States and other developed nations and ultimately among developing nations throughout the world (see “HIV Infection and AIDS Worldwide,” below). The staggering worldwide evolution of the HIV pandemic has been matched by an explosion of information in the areas of HIV virology, pathogenesis (both immunologic and virologic), treatment of HIV disease, treatment and prophylaxis of the opportunistic diseases associated with HIV infection, and prevention of HIV infection. The information flow related to HIV disease is enormous and continues to expand, and it has become almost impossible for the health care generalist to stay abreast of the literature. The purpose of this chapter is to present the most current information available on the scope of the pandemic; on its pathogenesis, treatment, and prevention; and on prospects for vaccine development. Above all, the aim is to provide a solid scientific basis and practical clinical guidelines for a state-of-the-art approach to the HIV-infected patient.
The current CDC classification system for HIV infection and AIDS categorizes patients based on clinical conditions associated with HIV infection together with the level of the CD4+ T lymphocyte count. A confirmed HIV case can be classified in one of five HIV infection stages (0, 1, 2, 3, or unknown). If there was a negative HIV test within 6 months of the first HIV infection diagnosis, the stage is 0, and remains 0 until 6 months after diagnosis. Advanced HIV disease (AIDS) is classified as stage 3 if one or more specific opportunistic illness has been diagnosed (Table 197-1). Otherwise, the stage is determined by CD4+ T lymphocyte test results and immunologic criteria (Table 197-2). If none of these criteria apply (e.g., because of missing information on CD4+ T lymphocyte test results), the stage is U (unknown).
TABLE 197-1CDC Stage 3 (AIDS)-Defining Opportunistic Illnesses in HIV Infection ||Download (.pdf) TABLE 197-1 CDC Stage 3 (AIDS)-Defining Opportunistic Illnesses in HIV Infection
|Bacterial infections, multiple or recurrenta |
|Candidiasis of bronchi, trachea, or lungs |
|Candidiasis of esophagus |
|Cervical cancer, invasiveb |
|Coccidioidomycosis, disseminated or extrapulmonary |
|Cryptococcosis, extrapulmonary |
|Cryptosporidiosis, chronic intestinal (>1 month’s duration) |
|Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month |
|Cytomegalovirus retinitis (with loss of vision) |
|Encephalopathy attributed to HIV |
|Herpes simplex: chronic ulcers (>1 month’s duration) or bronchitis, pneumonitis, or esophagitis (onset at age >1 month) |
|Histoplasmosis, disseminated or extrapulmonary |
|Isosporiasis, chronic intestinal (>1 month’s duration) |
|Kaposi’s sarcoma |
|Lymphoma, Burkitt’s (or equivalent term) |
|Lymphoma, immunoblastic (or equivalent term) |
|Lymphoma, primary, of brain |
|Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary |
|Mycobacterium tuberculosis of any site, pulmonary,b disseminated, or extrapulmonary |
|Mycobacterium, other species or unidentified species, disseminated or extrapulmonary |
|Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia |
|Pneumonia, recurrentb |
|Progressive multifocal leukoencephalopathy |
|Salmonella septicemia, recurrent |
|Toxoplasmosis of brain, onset at age >1 month |
|Wasting syndrome attributed to HIV |
TABLE 197-2CDC HIV Infection Stages 1–3 Based on Age-Specific CD4+ T Lymphocyte Count or CD4+ T Lymphocyte Percentage of Total Lymphocytesa ||Download (.pdf) TABLE 197-2 CDC HIV Infection Stages 1–3 Based on Age-Specific CD4+ T Lymphocyte Count or CD4+ T Lymphocyte Percentage of Total Lymphocytesa
| ||Age on Date of CD4 T+ Lymphocyte Test |
| ||<1 Year ||1–5 Years ||6 Years through Adult |
|Stagea ||Cells/µL ||% ||Cells/µL ||% ||Cells/µL ||% |
|1 ||≥1500 ||≥34 ||≥1000 ||≥30 ||≥500 ||≥26 |
|2 ||750–1499 ||26–33 ||500–999 ||22–29 ||200–499 ||14–25 |
|3 ||<750 ||<26 ||<500 ||<22 ||<200 ||<14 |
The definition and staging criteria of AIDS are complex and comprehensive and were established for surveillance purposes rather than for the practical care of patients. Thus, the clinician should not focus on whether the patient fulfills the strict definition of AIDS, but should view HIV disease as a spectrum ranging from primary infection, with or without the acute syndrome, to the relatively asymptomatic stage, to advanced stages associated with opportunistic diseases (see “Pathophysiology and Pathogenesis,” below).
HIV is the etiologic agent of AIDS; it belongs to the family of human retroviruses (Retroviridae) and the subfamily of lentiviruses (Chap. 196). Nononcogenic lentiviruses cause disease in other animal species, including sheep, horses, goats, cattle, cats, and monkeys. The four retroviruses known to cause human disease belong to two distinct groups: the human T lymphotropic viruses (HTLV)-1 and HTLV-2, which are transforming retroviruses; and the human immunodeficiency viruses, HIV-1 and HIV-2, which cause cytopathic effects either directly or indirectly (Chap. 196). The most common cause of HIV disease throughout the world, and certainly in the United States, is HIV-1, which comprises several subtypes with different geographic distributions (see “Molecular Heterogeneity of HIV-1,” below). HIV-2 was first identified in 1986 in West African patients and was originally confined to West Africa. However, cases traced to West Africa or to sexual contacts with West Africans have been identified throughout the world. The currently defined groups of HIV-1 (M, N, O, P) and the HIV-2 groups A through H each are likely derived from a separate transfer to humans from a nonhuman primate reservoir. HIV-1 viruses likely came from chimpanzees and/or gorillas, and HIV-2 from sooty mangabeys. The AIDS pandemic is primarily caused by the HIV-1 M group viruses. Although HIV-1 group O and HIV-2 viruses have been found in numerous countries, including those in the developed world, they have caused much more localized epidemics. The taxonomic relationship between primate lentiviruses is shown in Fig. 197-1.
A phylogenetic tree based on the nearly complete genomes (gag through nef genes) of primate immunodeficiency viruses. The scale (0.25) indicates a 25% phylogenetically corrected genetic distance at the nucleotide level. Clades in color represent viruses (HIV-1, HIV-2) identified in humans after relatively recent transfers from chimpanzee, gorilla, and sooty mangabey reservoirs. (Prepared by Brian Foley, PhD, of the HIV Sequence Database, Theoretical Biology and Biophysics Group, Los Alamos National Laboratory; additional information at www.hiv.lanl.gov/content/sequence/HelpDocs/subtypes.html.)
Electron microscopy shows that the HIV virion is an icosahedral structure (Fig. 197-2) containing numerous external spikes formed by the two major envelope proteins, the external gp120 and the transmembrane gp41. The HIV envelope exists as a trimeric heterodimer. The virion buds from the surface of the infected cell (Fig. 197-2A) and incorporates a variety of host cellular proteins into its lipid bilayer. The structure of HIV-1 is schematically diagrammed in Fig. 197-2B.
A. Electron micrograph of HIV. Figure illustrates a typical virion following budding from the surface of a CD4+ T lymphocyte, together with two additional incomplete virions in the process of budding from the cell membrane. B. Structure of HIV-1, including the gp120 envelope, gp41 transmembrane components of the envelope, genomic RNA, enzyme reverse transcriptase, p18(17) inner membrane (matrix), and p24 core protein (capsid). (Copyright by George V. Kelvin.) (Adapted from RC Gallo: Sci Am 256:46, 1987.) C. Scanning electron micrograph of HIV-1 virions infecting a human CD4+ T lymphocyte. The original photograph was imaged at 20,000× magnification. Cell is approximately 10 microns in diameter, and the HIV particles are approximately 120 nanometers. (Courtesy of Elizabeth R. Fischer, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases; with permission.)
HIV is an RNA virus whose hallmark is the reverse transcription of its genomic RNA to DNA by the enzyme reverse transcriptase. The replication cycle of HIV begins with the high-affinity binding via surface-exposed residues within the gp120 protein to its receptor on the host cell surface, the CD4 molecule (Fig. 197-3). The CD4 molecule is a 55-kDa protein found predominantly on a subset of T lymphocytes that are responsible for helper function in the immune system (Chap. 342). Once it binds to CD4, the gp120 protein undergoes a conformational change that facilitates binding to one of two major co-receptors. The two major co-receptors for HIV-1 are CCR5 and CXCR4. Both receptors belong to the family of seven-transmembrane-domain G protein–coupled cellular receptors, and the use of one or the other or both receptors by the virus for entry into the cell is an important determinant of the cellular tropism of the virus. Cell-to-cell spread is also facilitated by accessory molecules such as the C-type lectin receptor DC-SIGN expressed on certain dendritic cells (DCs) that bind to the HIV gp120 envelope protein, allowing virus captured on DCs to spread to CD4+ T cells. Following binding of the envelope protein to the CD4 molecule associated with the above-mentioned conformational change in the viral envelope gp120, fusion with the host cell membrane occurs via the newly exposed gp41 molecule penetrating the plasma membrane of the target cell and then coiling upon itself to bring the virion and target cell together (Fig. 197-4). Following fusion, uncoating of the capsid protein shell is initiated—a step that facilitates reverse transcription and leads to formation of the preintegration complex, composed of viral RNA, enzymes, and accessory proteins and surrounded by capsid and matrix proteins (Fig. 197-3). As the preintegration complex traverses the cytoplasm to reach the nucleus, the viral reverse transcriptase enzyme catalyzes the reverse transcription of the genomic RNA into DNA, resulting in the formation of double-stranded proviral HIV DNA. At several steps of the replication cycle, the virus is vulnerable to various cellular factors that can block the progression of infection. The cytoplasmic tripartite motif-containing protein 5-α (TRIM5-α) is a host restriction factor that interacts with retroviral capsids, causing their premature disassembly and induction of innate immune responses. While early studies with laboratory strains found the HIV-1 capsid bound weakly to the human form of TRIM5-α, capsids of primary isolates appear to be more susceptible to TRIM5-α-mediated disassembly. The apolipoprotein B mRNA editing enzyme (catalytic polypeptide-like 3 [APOBEC3]) family of cellular proteins also inhibits progression of virus infection after virus has entered the cell and prior to entering the nucleus. APOBEC3 proteins, which are incorporated into virions and released into the cytoplasm of a newly infected cell, bind to the single minus-strand DNA intermediate and deaminate viral cytidine, causing hypermutation of retroviral genomes. HIV has evolved a powerful strategy to protect itself from APOBEC. The viral protein Vif targets APOBEC3 for proteasomal degradation. SAMHD1 is another post-entry host factor that prevents reverse transcription by depleting pools of deoxynucleotides (dNTPs). The type I interferon (IFN)-induced myxovirus resistance protein 2 (MX2) is another restriction factor associated with innate immunity that inhibits HIV-1 nuclear entry.
The replication cycle of HIV. See text for description. (From the National Institute of Allergy and Infectious Diseases.)
Binding and fusion of HIV-1 with its target cell. HIV-1 binds to its target cell via the CD4 molecule, leading to a conformational change in the gp120 molecule that allows it to bind to the co-receptor CCR5 (for R5-using viruses). The virus then firmly attaches to the host cell membrane in a coiled-spring fashion via the newly exposed gp41 molecule. Virus-cell fusion occurs as the transitional intermediate of gp41 undergoes further changes to form a hairpin structure that draws the two membranes into close proximity (see text for details). (Adapted from D Montefiori, JP Moore: Science 283:336, 1999; with permission.)
With activation of the cell, the viral DNA accesses the nuclear pore and is transferred from the cytoplasm to the nucleus, where it is integrated into the host cell chromosomes through the action of another virally encoded enzyme, integrase (Fig. 197-3). HIV proviral DNA integrates into the host genomic DNA preferentially in regions of active transcription and regional hotspots. This provirus may remain transcriptionally inactive (latent) or it may manifest varying levels of gene expression, up to active transcription and production of virus depending on the metabolic state of the infected cell.
Cellular activation plays an important role in the replication cycle of HIV and is critical to the pathogenesis of HIV disease (see “Pathogenesis and Pathophysiology,” below). Following initial binding, fusion, and internalization of the nucleic acid contents of virions into the target cell, incompletely reverse-transcribed DNA intermediates are labile in quiescent cells and do not integrate efficiently into the host cell genome unless cellular activation occurs shortly after infection. Furthermore, some degree of activation of the host cell is required for the initiation of transcription of the integrated proviral DNA into either genomic RNA or mRNA. This latter process may not necessarily be associated with the detectable expression of the classic cell-surface markers of activation. In this regard, activation of HIV expression from the latent state depends on the interaction of a number of cellular and viral factors. Following transcription, HIV mRNA is translated into proteins that undergo modification through glycosylation, myristoylation, phosphorylation, and cleavage. The viral particle is formed by the assembly of HIV proteins, enzymes, and genomic RNA at the plasma membrane of the cells. Budding of the progeny virion through the lipid bilayer of the host cell membrane is the point at which the core acquires its external envelope and where the host restriction factor tetherin can inhibit the release of budding particles. Tetherin is an IFN-induced type II transmembrane protein that interferes with virion detachment, although the HIV accessory protein Vpu counteracts this effect through direct interactions with tetherin. During or soon after budding, the virally encoded protease catalyzes the cleavage of the gag-pol precursor to yield the mature virion. Progression through the virus replication cycle is profoundly influenced by a variety of viral regulatory gene products. Likewise, each point in the replication cycle of HIV is a real or potential target for therapeutic intervention. Thus far, the reverse transcriptase, protease, and integrase enzymes as well as the process of virus–target cell binding and fusion have proved to be susceptible to pharmacologic disruption.
Figure 197-5 illustrates schematically the arrangement of the HIV genome. Like other retroviruses, HIV-1 has genes that encode the structural proteins of the virus: gag encodes the proteins that form the core of the virion (including p24 antigen); pol encodes the enzymes responsible for protease processing of viral proteins, reverse transcription, and integration; and env encodes the envelope glycoproteins. However, HIV-1 is more complex than other retroviruses, particularly those of the nonprimate group, in that it also contains at least six other regulatory genes (tat, rev, nef, vif, vpr, and vpu), which code for proteins involved in the modification of the host cell to enhance virus growth and the regulation of viral gene expression. Several of these proteins are thought to play a role in the pathogenesis of HIV disease; their various functions are listed in Fig. 197-5. Flanking these genes are the long terminal repeats (LTRs), which contain regulatory elements involved in gene expression (Fig. 197-5). The major difference between the genomes of HIV-1 and HIV-2 is the fact that HIV-2 lacks the vpu gene and has a vpx gene not contained in HIV-1.
Organization of the genome of the HIV provirus together with a summary description of its 9 genes encoding 15 proteins. (Adapted from WC Greene, BM Peterlin: Nat Med 8:673, 2002.)
MOLECULAR HETEROGENEITY OF HIV-1
Molecular analyses of HIV isolates reveal varying levels of sequence diversity over all regions of the viral genome. For example, the degree of difference in the coding sequences of the viral envelope protein ranges from a few percent (very close, among isolates from the same infected individual) to more than 50% (extreme diversity, between isolates from the different groups of HIV-1: M, N, O, and P). The changes tend to cluster in hypervariable regions. HIV can evolve by several means, including simple base substitution, insertions and deletions, recombination, and gain and loss of glycosylation sites. HIV sequence diversity arises directly from the limited fidelity of the reverse transcriptase, i.e., a tendency toward copying errors. The balance of immune pressure and functional constraints on proteins influences the regional level of variation within proteins. For example, Envelope, which is exposed on the surface of the virion and is under immune selective pressure from both antibodies and cytolytic T lymphocytes, is extremely variable, with clusters of mutations in hypervariable domains. In contrast, reverse transcriptase, with important enzymatic functions, is relatively conserved, particularly around the active site. The extraordinary variability of HIV-1 contrasts markedly with the relative stability of HTLV-1 and 2.
The four groups (M, N, O and P) of HIV-1 are the result of four separate chimpanzee-to-human (or possibly gorilla-to-human for groups O and P) transfers. Group M (major), which is responsible for most of the infections in the world, has diversified into subtypes and intersubtype recombinant forms, due to “sub-epidemics” within humans after one of those transfers.
Among primate lentiviruses, HIV-1 is most closely related to viruses isolated from chimpanzees and gorillas (Fig. 197-1). The chimpanzee subspecies Pan troglodytes troglodytes has been established to be the natural reservoir of the HIV-1 M and N groups. The rare viruses of the HIV-1 O and P groups are most closely related to viruses found in Cameroonian gorillas. The M group comprises nine subtypes, or clades, designated A, B, C, D, F, G, H, J, and K, as well as more than 90 known circulating recombinant forms (CRFs) and numerous unique recombinant forms. Intersubtype recombinants are generated by infection of an individual with two subtypes that then recombine and create a virus with a selective advantage. These CRFs range from highly prevalent forms such as CRF01_AE, common in southeast Asia, and CRF02_AG from west and central Africa, to a large number of CRFs that are relatively rare, either because they are of a more recent origin (newly recombined) or because they have not broken out into a major population. The subtypes and CRFs create the major lineages of the M group of HIV-1. HIV-1 M group subtype C dominates the global pandemic, and although there is much speculation that it is more transmissible than other subtypes, solid data on variations in transmissibility between subtypes are lacking. Human population densities, access to prevention and treatment, prevalence of genital ulcers, iatrogenic transmissions, and other confounding host factors are all possible reasons why one subtype has spread more than another.
Figure 197-6 schematically diagrams the worldwide distribution of HIV-1 subtypes by region. Nine strains account for the vast majority of HIV infections globally: HIV-1 subtypes A, B, C, D, F, G and three of the CRFs, CRF01_AE, CRF02_AG, and CRF07_BC. Subtype C viruses (of the M group) are by far the most common form worldwide, likely accounting for ~50% of prevalent infections worldwide. In sub-Saharan Africa, home to approximately two-thirds of all individuals living with HIV/AIDS, most infections are caused by subtype C, with smaller proportions of infections caused by subtype A, subtype D, CRF02_AG, and other subtypes and recombinants. In South Africa, the country with the largest number of prevalent infections (7.1 million in 2016), >98% of the HIV-1 isolates sequenced are of subtype C. In Asia, HIV-1 isolates of the CRF01_AE lineage and subtypes B and C predominate. CRF01_AE accounts for most infections in south and southeast Asia, while >95% of infections in India, home to an estimated 2.1 million HIV-infected individuals, are of subtype C (see “HIV Infection and AIDS Worldwide,” below). Subtype B viruses are the overwhelmingly predominant viruses seen in the United States, Canada, certain countries in South America, western Europe, and Australia. It is thought that, purely by chance, subtype B was seeded into the United States and Europe in the late 1970s, thereby establishing an overwhelming founder effect. Many countries have co-circulating viral subtypes that are giving rise to new CRFs. Sequence analyses of HIV-1 isolates from infected individuals indicate that recombination among viruses of different clades likely occurs when an individual is infected with viruses of more than one subtype, particularly in geographic areas where subtypes overlap, and more often in sub-epidemics driven by IV drug use than in those driven by sexual transmission.
Global geographic distribution of HIV-1 subtypes and recombinant forms. Distributions derived from relative frequency of subtypes among >710,000 HIV genomic sequences in the Los Alamos National Laboratory HIV Sequence Database. (Additional information available at www.hiv.lanl.gov/components/sequence/HIV/geo/geo.comp.)
The extraordinary diversity of HIV, reflected by the presence of multiple subtypes, circulating recombinant forms, and continuous viral evolution, has implications for possible differential rates of transmission, rates of disease progression, and the development of resistance to antiretroviral drugs. This diversity may also prove to be a formidable obstacle to HIV vaccine development, as a broadly useful vaccine would need to induce protective responses against a wide range of viral strains.
HIV is transmitted primarily by sexual contact (both heterosexual and male to male); by blood and blood products; and by infected mothers to infants intrapartum, perinatally, or via breast milk. After more than 35 years of experience and observations, there is no evidence that HIV is transmitted by any other modality. Table 197-3 lists the estimated risk of HIV transmission for various types of exposures.
TABLE 197-3Estimated Per-Act Probability of Acquiring HIV From an Infected Source, By Exposure Act ||Download (.pdf) TABLE 197-3 Estimated Per-Act Probability of Acquiring HIV From an Infected Source, By Exposure Act
|Type of Exposure ||Risk per 10,000 Exposures |
|Blood transfusion ||9250 |
|Needle-sharing during injection drug use ||63 |
|Percutaneous (needle-stick) ||23 |
|Receptive anal intercourse ||138 |
|Insertive anal intercourse ||11 |
|Receptive penile-vaginal intercourse ||8 |
|Insertive penile-vaginal intercourse ||4 |
|Receptive oral intercourse ||Low |
|Insertive oral intercourse ||Low |
|Biting ||Negligible |
|Spitting ||Negligible |
|Throwing body fluids (including semen or saliva) ||Negligible |
|Sharing sex toys ||Negligible |
HIV infection is predominantly a sexually transmitted infection (STI) worldwide. By far the most common mode of infection, particularly in developing countries, is heterosexual transmission, although in many western countries male-to-male sexual transmission dominates. Although a wide variety of factors including viral load and the presence of ulcerative genital diseases influence the efficiency of heterosexual transmission of HIV, such transmission is generally inefficient. A recent systemic review found a low per-act risk of heterosexual transmission in the absence of antiretrovirals: 0.04% for female-to-male transmission and 0.08% for male-to-female transmission during vaginal intercourse in the absence of antiretroviral therapy or condom use (Table 197-3).
HIV has been demonstrated in seminal fluid both within infected mononuclear cells and in cell-free material. The virus appears to concentrate in the seminal fluid, particularly in situations where there are increased numbers of lymphocytes and monocytes in the fluid, as seen in genital inflammatory states such as urethritis and epididymitis, conditions closely associated with other STIs. The virus has also been demonstrated in cervical smears and vaginal fluid. There is an elevated risk of HIV transmission associated with unprotected receptive anal intercourse (URAI) among both men and women compared to the risk associated with unprotected receptive vaginal intercourse. Although data are limited, the per-act risk for HIV transmission via URAI has been estimated to be ~1.4% (Table 197-3). The risk of HIV acquisition associated with URAI is higher than that seen in penile-vaginal intercourse probably because only a thin, fragile rectal mucosal membrane separates the deposited semen from potentially susceptible cells in and beneath the mucosa, and micro-trauma of the mucosal membrane has been associated with anal intercourse. Anal douching and sexual practices that traumatize the rectal mucosa also increase the likelihood of infection. It is likely that anal intercourse provides at least two modalities of infection: (1) direct inoculation into blood in cases of traumatic tears in the mucosa; and (2) infection of susceptible target cells, such as Langerhans cells, in the mucosal layer in the absence of trauma. Insertive anal intercourse also confers an increased risk of HIV acquisition compared to insertive vaginal intercourse in the receptive partner since the vaginal mucosa is several layers thicker than the rectal mucosa and less likely to be traumatized during intercourse. Nonetheless, the virus can be transmitted to either partner through vaginal intercourse. As noted in Table 197-3, male-to-female HIV transmission is more efficient than female-to-male transmission. The differences in reported transmission rates between men and women may be due in part to the prolonged exposure to infected seminal fluid of the vaginal and cervical mucosa, as well as the endometrium (when semen enters through the cervical os). By comparison, the penis and urethral orifice of the uninfected male partner are exposed relatively briefly to infected vaginal fluid. Among various cofactors examined in studies of heterosexual HIV transmission, the presence of other STIs has been strongly associated with HIV transmission. In this regard, there is a close association between genital ulcerations and transmission, owing to both susceptibility to infection and infectivity. Infections with microorganisms such as Treponema pallidum (Chap. 177), Haemophilus ducreyi (Chap. 152), and herpes simplex virus (HSV; Chap. 187) are important causes of genital ulcerations linked to transmission of HIV. In addition, pathogens responsible for non-ulcerative inflammatory STIs such as those caused by Chlamydia trachomatis (Chap. 184), Neisseria gonorrhoeae (Chap. 151), and Trichomonas vaginalis (Chap. 224) also are associated with an increased risk of transmission of HIV infection. Bacterial vaginosis, an infection related to sexual behavior, but not strictly an STI, also may be linked to an increased risk of transmission of HIV infection. Several studies suggest that treating other STIs and genital tract syndromes may help prevent transmission of HIV. This effect is most prominent in populations in which the prevalence of HIV infection is relatively low. It is noteworthy that this principle may not apply to the treatment of HSV infections since it has been shown that even following anti-HSV therapy with resulting healing of HSV-related genital ulcers, HIV acquisition is not reduced. Biopsy studies revealed that the likely explanation is that HIV receptor–positive inflammatory cells persisted in the genital tissue despite the healing of ulcers, and so HIV-susceptible targets remained at the site.
The quantity of HIV-1 in plasma (viral load) is a primary determinant of the risk of HIV-1 transmission. In a cohort of heterosexual couples in Uganda discordant for HIV infection and not receiving antiretroviral therapy, the mean serum HIV RNA level was significantly higher among HIV-infected subjects whose partners seroconverted than among those whose partners did not seroconvert. In fact, transmission was rare when the infected partner had a plasma level of <1700 copies of HIV RNA per milliliter, even when genital ulcer disease was present (Fig. 197-7). The rate of HIV transmission per coital act was highest during the early stage of HIV infection when plasma HIV RNA levels were high and in advanced disease with high viral set points.
Probability of HIV transmission per coital act among monogamous, heterosexual, HIV-serodiscordant couples in Uganda. (From RH Gray et al: Lancet 357:1149, 2001.)
Antiretroviral therapy dramatically reduces plasma viremia in most HIV-infected individuals (see “Treatment,” below) and is associated with a dramatic reduction in risk of transmission. In a large study of serodiscordant couples, earlier treatment of the HIV-infected partner with antiretroviral therapy rather than treatment delayed until the CD4+ T cell counts fell below 250 cells per μL was associated with a 96% reduction in HIV transmission to the uninfected partner. This approach has been widely referred to as treatment as prevention or TasP. Recent cohort studies have indicated that if the viral load of the infected partner is decreased to below detectable levels by antiretroviral therapy, there is essentially no chance of sexual transmission to the uninfected partner.
A number of studies including large, randomized, controlled trials clearly have indicated that male circumcision is associated with a lower risk of acquisition of HIV infection for heterosexual men. Studies also suggest that circumcision is protective in those men who have sex with men who are insertive only. The benefit of circumcision may be due to increased susceptibility of uncircumcised men to ulcerative STIs, as well as to other factors such as microtrauma to the foreskin and glans penis. In addition, the highly vascularized inner layer of foreskin tissue contains a high density of Langerhans cells as well as increased numbers of CD4+ T cells, macrophages, and other cellular targets for HIV. Finally, the moist environment under the foreskin may promote the presence or persistence of microbial flora that, via inflammatory changes, may lead to even higher concentrations of target cells for HIV in the foreskin. In addition, randomized clinical trials have demonstrated that male circumcision also reduces herpes simplex virus (HSV) type 2, human papillomavirus virus (HPV), and genital ulcer disease in men as well as HPV, genital ulcer disease, bacterial vaginosis, and Trichomonas vaginalis infections among female partners of circumcised men. Thus, there may be an added indirect benefit of diminution of risk for HIV acquisition to the female sexual partners of circumcised men.
In some studies the use of oral contraceptives was associated with an increase in incidence of HIV infection over and above that which might be expected by not using a condom for birth control. This phenomenon may be due to drug-induced changes in the cervical mucosa, rendering it more vulnerable to penetration by the virus. Adolescent girls might also be more susceptible to infection upon exposure due to the properties of an immature genital tract with increased cervical ectopy or exposed columnar epithelium.
Oral sex is a much less efficient mode of transmission of HIV than is anal intercourse or vaginal intercourse (Table 197-3). A number of studies have reported that the incidence of transmission of infection by oral sex among couples discordant for HIV was extremely low. However, there have been well-documented reports of HIV transmission that likely resulted from fellatio or cunnilingus. Therefore, the assumption that oral sex is completely safe is not warranted.
The association of alcohol consumption and illicit drug use with unsafe sexual behavior, both homosexual and heterosexual, leads to an increased risk of sexual transmission of HIV. Methamphetamine and other so-called club drugs (e.g., MDMA, ketamine, and gamma hydroxybutyrate), sometimes taken in conjunction with PDE-5 inhibitors such as sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra), have been associated with risky sexual practices and increased risk of HIV infection, particularly among men who have sex with men.
TRANSMISSION THROUGH INJECTION DRUG USE
HIV can be transmitted to injection drug users (IDUs) who are exposed to HIV while sharing injection paraphernalia such as needles, syringes, the water in which drugs are mixed, or the cotton through which drugs are filtered. Parenteral transmission of HIV during injection drug use does not require IV puncture; subcutaneous (“skin popping”) or intramuscular (“muscling”) injections can transmit HIV as well, even though these behaviors are sometimes erroneously perceived as low-risk. Among IDUs, the risk of HIV infection increases with the duration of injection drug use; the frequency of needle sharing; the number of partners with whom paraphernalia are shared, particularly in the setting of “shooting galleries” where drugs are sold and large numbers of IDUs may share a limited number of “works”; comorbid psychiatric conditions such as antisocial personality disorder; the use of cocaine in injectable form or smoked as “crack”; and the use of injection drugs in a geographic location with a high prevalence of HIV infection. As noted in Table 197-3, the per-act risk of transmission from injection drug use with a contaminated needle has been estimated to be approximately 0.6%.
TRANSMISSION BY TRANSFUSED BLOOD AND BLOOD PRODUCTS
HIV can be transmitted to individuals who receive HIV-contaminated blood transfusions, blood products, or transplanted tissue. The vast majority of HIV infections acquired via contaminated blood transfusions, blood components, or transplanted tissue in resource-rich countries occurred prior to the spring of 1985, when mandatory testing of donated blood for HIV-1 was initiated. It is estimated that >90% of individuals exposed to HIV-contaminated blood products become infected (Table 197-3). Transfusions of whole blood, packed red blood cells, platelets, leukocytes, and plasma are all capable of transmitting HIV infection. In contrast, hyperimmune gamma globulin, hepatitis B immune globulin, plasma-derived hepatitis B vaccine, and Rho immune globulin have not been associated with transmission of HIV infection. The procedures involved in processing these products either inactivate or remove the virus.
Currently, in the United States and in most developed countries, the following measures have made the risk of transmission of HIV infection by transfused blood or blood products extremely small: the screening of blood donations for antibodies to HIV-1 and HIV-2 and determination of the presence of HIV nucleic acid usually in minipools of several specimens; the careful selection of potential blood donors with health history questionnaires to exclude individuals with risk behavior; and opportunities for self-deferral and the screening out of HIV-negative individuals with serologic testing for infections that have shared risk factors with HIV, such as hepatitis B and C and syphilis. The chance of infection of a hemophiliac via clotting factor concentrates has essentially been eliminated because of standard screening of blood together with the added layer of safety resulting from heat treatment of the concentrates. It is currently estimated that the risk of infection with HIV in the United States via transfused screened blood is approximately 1 in 1.5 million units. Therefore, since nearly 21 million blood components are transfused in the United States each year, despite the best efforts of science, one cannot completely eliminate the risk of transfusion-related transmission of HIV. In this regard, a case of transfusion-related transmission of HIV was reported in the United States in 2010, which was tracked to a blood donation in 2008; this was the first such reported case since 2002 and only the third in that decade. Transmission of HIV (both HIV-1 and HIV-2) by blood or blood products is still an ongoing threat in certain developing countries where routine screening of blood is not universally practiced. In 2013, 108 out of 167 countries (65%) had specific legislation covering the safety and quality of blood transfusion, including 79% of high-income countries, 64% of middle-income countries, and 41% of low-income countries. Furthermore, there have been reports in certain countries of sporadic breakdowns in routinely available screening procedures in which contaminated blood was allowed to be transfused, resulting in small clusters of patients becoming infected.
OCCUPATIONAL TRANSMISSION OF HIV: HEALTH CARE WORKERS, LABORATORY WORKERS, AND THE HEALTH CARE SETTING
There is a small but definite occupational risk of HIV transmission to health care workers and laboratory personnel and potentially others who work with HIV-containing materials, particularly when sharp objects are used. An estimated 600,000 to 800,000 health care workers are stuck with needles or other sharp medical instruments in the United States each year. The global number of HIV infections among health care workers attributable to sharps injuries has been estimated to be 1000 cases (range, 200–5000) per year. In the United States, 58 documented cases of occupational HIV transmission to health care workers, and 150 possible transmissions have been reported by the CDC. There have been no confirmed cases reported since 1999.
Exposures that place a health care worker at potential risk of HIV infection are percutaneous injuries (e.g., a needle stick or cut with a sharp object) or contact of mucous membrane or nonintact skin (e.g., exposed skin that is chapped, abraded, or afflicted with dermatitis) with blood, tissue, or other potentially infectious body fluids. Large, multi-institutional studies have indicated that the risk of HIV transmission following skin puncture from a needle or a sharp object that was contaminated with blood from a person with documented HIV infection is ~0.23% and after a mucous membrane exposure it is 0.09% (see “HIV and the Health Care Worker,” below) if the injured and/or exposed person is not treated within 24 h with antiretroviral drugs. The risk of hepatitis B virus (HBV) infection following a similar type of exposure is ~6–30% in nonimmune individuals; if a susceptible worker is exposed to HBV, postexposure prophylaxis with hepatitis B immune globulin and initiation of HBV vaccine is >90% effective in preventing HBV infection. The risk of HCV infection following percutaneous injury is ~1.8% (Chap. 332).
Rare HIV transmission after nonintact skin exposure has been documented, but the average risk for transmission by this route has not been precisely determined; however, it is estimated to be less than the risk for mucous membrane exposure. Transmission of HIV through intact skin has not been documented. Currently in developed countries, virtually all puncture wounds and mucous membrane exposures in health care workers involving blood from a patient with documented HIV infection are treated prophylactically with combination antiretroviral therapy (cART). This practice, referred to as postexposure prophylaxis or PEP, has dramatically reduced the occurrence of puncture-related transmissions of HIV to health care workers.
In addition to blood and visibly bloody body fluids, semen and vaginal secretions also are considered potentially infectious; however, they have not been implicated in occupational transmission from patients to health care workers. The following fluids also are considered potentially infectious: cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid. The risk for transmission after exposure to fluids or tissues other than HIV-infected blood also has not been quantified, but it is probably considerably lower than the risk after blood exposures. Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious for HIV unless they are visibly bloody. Rare cases of HIV transmission via human bites have been reported, but not in the setting of occupational exposure.
An increased risk for HIV infection following percutaneous exposures to HIV-infected blood is associated with exposures involving a relatively large quantity of blood, as in the case of a device visibly contaminated with the patient’s blood, a procedure that involves a hollow-bore needle placed directly in a vein or artery, or a deep injury. Factors that might be associated with mucocutaneous transmission of HIV include exposure to an unusually large volume of blood and prolonged contact. In addition, the risk increases for exposures to blood from untreated patients with high levels of HIV in the blood. Since the beginning of the HIV epidemic, there have been rare instances where transmission of infection from a health care worker to patients seemed highly probable. Despite these small number of documented cases, the risk of HIV transmission involving health care workers (infected or not) to patients is extremely low in developed countries—in fact, too low to be measured accurately. In this regard, several retrospective epidemiologic studies have been performed tracing thousands of patients of HIV-infected dentists, physicians, surgeons, obstetricians, and gynecologists, and no other cases of HIV transmission that could be linked to the health care providers were identified.
Breaches in infection control and the reuse of contaminated syringes, failure to properly sterilize surgical instruments, and/or hemodialysis equipment also have resulted rarely in the transmission of HIV from patient to patient in hospitals, nursing homes, and outpatient settings. Finally, these very rare occurrences of transmission of HIV as well as HBV and HCV to and from health care workers in the workplace underscore the importance of the use of universal precautions when caring for all patients (see below and Chap. 137).
MOTHER-TO-CHILD TRANSMISSION OF HIV
HIV infection can be transmitted from an infected mother to her fetus during pregnancy, during delivery, or by breast-feeding. This remains an important form of transmission of HIV infection in some developing countries. Virologic analyses of aborted fetuses indicate that HIV can be transmitted to the fetus during the first or second trimesters of pregnancy. However, maternal transmission to the fetus occurs most commonly in the perinatal period. Two studies performed in Rwanda and the Democratic Republic of Congo (then called Zaire) indicated that among all mother-to-child transmissions of HIV, the relative proportions were 23–30% before birth, 50–65% during birth, and 12–20% via breast-feeding.
In the absence of antiretroviral therapy for the mother during pregnancy, labor, and delivery, and for the fetus prophylactically following birth, the probability of transmission of HIV from mother to infant/fetus ranges from 15% to 25% in industrialized countries and from 25% to 35% in developing countries. These differences may relate to the adequacy of prenatal care as well as to the stage of HIV disease and the general health of the mother during pregnancy. Higher rates of transmission have been reported to be associated with many factors—the best documented of which is the presence of high maternal levels of plasma viremia, with the risk increasing linearly with the level of maternal plasma viremia. It is very unlikely that mother-to-child transmission will occur if the mother’s level of plasma viremia is <1000 copies of HIV RNA/mL of blood and extremely unlikely if the level is undetectable (i.e., <50 copies/mL). However, there may not be a lower “threshold” below which transmission never occurs, since certain studies have reported rare transmission by women with viral RNA levels <50 copies/mL. Increased mother-to-child transmission is also correlated with closer human leukocyte antigen (HLA) match between mother and child. A prolonged interval between membrane rupture and delivery is another well-documented risk factor for transmission. Other conditions that are potential risk factors, but that have not been consistently demonstrated, are the presence of chorioamnionitis at delivery; STIs during pregnancy; illicit drug use during pregnancy; cigarette smoking; preterm delivery; and obstetric procedures such as amniocentesis, amnioscopy, fetal scalp electrodes, and episiotomy. Today, the rate of mother-to-child transmission has fallen to 1% or less in pregnant women who are receiving cART for their HIV infection. Such treatment, combined with cesarean section delivery, has rendered mother-to-child transmission of HIV an unusual event in the United States and other developed nations. In this regard, both the United States Public Health Service and the World Health Organization guidelines recommend that all pregnant HIV-infected women should receive life-long cART for the health of the mother and to prevent perinatal transmission regardless of plasma HIV RNA copy number or CD4+ T cell counts.
Breast-feeding is an important modality of transmission of HIV infection in certain developing countries, particularly where mothers continue to breast-feed for prolonged periods. The risk factors for mother-to-child transmission of HIV via breast-feeding include detectable levels of HIV in breast milk, the presence of mastitis, low maternal CD4+ T cell counts, and maternal vitamin A deficiency. The risk of HIV infection via breast-feeding is highest in the early months of breast-feeding. In addition, exclusive breast-feeding has been reported to carry a lower risk of HIV transmission than mixed feeding. In developed countries, breast feeding of babies by an HIV-infected mother is contraindicated since alternative forms of adequate nutrition, i.e., formulas, are readily available. In developing countries, where breast-feeding may be essential for the overall health of the infant, the continuation of cART in the infected mother during the period of breastfeeding markedly diminishes the risk of transmission of HIV to the infant. In fact, once cART has been initiated in a pregnant woman, it should be continued for life.
TRANSMISSION OF HIV BY OTHER BODY FLUIDS
Although HIV can be isolated typically in low titers from saliva of a small proportion of infected individuals, there is no convincing evidence that saliva can transmit HIV infection, either through kissing or through other exposures, such as occupationally to health care workers. Saliva contains endogenous antiviral factors; among these factors, HIV-specific immunoglobulins of IgA, IgG, and IgM isotypes are detected readily in salivary secretions of infected individuals. It has been suggested that large glycoproteins such as mucins and thrombospondin 1 sequester HIV into aggregates for clearance by the host. In addition, a number of soluble salivary factors inhibit HIV to various degrees in vitro, probably by targeting host cell receptors rather than the virus itself. Perhaps the best studied of these, secretory leukocyte protease inhibitor (SLPI), blocks HIV infection in several cell culture systems, and it is found in saliva at levels that approximate those required for inhibition of HIV in vitro. In this regard, higher salivary levels of SLPI in breast-fed infants were associated with a decreased risk of HIV transmission through breast milk. It has also been suggested that submandibular saliva reduces HIV infectivity by stripping gp120 from the surface of virions, and that saliva-mediated disruption and lysis of HIV-infected cells occurs because of the hypotonicity of oral secretions. There have been outlier cases of suspected transmission by saliva, but these have probably been blood-to-blood transmissions. Transmission of HIV by a human bite can occur but is a rare event. Although virus can be identified, if not isolated, from virtually any body fluid, there is no evidence that HIV transmission can occur as a result of exposure to tears, sweat, or urine. However, there have been isolated cases of transmission of HIV infection by body fluids that may or may not have been contaminated with blood. Most of these situations occurred in the setting of a close relative providing intensive nursing care for an HIV-infected person without observing universal precautions, underscoring the importance of adhering to such precautions in the handling of body fluids and wastes from HIV-infected individuals.
HIV INFECTION AND AIDS WORLDWIDE
HIV infection/AIDS is a global pandemic, with cases reported from virtually every country. At the end of 2016, an estimated 36.7 million individuals were living with HIV infection, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS). An estimated 95% of people living with HIV/AIDS reside in low- and middle-income countries; ~50% are female, and 2.1 million are children <15 years. The regional distribution of these cases is illustrated in Fig. 197-8. The estimated number of people living with HIV—i.e., the global prevalence—has increased more than fourfold since 1990, reflecting the combined effects of continued high rates of new HIV infections and the life-prolonging impact of antiretroviral therapy (Fig. 197-9). In 2016, the global prevalence of HIV infection among people aged 15–49 years was 0.8%, with rates varying widely by country and region as illustrated in Fig. 197-10.
Estimated number of adults and children living with HIV infection as of December, 2016. Total: 36.7 million (30.8 million–42.9 million). (From Joint United Nations Programme on HIV/AIDS [UNAIDS].)
Global estimates of HIV incidence, AIDS deaths, and HIV prevalence 1990–2016. (From UNAIDS.)
Adult HIV prevalence rates by country, 2016. Data are estimates for adults age 15–49 years. (From UNAIDS.)
In 2016, an estimated 1.8 million new cases of HIV infection occurred worldwide, including 160,000 among children <15 years; about one-third of new infections were among people age 15–24 years. Globally, the majority of new HIV infections are due to heterosexual transmission. Members of certain high-risk populations are disproportionately affected. Sex workers, people who inject drugs, transgender people, prisoners, gay men, other men who have sex with men, and their sexual partners accounted for 34% of all new HIV infections in 2015 (Fig. 197-11).
Global distribution of new HIV infections by population. Data for 2015. (From UNAIDS.)
Between 2000 and 2016, the estimated annual number of new HIV infections globally fell by 40% (Fig. 197-9). These reductions in global HIV incidence likely reflect progress with HIV prevention efforts and the increased provision to HIV-infected people of antiretroviral therapy, which makes them much less likely to transmit the virus to sexual partners. Among adults, the estimated incidence declined by 11% from 2010 to 2016. From 2010 to 2016 there was a ~47% reduction in HIV infections among children <15 years, progress that is due largely to the increasing availability of antiretroviral medications to prevent the transmission of HIV from mother to infant.
In 2016, global AIDS deaths totaled 1.0 million (including 120,000 children <15 years), a 48% decrease since 2005 that coincides with a rapid expansion of access to antiretroviral therapy (Fig. 197-12). Since the beginning of the pandemic, an estimated 35 million people have died of an AIDS-related illness.
Global antiretroviral therapy coverage and number of AIDS-related deaths, 2000–2016. (From UNAIDS).
The HIV epidemic has occurred in “waves” in different regions of the world, each wave having somewhat different characteristics depending on the demographics of the country and region in question and the timing of the introduction of HIV into the population. Although the AIDS epidemic was first recognized in the United States and shortly thereafter in Western Europe, it very likely began in sub-Saharan Africa (see above), which has been particularly devastated by the epidemic. East and Southern Africa is the region hardest hit by HIV. The region is home to 6.2% of the world’s population but has 19.4 million people living with HIV, >50% of the global total (Fig. 197-8). In eight countries in the region, >10% of the adult population age 15–49 is HIV-infected (Fig. 197-10). South Africa has the highest number of people living with HIV in the world (7.1 million); Swaziland has the highest adult HIV prevalence in the world (27.2%). Among high-risk individuals, rates are much higher than in the general population. HIV prevalence among sex workers varies between 50% and 70% in several countries in the region. Recent data offer promising signs of declining HIV incidence and prevalence in many countries in the region, although frequently at levels that remain high. Heterosexual exposure is the primary mode of HIV transmission in most countries in sub-Saharan Africa. Women and girls account for ~60 percent of all HIV infections in that region.
The 25 countries of West and Central Africa are home to 6.1 million people living with HIV, of whom half a million are children. HIV prevalence in most of the countries is relatively low compared with East and Southern Africa. HIV prevalence among adults across the region overall stands at 2.2% although there is wide variation between countries, ranging from 0.5% in Niger and Senegal to 4.9% in Equatorial Guinea. An estimated 60% of new infections in the region in 2015 occurred in Nigeria. As in East and Southern Africa, heterosexual transmission accounts for most HIV transmission West and Central Africa.
The Middle East and North Africa region has one of the lowest HIV prevalence rates in the world (0.1%). In 2016, an estimated 230,000 people were living with HIV in the region. Cases are largely concentrated among IDUs, men who have sex with men, and sex workers and their clients.
In Asia and the Pacific, an estimated 5.1 million people were living with HIV at the end of 2016. In this region of the world, HIV prevalence is highest in southeast Asian countries, with wide variation in trends between different countries. Among countries in Asia, only Thailand has an adult seroprevalence rate of >1%. However, the populations of many Asian nations are so large that even low infection and seroprevalence rates result in large numbers of people living with HIV. In this regard, three populous countries—China, India and Indonesia—account for around three-quarters of all people living with HIV in the region. Although the HIV epidemic in Asia has long been concentrated among specific populations—sex workers and their clients, men who have sex with men, and IDUs—it is expanding to the heterosexual partners of those most at risk.
Eastern Europe and Central Asia is the only region in the world where the HIV epidemic continues to expand rapidly, with a >60% increase in annual new HIV infections between 2010 and 2016. The Russian Federation and Ukraine account for the majority of HIV cases in the region, where the epidemic has been driven by injection drug use and increasingly by heterosexual transmission.
Approximately 2.1 million people were living with HIV/AIDS in Latin America and the Caribbean at the end of 2016. The rate of new HIV infections in the region held steady from 2010 to 2016. Brazil is home to the largest number of HIV-infected persons (830,000) in the region, and the Bahamas has the region’s highest prevalence (3.3%). Men who have sex with men account for the largest proportion of HIV infections in Central and South America. In the Caribbean, heterosexual transmission, often tied to sex work, is the main driver of transmission.
Approximately 2.1 million people were living with HIV/AIDS in North America and western and central Europe at the end of 2016. While modes of transmission vary greatly by country, HIV disproportionately affects men who have sex with men. Over the past decade, the number of HIV diagnoses decreased dramatically in all risk groups in western Europe but increased slightly in central Europe. North America saw a decrease in HIV diagnoses overall but a small increase among gay and bisexual men.
HIV INFECTION AND AIDS IN THE UNITED STATES
About 1.8 million people have been infected with HIV in the United States since the beginning of the epidemic, of whom ~693,000 have died. Approximately 1.1 million individuals in the United States are living with HIV infection, ~15% of whom are unaware of their infection, according to recent estimates. As illustrated in Fig. 197-13, only about half of HIV-infected people in the United States have been able to negotiate the steps in the HIV “care continuum,” from diagnosis, to entering into care and receiving antiretroviral therapy, and ultimately to achieving a suppressed viral load (see “Treatment,” below).
Estimated percentage of HIV-infected people engaged at selected stages of the continuum of HIV care in the United States. (From Centers for Disease Control and Prevention [CDC]: HIV Surveillance Supplemental Report 21[No. 7], 2016.)
More than 60% of people living with HIV in the United States are Black/African American or Hispanic/Latino, and more than half are men who have sex with men. The estimated HIV seroprevalence rate among all individuals age 13 years or older in the United States is ~0.5%. Approximately 2% of Black/African-American adults are HIV-infected in the United States, higher than any other group.
The number of new HIV infections in the United States, HIV incidence, peaked at about 130,000 per year in the late 1980s, followed by declines. After remaining stable since the mid-1990s, the estimated number of annual HIV infections in the United States fell ~15% between 2008 and 2015 (from 45,200 to 38,500). The distribution of incident HIV cases in 2015 is shown in Fig. 197-14. Gay and bisexual men account for more than two-thirds of incident infections and were the only group that did not experience an overall decline in annual HIV infections from 2008 to 2015. While infections among white gay and bisexual men and men age 15–24 years fell during that period, these declines were offset by increases among 25- to 34-year-old gay and bisexual men, and among Hispanic/Latino gay and bisexual males.
Estimated distribution of new HIV infections in the United States. Total: 38,500. Incidence estimate for 2015. (From CDC.)
In the United States, the burden of HIV and AIDS is not evenly distributed across states and regions. In most areas of the country, HIV is concentrated in urban areas. In the southern United States, larger percentages of diagnoses are in smaller metropolitan and nonmetropolitan areas. HIV infection and AIDS have disproportionately affected minority populations in the United States in both urban and rural areas. Among those diagnosed with HIV (regardless of stage of infection) in 2016, 44% percent were Blacks/African Americans, a group that constitutes only 12% of the U.S. population. The estimated rate of new HIV diagnoses in 2016 by race/ethnicity per 100,000 population in the United States is shown in Fig. 197-15.
Estimated rate of HIV infections (including children) diagnosed during 2016 in the United States, by race/ethnicity (per 100,000 population). (From CDC.)
Perinatal HIV transmission, from an HIV-infected mother to her baby, has declined significantly in the United States, largely due to the implementation of guidelines for the universal counseling and voluntary HIV testing of pregnant women and the use of antiretroviral therapy for pregnant women and newborn infants to prevent infection. In 2016, 122 children were newly diagnosed with HIV infection in the United States, down from a peak of ~1750 in 1991.
The rate of HIV-related deaths in the United States rose steadily through the 1980s and peaked in 1995. Since then, the HIV death rate has fallen fourfold (Fig. 197-16). This trend is likely due to several factors, including improved prophylaxis and treatment of opportunistic infections, growing experience among the health professions in caring for HIV-infected individuals, improved access to health care, and a decrease in new infections. However, the most influential factor clearly has been the increased use of potent antiretroviral drugs, generally administered in a combination of three or four agents.
Trends in annual age-adjusted rates of death due to HIV infection, United States, 1987–2014. Age distribution based on 2000 population. (From CDC.)
PATHOPHYSIOLOGY AND PATHOGENESIS
The hallmark of HIV disease is a profound immunodeficiency resulting primarily from a progressive quantitative and qualitative deficiency of the subset of T lymphocytes referred to as helper T cells occurring in a setting of polyclonal immune activation. The helper subset of T cells is defined phenotypically by the presence on its surface of the CD4 molecule (Chap. 342), which serves as the primary cellular receptor for HIV. A co-receptor also must be present together with CD4 for efficient binding, fusion, and entry of HIV-1 into its target cells (Figs. 197-3 and 197-4). HIV-1 uses two major co-receptors, CCR5 and CXCR4, for fusion and entry; these co-receptors are also the primary receptors for certain chemoattractive cytokines termed chemokines and belong to the seven-transmembrane-domain G protein–coupled family of receptors. A number of mechanisms responsible for cellular depletion and/or immune dysfunction of CD4+ T cells have been demonstrated in vitro; these include direct infection and destruction of these cells by HIV, as well as indirect effects such as immune clearance of infected cells, cell death associated with aberrant immune activation, and immune exhaustion due to aberrant cellular activation with resulting cellular dysfunction. Patients with CD4+ T cell levels below certain thresholds are at high risk of developing a variety of opportunistic diseases, particularly the infections and neoplasms that are AIDS-defining illnesses. Some features of AIDS, such as Kaposi’s sarcoma and certain neurologic abnormalities, cannot be explained completely by the immunodeficiency caused by HIV infection, since these complications may occur prior to the development of severe immunologic impairment.
The combination of viral pathogenic and immunopathogenic events that occurs during the course of HIV disease from the moment of initial (primary) infection through the development of advanced-stage disease is complex and varied. It is important to appreciate that the pathogenic mechanisms of HIV disease are multifactorial and multiphasic and are different at different stages of the disease. Therefore, it is essential to consider the typical clinical course of an untreated HIV-infected individual in order to more fully appreciate these pathogenic events (Fig. 197-17).
Typical course of an untreated HIV-infected individual. See text for detailed description. (From G Pantaleo et al: N Engl J Med 328:327, 1993. Copyright 1993 Massachusetts Medical Society. All rights reserved.)
EARLY EVENTS IN HIV INFECTION: PRIMARY INFECTION AND INITIAL DISSEMINATION OF VIRUS
Using rectal or vaginal mucosal transmission in nonhuman primates as a model, the earliest events (within hours) that occur following exposure of HIV to the mucosal surface determine whether an infection will be established or aborted as well as the subsequent course of events following infection. Although the mucosal barrier is relatively effective in limiting access of HIV to susceptible targets in the submucosal tissue, the virus can cross the barrier by transport on Langerhans cells, an epidermal type of DC, just beneath the surface or through microscopic rents in the mucosa. Significant disruptions in the mucosal barrier as seen in ulcerative genital disease facilitate viral entry and increase the efficiency of infection. Virus then seeks susceptible targets, which are primarily CD4+ T cells that are spatially dispersed in the mucosa. This spatial dispersion of targets provides a significant obstacle to the establishment of infection. Such obstacles account for the low efficiency of sexual transmission of HIV (see “Sexual Transmission,” above). Both “partially” resting CD4+ T cells and activated CD4+ T cells serve as early amplifiers of infection. Resting CD4+ T cells are more abundant; however, activated CD4+ T cells produce larger amounts of virus. In order for infection to become established, the basic reproductive rate (R0) must become equal to or greater than 1, i.e., each infected cell would infect at least one other cell. Once infection is established, the virus replicates in lymphoid cells in the mucosa, the submucosa, and to some extent the lymphoreticular tissues that drain the gut or genital tissues. For a variable period of time ranging from a few to several days, the virus cannot yet be detected in the plasma. This period is referred to as the “eclipse” phase of infection. As more virus is produced within several days to weeks, it is disseminated, first to the draining lymph nodes and then to other lymphoid compartments where it has easy access to dense concentrations of CD4+ T cell targets, allowing for a burst of high-level viremia that is readily detectable by currently available assays (Fig. 197-18). The gut-associated lymphoid tissue (GALT) is a major target of HIV infection and the location where large numbers of CD4+ T cells (usually memory cells) are infected and depleted, both by direct viral effects and by activation-associated apoptosis. Once virus replication reaches this threshold and virus is widely disseminated, infection is firmly established throughout the lymphoid tissues of the body and the process is irreversible. It is important to point out that the initial infection of susceptible cells may vary somewhat with the route of infection. Virus that enters directly into the bloodstream via infected blood or blood products (i.e., transfusions, use of contaminated needles for injection drugs, sharp-object injuries, maternal-to-fetal transmission either intrapartum or perinatally, or sexual intercourse where there is enough trauma to cause bleeding) is likely first cleared from the circulation to the spleen and other lymphoid organs, where primary focal infections begin, followed by wider dissemination throughout other lymphoid tissues as described above.
Summary of early events in HIV infection. See text for detailed description. CTLs, cytolytic T lymphocytes; HIV, human immunodeficiency virus. (Adapted from AT Haase: Nat Rev Immunol 5:783, 2005.)
It has been demonstrated that sexual transmission of HIV is the result of a single infectious event and that a viral genetic bottleneck exists for transmission with selective transmission of certain viruses. In this regard, certain characteristics of the HIV envelope glycoprotein have a major influence on transmission, at least in subtype A and C viruses. Transmitting viruses, often referred to as “founder viruses,” are usually underrepresented in the circulating viremia of the transmitting partner and are less-diverged viruses with signature sequences including shorter V1–V2 loop sequences and fewer predicted N-linked glycosylation sites relative to the major circulating variants. These viruses are almost exclusively R5 strains and are usually sensitive to neutralizing antibody. Once replication proceeds in the newly infected partner, the founder virus diverges and accumulates glycosylation sites, becoming progressively more resistant to neutralization (Fig. 197-19).
As HIV diverges from founder to chronically replicating virus, it accumulates N-linked glycosylation sites. See text for detailed description. (Adapted from CA Derdeyn et al: Science 303:2019, 2004; B Chohan et al: J Virol 79:6528, 2005; and BF Keele et al: Proc Natl Acad Sci USA 105:7552, 2008.)
The acute burst of viremia and wide dissemination of virus in primary HIV infection may be associated with an acute HIV syndrome, which occurs to varying degrees in ~50% of individuals within 2 to 4 weeks of initial infection (see below). This syndrome is usually associated with high levels of viremia measured in millions of copies of HIV RNA per milliliter of plasma that last for several weeks. Acute mononucleosis-like symptoms are well correlated with the presence of viremia. Virtually all patients develop some degree of viremia during primary infection, which contributes to virus dissemination throughout the lymphoid tissue, even though they may remain asymptomatic or not recall experiencing symptoms. The initial level of plasma viremia in primary HIV infection does not necessarily determine the rate of disease progression; however, the set point of the level of steady-state plasma viremia after ~1 year seems to correlate with the slope of disease progression in the untreated patient. The strikingly high levels of viremia observed in many patients with acute HIV infection is felt to be associated with a higher likelihood of transmission of the virus to others by a variety of routes including sexual transmission, shared needles and syringes, and mother-to-child transmission intrapartum, perinatally, or via breast milk.
ESTABLISHMENT OF CHRONIC AND PERSISTENT INFECTION
Persistence of Virus Replication
HIV infection is unique among human viral infections. Despite the robust cellular and humoral immune responses that are mounted following primary infection (see “Immune Response to HIV,” below), once infection has been established the virus succeeds in escaping complete immune-mediated clearance, paradoxically seems to thrive on immune activation, and is never eliminated completely from the body. Rather, a chronic infection develops and persists with varying degrees of continual virus replication in the untreated patient for a median of ~10 years before the patient becomes clinically ill (see “Advanced HIV Disease,” below). It is this establishment of a chronic, persistent infection that is the hallmark of HIV disease. Throughout the often-protracted course of chronic infection, virus replication can invariably be detected in untreated patients by widely available assays that measure copies of virion-associated HIV RNA in plasma (copies per milliliter). Levels of virus vary greatly in most untreated patients, usually ranging from several thousand to a few million copies of HIV RNA per milliliter of plasma. Studies using highly sensitive molecular techniques have demonstrated that even in certain patients in whom plasma viremia is suppressed to below detection (lower limit, 20–50 copies of HIV RNA per milliliter depending on assay kit manufacturer) by cART, there is a continual low level of virion production in the majority of infected patients. In other human viral infections, with very few exceptions, if the host survives, the virus is completely cleared from the body and a state of immunity against subsequent infection develops. HIV infection very rarely kills the host during primary infection. Certain viruses, such as HSV (Chap. 187), are not completely cleared from the body after infection, but instead enter a latent state; in these cases, clinical latency is accompanied by microbiologic latency. This is not the case with HIV infection as described above. Chronicity associated with persistent virus replication can also be seen in certain cases of HBV and HCV infections (Chap. 334); however, in these infections the immune system is not a target of the virus.
Escape of HIV from Effective Immune System Control
Inherent to the establishment of chronicity of HIV infection is the ability of the virus to evade adequate control and elimination by both the cellular and humoral immune responses. There are a number of mechanisms whereby the virus accomplishes this evasion. Paramount among these is the establishment of a sustained level of replication associated with the generation of viral diversity via mutation and recombination. The selection of mutants that escape control by CD8+ cytolytic T lymphocytes (CTLs) is critical to the propagation and progression of HIV infection. The high rate of virus replication associated with inevitable mutations also contributes to the inability of antibody to clear the autologous virus. Furthermore, for reasons that remain unclear, the humoral immune system does not readily produce classic neutralizing antibodies against the HIV envelope and does so only after years of persistent virus replication and after the infection is firmly established (see below). Extensive analyses of sequential HIV isolates and host responses have demonstrated that viral escape from B cell and CD8+ T cell responses occurs early after infection and allows the virus to stay one step ahead of effective immune responses. Virus-specific CD8+ CTLs expand greatly during primary HIV infection, and they likely represent the high-affinity responses that would be expected to be most efficient in eliminating virus-infected cells; however, viral control is generally incomplete as viral replication persists at relatively high levels in the majority of individuals. In addition to viral escape from CTLs through high rates of mutation, it is thought that the initially strong response becomes qualitatively dysfunctional owing to the overwhelming immune activation associated with persistent viral replication, leading to immune “exhaustion” that affects both arms of adaptive immunity. Several studies have indicated that exhaustion of HIV-specific CD8+ T cells during prolonged immune activation is associated with upregulation of several inhibitory receptors, such as programmed death (PD) 1 molecule (of the B7-CD28 family of molecules), T cell immunoreceptor with Ig and ITIM domains (TIGIT), T cell immunoglobulin and mucin-domain containing molecule 3 (Tim-3), and lymphocyte activating gene 3 (Lag-3), collectively referred to as immune-checkpoint receptors. Upregulation of these surface proteins restricts polyreactivity and proliferative capacity, functional attributes of CD8+ T cells that are essential for effective killing of pathogens. Another mechanism contributing to the evasion by HIV of immune system control is the downregulation of HLA class I molecules on the surface of HIV-infected cells by the viral proteins Nef, Tat, and Vpu, resulting in the lack of ability of CD8+ CTLs to recognize and kill infected target cells. Although this downregulation of HLA class I molecules would seem to favor elimination of HIV-infected cells by natural killer (NK) cells, this latter mechanism does not remove HIV-infected cells effectively (see below). Another potential means of escape of HIV-infected cells from elimination by CD8+ CTLs is the sequestration of infected cells in immunologically privileged sites such as the central nervous system (CNS), as well as the low frequency of virus-specific CD8+ CTLs in areas of lymphoid tissues, namely germinal centers, where HIV actively replicates.
The principal targets of neutralizing antibodies against HIV are the envelope proteins gp120 and gp41. HIV employs at least three mechanisms to evade neutralizing antibody responses: hypervariability in the primary sequence of the envelope, extensive glycosylation of the envelope, and conformational masking of neutralizing epitopes. Several studies that have followed the evolution of the humoral immune response to HIV from the earliest points after primary infection indicate that the virus continually mutates to escape the emerging antibody response such that the sequential antibodies that are induced do not neutralize the currently autologous virus. Broadly neutralizing antibodies capable of neutralizing a wide range of primary HIV isolates in vitro occur in only about 20% of HIV-infected individuals, and, when they do occur, 2 to 3 years of infection with continual virus replication are generally required to drive the affinity maturation of the antibodies. Unfortunately, by the time these broadly neutralizing antibodies are formed, they are ineffective in containing the virus currently replicating in the patient. Persistent viremia also results in exhaustion of B cells similar to the exhaustion reported for CD8+ T cells, adding to the defects in the humoral response to HIV.
CD4+ T cell help is essential for the integrity of antigen-specific immune responses, both humoral and cell-mediated. HIV preferentially infects activated CD4+ T cells including HIV-specific CD4+ T cells, and so this loss of viral-specific helper T cell responses has profoundly negative consequences for the immunologic control of HIV replication. Furthermore, this loss occurs early in the course of infection, and animal studies indicate that 40–70% of all memory CD4+ T cells in the GALT are eliminated during acute infection. During chronic HIV viremia, CD4+ T cells also exhibit evidence of exhaustion, including by upregulation of the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), also a member of the B7-CD28 family.
Finally, the escape of HIV from immune-mediated elimination during primary infection allows the formation of a pool of latently infected cells, referred to as the viral reservoir, that may not be recognized or completely eliminated by virus-specific CTLs or by ART (see below). Thus, despite a potent immune response and the marked downregulation of virus replication following primary HIV infection, HIV succeeds in establishing a state of chronic infection with a variable degree of persistent virus replication. During this period most patients make the clinical transition from acute primary infection to variable periods of clinical latency or smoldering disease activity (see below).
The HIV Reservoir: Obstacles to the Eradication of Virus
A pool of latently infected, resting CD4+ T cells that serves as at least one component of the persistent reservoir of virus exists in virtually all HIV-infected individuals, including those who are receiving cART. Such cells carry an integrated form of HIV DNA in the genome of the host and can remain in this state until an activation signal drives the expression of HIV transcripts. Only a small fraction of the latently infected cells in the viral reservoir contain replication-competent virus with the overwhelming majority of cells containing defective proviruses incapable of a full replication cycle. However, upon activation of the reservoir variable degrees of sustained virus replication invariably occur. This form of latency is to be distinguished from preintegration latency, in which HIV enters a resting CD4+ T cell and, in the absence of an activation signal, reverse transcription of the HIV genome occurs to a certain extent but the resulting proviral DNA fails to integrate into the host genome. This period of preintegration latency may last hours to days, and if no activation signal is delivered to the cell, the proviral DNA loses its capacity to initiate a productive infection. If these cells do become activated prior to decay of the preintegration complex, reverse transcription proceeds to completion and the virus continues along its replication cycle (see above and Fig. 197-20). The pool of cells that are in the postintegration state of latency is established early during the course of primary HIV infection. Despite the suppression of plasma viremia to undetectable levels by potent regimens of cART administered over several years, this pool of latently infected cells persists and can give rise to replication-competent virus upon cellular activation ex vivo. Modeling studies built on projections of decay curves have estimated that in such a setting of prolonged viral suppression, it would require a few to several years for the pool of latently infected cells to be completely eliminated. This has not been documented to occur spontaneously in any patients very likely because the latent viral reservoir is long-lived and is continually replenished by the low levels of persistent virus replication that may remain below the limits of detection of current assays (see below) as well as by the expansion by proliferation of the pool of latently infected cells (Fig. 197-20), even in patients who for the most part are treated successfully. Reservoirs of HIV-infected cells, latent or otherwise, can exist in a number of compartments including the lymphoid tissue, peripheral blood, and the CNS (likely in cells of the monocyte/macrophage lineage) as well as in other unidentified locations. Over the past several years attempts have been made to eliminate HIV in the latent viral reservoir using agents that activate resting CD4+ T cells during the course of cART; however, such attempts, referred to as “shock and kill,” have been unsuccessful. Thus, this persistent reservoir of infected cells and/or low levels of persistent virus replication remain major obstacles to the goal of eradication of virus from infected individuals and hence a “cure,” despite the favorable clinical outcomes that have resulted from cART.
Generation of latently infected, resting CD4+ T cells in HIV-infected individuals. See text for details. Ag, antigen; CTLs, cytolytic T lymphocytes. (Courtesy of TW Chun; with permission.)
The dynamics of viral production and turnover have been quantified using mathematical modeling in the setting of the administration of reverse transcriptase and protease inhibitors to HIV-infected individuals in clinical studies. Treatment with these drugs resulted in a precipitous decline in the level of plasma viremia, which typically fell by well over 90% within 2 weeks. It was determined on the basis of modeling the kinetics of viral decline and the emergence of resistant mutants during therapy that 93–99% of the circulating virus originated from recently infected, rapidly turning over CD4+ T cells and that ~1–7% of circulating virus originated from longer-lived cells, likely monocytes/macrophages. A negligible amount of circulating virus originated from the pool of latently infected cells (Fig. 197-21). It was also determined that the half-life of a circulating virion was ~30–60 min and that of productively infected cells was 1 day. Given the relatively steady level of plasma viremia and of infected cells, it appears that extremely large amounts of virus (~1010–1011 virions) are produced and cleared from the circulation each day. In addition, data suggest that the minimal duration of the HIV-1 replication cycle in vivo is ~2 days. Other studies have demonstrated that the decrease in plasma viremia that results from cART correlates closely with a decrease in virus replication in lymph nodes, further confirming that lymphoid tissue is the main site of HIV replication and the main source of plasma viremia.
Dynamics of HIV infection in vivo. See text for detailed description. (From AS Perelson et al: Science 271:1582, 1996.)
The level of steady-state viremia, called the viral set point, at ~1 year following acquisition of HIV infection has important prognostic implications for the progression of HIV disease in the untreated patient. It has been demonstrated that, as a group, untreated HIV-infected individuals who have a low set point at 6 months to 1 year following infection progress to AIDS much more slowly than do individuals whose set point is very high at that time (Fig. 197-22).
Relationship between levels of virus and rates of disease progression. Kaplan-Meier curves for AIDS-free survival stratified by baseline HIV-1 RNA categories (copies per milliliter). (From JW Mellors et al: Science 272:1167, 1996.)
Clinical Latency versus Microbiologic Latency
With the exception of certain long-term nonprogressors and “elite controllers” of HIV replication, the level of CD4+ T cells in the blood inevitably decreases progressively in viremic HIV-infected individuals in the absence of cART. The decline in CD4+ T cells may be gradual or abrupt, the latter usually reflecting a significant spike in the level of plasma viremia. Most patients are relatively asymptomatic while this progressive decline is taking place (see below) and are often described as being in a state of clinical latency. However, this term is misleading; it does not mean disease latency, since progression, although slow in many cases and often without symptoms, is generally relentless during this period. Furthermore, clinical latency should not be confused with microbiologic latency, since varying levels of virus replication inevitably occur during this period of clinical latency. Even in those rare patients who have <50 copies of HIV RNA per milliliter in the absence of therapy, there is virtually always some degree of low-level ongoing virus replication.
In untreated patients or in patients in whom therapy has not adequately controlled virus replication, after a variable period, usually measured in years, the CD4+ T cell count falls below a critical level (<200/μL) and the patient becomes highly susceptible to opportunistic disease (Fig. 197-17). For this reason, the CDC case definition of AIDS includes all HIV-infected individuals >5 years of age with CD4+ T cell counts below this level (Table 197-2). Patients may experience constitutional signs and symptoms or may develop an opportunistic disease abruptly without any prior symptoms. The depletion of CD4+ T cells continues to be progressive and unrelenting in this phase. It is not uncommon for CD4+ T cell counts in the untreated patient to drop to as low as 10/μL or even to zero. In countries where cART and prophylaxis and treatment for opportunistic infections are readily accessible to such patients, survival is increased dramatically even in those patients with advanced HIV disease. In contrast, untreated patients who progress to this severest form of immunodeficiency usually succumb to opportunistic infections or neoplasms (see below).
LONG-TERM SURVIVORS, LONG-TERM NONPROGRESSORS, AND ELITE CONTROLLERS
It is important to distinguish between the terms long-term survivor and long-term nonprogressor. Long-term nonprogressors are by definition long-term survivors; however, the reverse is not always true. Predictions from one study that antedated the availability of effective cART estimated that ~13% of homosexual/bisexual men who were infected at an early age may remain free of clinical AIDS for >20 years. Many of these individuals may have progressed in their degree of immune deficiency; however, they certainly survived for a considerable period of time. With the advent of effective cART, the survival of HIV-infected individuals has dramatically increased. Early in the AIDS epidemic, prior to the availability of therapy, if a patient presented with a life-threatening opportunistic infection, the median survival was 26 weeks from the time of presentation. Currently, an HIV-infected 20-year-old individual in a high-income country who is appropriately treated with cART can expect to live at least 50 years according to mathematical model projections. In the face of cART, long-term survival is becoming commonplace. Definitions of long-term nonprogressors have varied considerably over the years, and so such individuals constitute a heterogeneous group. Long-term nonprogressors were first described in the 1990s. Originally, individuals were considered to be long-term nonprogressors if they had been infected with HIV for a long period (≥10 years), their CD4+ T cell counts were in the normal range, and they remained stable over years without receiving cART. Approximately 5–15% of HIV-infected individuals fell into this broader nonprogressor category. However, this group was rather heterogenous and over time a significant proportion of these individuals progressed and ultimately required therapy. From this broader group, a much smaller subgroup of “elite” controllers or nonprogressors was identified, and they constituted a fraction of 1% of HIV-infected individuals. These elite controllers, by definition, have extremely low levels of plasma viremia that is often undetectable by standard assays and normal CD4+ T cell counts. It is noteworthy that certain of their HIV-specific immune responses are robust and clearly superior to those of HIV-infected progressors. In this group of elite controllers certain HLA class I haplotypes are overrepresented, particularly HLA-B57-01 and HLA-B27-05. Outside of the subgroup of elite controllers, a number of other genetic factors have been shown to be involved to a greater or lesser degree in the control of virus replication and thus in the rate of HIV disease progression (see “Genetic Factors in HIV-1 and AIDS Pathogenesis,” below).
LYMPHOID ORGANS AND HIV PATHOGENESIS
Regardless of the portal of entry of HIV, lymphoid tissues are the major anatomic sites for the establishment and propagation of HIV infection. Despite the use of measurements of plasma viremia to determine the level of disease activity, virus replication occurs mainly in lymphoid tissue and not in blood; indeed, the level of plasma viremia directly reflects virus production in lymphoid tissue.
Some patients experience progressive generalized lymphadenopathy early in the course of the infection; others experience varying degrees of transient lymphadenopathy. Lymphadenopathy reflects the cellular activation and immune response to the virus in the lymphoid tissue, which is generally characterized by follicular or germinal center hyperplasia. Lymphoid tissue involvement is a common denominator of virtually all patients with HIV infection, even those without easily detectable lymphadenopathy.
Examinations of lymph tissue and peripheral blood in patients and monkeys during various stages of HIV and SIV infection, respectively, have led to substantial insight into the pathogenesis of HIV disease. In most of the original human studies, peripheral lymph nodes have been used predominantly as the source of lymphoid tissue. More recent studies in monkeys and humans have also focused on the GALT, where the earliest burst of virus replication occurs associated with marked depletion of CD4+ T cells. In detailed studies of peripheral lymph node tissue that utilized a variety of molecular techniques to measure the level of HIV DNA and RNA and imaging techniques to visualize virus and cells, the following picture has emerged. During acute HIV infection resulting from mucosal transmission, virus replication progressively amplifies from scattered lymphoid cells in the lamina propria of the gut to draining lymphoid tissue, leading to high levels of plasma viremia. The GALT plays a major role in the amplification of virus replication, and virus is disseminated from replication in the GALT to peripheral lymphoid tissue. A profound degree of cellular activation occurs within lymphoid tissue (see below) and is reflected in follicular or germinal center hyperplasia. At this time copious amounts of extracellular virions (both infectious and defective) are trapped on the processes of the follicular dendritic cells (FDCs) in the germinal centers of the lymph nodes. Virions that have bound complement components on their surfaces attach to the surface of FDCs via interactions with complement receptors and likely via Fc receptors that bind to antibodies that are attached to the virions. In situ hybridization reveals expression of virus in individual cells of the paracortical area and, to a lesser extent, the germinal center (Fig. 197-23). The persistence of trapped virus likely reflects a steady state whereby trapped virus turns over and is replaced by fresh virions that are continually produced. The trapped virus, either as whole virion or shed envelope, serves as a continual activator of CD4+ T cells, thus driving further virus replication.
HIV in the lymph node of an HIV-infected individual. An individual cell infected with HIV shown expressing HIV RNA by in situ hybridization using a radiolabeled molecular probe. Original ×500. (Adapted from G Pantaleo, AS Fauci et al: Nature 362:355, 1993.)
During the early stages of HIV disease, the architecture of lymphoid tissues is generally preserved and may even be hyperplastic owing to an increased presence of B cells and specialized CD4+ T cells called follicular helper CD4+ T cells (TFH) in prominent germinal centers. Extracellular virions can be seen by electron microscopy attached to FDC processes. The trapping of antigen is a physiologically normal function for the FDCs, which present antigen to B cells and, along with stimulatory factors produced by TFH cells, contribute to the generation of B cell memory. However, in the case of HIV, persistent cellular activation, resulting in a shift to secretion of proinflammatory cytokines such as interleukin (IL) 1β, tumor necrosis factor (TNF) α, IFN-γ, and IL-6, can induce viral replication (see below) and diminish the effectiveness of the immune response against the virus. In addition, the CD4+ TFH cells that are recruited into the germinal center to provide help to B cells in the generation of an HIV-specific immune response are highly susceptible to infection and may be an important component of the HIV reservoir. Thus, in HIV infection, a normal physiologic function of the immune system that contributes to the clearance of virus, as well as to the generation of a specific immune response, can also have deleterious consequences.
As HIV disease progresses, the architecture of lymphoid tissues begins to show disruption. Confocal microscopy reveals destruction of the fibroblastic reticular cell (FRC) and FDC networks in the T cell zone and B cell follicles, respectively. The mechanisms of destruction are not completely understood, but they are thought to be associated with collagen deposition causing fibrosis and loss of production of cytokines such as IL-7 and lymphotoxin-α, which are critical to the maintenance of lymphoid tissues and their lymphocyte constituents. As the disease progresses to an advanced stage, there is complete disruption of the architecture of the lymphoid tissues, accompanied by dissolution of the FRC and FDC networks. At this point, the lymph nodes are “burnt out.” This destruction of lymphoid tissue compounds the immunodeficiency of HIV disease and contributes both to the inability to control HIV replication and to the inability to mount adequate immune responses against opportunistic pathogens. The events from primary infection to the ultimate destruction of the immune system are illustrated in Fig. 197-24. More recently, nonhuman primate studies and some human studies have examined GALT at various stages of HIV disease. Within the GALT, the basal level of cellular activation combined with virus-mediated activation results in the infection and elimination of an estimated 50–90% of CD4+ T cells in the gut. The extent of this early damage to GALT, which constitutes a major component of lymphoid tissue in the body, may play a role in determining the potential for immunologic recovery of the memory cell subset.
Events that transpire from primary HIV infection through the establishment of chronic persistent infection to the ultimate destruction of the immune system. See text for details. CTLs, cytolytic T lymphocytes; GALT, gut-associated lymphoid tissue.
THE ROLE OF IMMUNE ACTIVATION AND INFLAMMATION IN HIV PATHOGENESIS
Activation of the immune system and variable degrees of inflammation are essential components of any appropriate immune response to a foreign antigen. However, immune activation and inflammation, which can be considered aberrant in HIV-infected individuals, play a critical role in the pathogenesis of HIV disease as well as other chronic conditions associated with HIV infection. Immune activation and inflammation in the HIV-infected individual contribute substantially to (1) the replication of HIV, (2) the induction of immune dysfunction, and (3) the increased incidence of chronic conditions such as premature cardiovascular disease (Table 197-4).
TABLE 197-4Conditions Associated with Persistent Immune Activation and Inflammation in Patients with HIV Infection ||Download (.pdf) TABLE 197-4 Conditions Associated with Persistent Immune Activation and Inflammation in Patients with HIV Infection
|Accelerated aging syndrome |
|Bone fragility |
|Cardiovascular disease |
|Kidney disease |
|Liver disease |
|Neurocognitive dysfunction |
INDUCTION OF HIV REPLICATION BY ABERRANT IMMUNE ACTIVATION
The immune system is normally in a state of homeostasis, awaiting perturbation by foreign antigenic stimuli. Once the immune response deals with and clears the antigen, the system returns to relative quiescence (Chap. 342). This is generally not the case in HIV infection where, in the untreated patient, virus replication is invariably persistent with very few exceptions and immune activation is persistent. HIV replicates most efficiently in activated CD4+ T cells; in HIV infection, chronic activation provides the cell substrates necessary for persistent virus replication throughout the course of HIV disease, particularly in the untreated patient. Even in certain patients receiving cART whose levels of plasma viremia are suppressed to below the level of detection by standard assays, there are low but detectable degrees of virus replication that drives persistent immune activation. From a virologic standpoint, although quiescent CD4+ T cells can be infected, albeit inefficiently, with HIV, reverse transcription, integration, and virus spread are much more efficient in activated cells. Furthermore, cellular activation induces expression of virus in cells latently infected with HIV. In essence, immune activation and inflammation provide the engine that drives HIV replication. In addition to endogenous factors such as cytokines, a number of exogenous factors such as other microbes that are associated with heightened cellular activation can enhance HIV replication and thus may play a role in HIV pathogenesis. Co-infection with a range of viruses, such as HSV types 1 and 2, cytomegalovirus (CMV), human herpesvirus (HHV) 6, Epstein-Barr virus (EBV), HBV, HCV, adenovirus, and HTLV-1 have been shown to upregulate HIV expression. In addition, infestation with nematodes has been shown to be associated with a heightened state of immune activation that facilitates HIV replication; in certain studies deworming of the infected host has resulted in a decrease in plasma viremia. Two diseases of extraordinary global health significance, malaria and tuberculosis (TB), have been shown to increase HIV viral load in dually infected individuals. Globally, Mycobacterium tuberculosis is the most common opportunistic infection in HIV-infected individuals (Chap. 173). In addition to the fact that HIV-infected individuals are more likely to develop active TB after exposure and to reactivate latent TB, it has been demonstrated that active TB can accelerate the course of HIV infection. It has also been shown that levels of plasma viremia are greatly elevated in HIV-infected individuals with active TB who are not receiving cART, compared with pre-TB levels and levels of viremia after successful treatment of the active TB. The situation is similar in the interaction between HIV and malaria parasites (Chap. 219). Acute infection of HIV-infected individuals with Plasmodium falciparum increases HIV viral load, and the increased viral load is reversed by effective treatment of malaria.
MICROBIAL TRANSLOCATION AND PERSISTENT IMMUNE ACTIVATION
One proposed mechanism of persistent immune activation involves the disruption of the mucosal barrier in the gut due to HIV replication in submucosal lymphoid tissue. As a result of this disruption, there is an increase in the products, particularly lipopolysaccharide (LPS), of bacteria that translocate from the bowel lumen through the damaged mucosa to the circulation, leading to persistent systemic immune activation and inflammation. This effect can persist even after the HIV viral load is brought to <50 copies/mL by cART. Depletion in the GALT of IL-17–producing T cells, which are responsible for defense against extracellular bacteria and fungi, also is thought to contribute to HIV pathogenesis.
PERSISTENT IMMUNE ACTIVATION AND INFLAMMATION INDUCE IMMUNE DYSFUNCTION
The immune activated state in HIV infection is reflected by hyperactivation of B cells leading to hypergammaglobulinemia; increased lymphocyte turnover; activation of monocytes; expression of activation markers and immune checkpoint receptors on CD4+ and CD8+ T cells; increased activation-associated cellular apoptosis; lymph node hyperplasia, particularly early in the course of disease; increased secretion of proinflammatory cytokines, particularly IL-6; elevated levels of high-sensitivity C-reactive protein, fibrinogen, D-dimer, neopterin, β2-microglobulin, acid-labile interferon, soluble (s) IL-2 receptors (R), sTNFR, sCD27, and sCD40L; and autoimmune phenomena (see “Autoimmune Phenomena,” below). Even in the absence of direct infection of a target cell, HIV envelope proteins can interact with cellular receptors (CD4 molecules and chemokine receptors) to deliver potent activation signals resulting in calcium flux, the phosphorylation of certain proteins involved in signal transduction, co-localization of cytoplasmic proteins including those involved in cell trafficking, immune dysfunction, and, under certain circumstances, apoptosis. From an immunologic standpoint, chronic exposure of the immune system to a particular antigen over an extended period of time may ultimately lead to an inability to sustain an adequate immune response to the antigen in question. In many chronic viral infections, including HIV infection, persistent viremia is associated with “functional exhaustion” of virus-specific T cells, decreasing their capacity to proliferate and perform effector functions. It has been demonstrated that this phenomenon of immune exhaustion may be mediated, at least in part, by the upregulation of inhibitory receptors on HIV-specific T cells, such as PD-1 and Tim-3 that are shared by both CD4+ and CD8+ T cells, as well as CTLA-4 on CD4+ and 2B4 and CD106 on CD8+ T cells. Furthermore, the ability of the immune system to respond to a broad spectrum of non-HIV antigens may be compromised if immunocompetent bystander cells are maintained in a state of chronic activation.
The deleterious effects of chronic immune activation on the progression of HIV disease are well established. As in most conditions of persistent antigen exposure, the host must maintain sufficient activation of antigen (HIV)-specific responses but must also prevent excessive activation and potential immune-mediated damage to tissues. Certain studies suggest that normal immunoregulatory mechanisms that act to keep hyperimmune activation in check, particularly CD4+, FoxP3+, and CD25+ regulatory T cells (T-regs), may be dysfunctional or depleted in the context of advanced HIV disease.
Apoptosis is a form of programmed cell death that is a normal mechanism for the elimination of effete cells in organogenesis as well as in the cellular proliferation that occurs during a normal immune response (Chap. 342). Apoptosis can occur by intrinsic or extrinsic pathways, the latter of which is largely dependent on cellular activation, and the aberrant cellular activation associated with HIV disease is correlated with a heightened state of apoptosis. HIV can trigger activation-induced cell death through the upregulation of the death receptors, such as Fas/CD95, TNFR1, or TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2. Their corresponding ligands FasL, TNF, and TRAIL also are upregulated in HIV disease. HIV-induced stress and alterations in homeostasis also can trigger intrinsic apoptosis due to the downregulation of antiapoptotic proteins such as Bcl-2. Other mechanisms of HIV-induced cell death have been described, including autophagy, necrosis, necroptosis, and pyroptosis. The phenomenon of pyroptosis, an inflammatory form of cell death involving the upregulation of the proinflammatory enzyme caspase 1 and release of the proinflammatory cytokines IL-1β and IL-18, has been linked to a bystander effect of HIV replication on CD4+ T cells. The process of pyroptosis generates multimeric complexes called inflammasomes, which can also be activated by LPS. Certain viral gene products have been associated with enhanced susceptibility to apoptosis; these include Env, Tat, and Vpr. In contrast, Nef has been shown to possess antiapoptotic properties. The intensity of apoptosis correlates with the general state of activation of the immune system and not with the stage of disease or with viral burden. A number of studies, including those examining lymphoid tissue, have demonstrated that the rate of apoptosis is elevated in HIV infection and that apoptosis is seen in “bystander” cells such as CD8+ T cells and B cells as well as in uninfected CD4+ T cells. It is likely that this bystander apoptosis of immunocompetent cells related to immune activation contributes to the general immune abnormalities in HIV disease.
MEDICAL CONDITIONS ASSOCIATED WITH PERSISTENT IMMUNE ACTIVATION AND INFLAMMATION IN HIV DISEASE
It has become clear, as the survival of HIV-infected individuals has increased, that a number of previously unrecognized medical complications are associated with HIV disease—and that these complications relate to chronic immune activation and inflammation (Table 197-4). These complications can appear even after patients have experienced years of adequate control of viral replication (plasma viremia below detectable levels) for several years. Of particular note are endothelial cell dysfunction and its relationship to cardiovascular disease. Other chronic conditions that have been reported include bone fragility, certain cancers, diabetes, kidney and liver disease, and neurocognitive dysfunction, thus presenting an overall picture of accelerated aging.
Autoimmune phenomena are commonly observed in HIV-infected individuals and they reflect, at least in part, chronic immune activation and the dysregulation of B and T cells. Although these phenomena usually occur in the absence of autoimmune disease, a wide spectrum of clinical manifestations that may be associated with autoimmunity have been described (see “Immunologic and Rheumatologic Diseases,” below). Autoimmune phenomena include antibodies against autoantigens expressed on intact lymphocytes and other cells, or against proteins released from dying cells. Antiplatelet antibodies have some clinical relevance in that they may contribute to the thrombocytopenia of HIV disease (see below). Antibodies to nuclear and cytoplasmic components of cells have been reported, as have antibodies to cardiolipin and phospholipids; CD4 molecules; CD43 molecules; C1q-A; variable regions of the T cell receptor α, β, and γ chains; Fas; denatured collagen; and IL-2. In addition, autoantibodies to a range of serum proteins, including albumin, immunoglobulin, and thyroglobulin, have been reported. Molecular mimicry, either from opportunistic pathogens or from HIV itself, also is a trigger or cofactor in autoimmunity. Antibodies against the HIV envelope proteins, especially gp41, often cross-react with host proteins; the best known examples are antibodies directed against the membrane-proximal external region (MPER) of gp41 that also react with phospholipids and cardiolipin. The phenomenon of polyreactive HIV-specific antibodies may be beneficial to the host (see “Immune Response to HIV,” below).
The increased occurrence and/or exacerbation of certain autoimmune diseases have been reported in HIV infection; these diseases include psoriasis, idiopathic thrombocytopenic purpura, Graves’ disease, antiphospholipid syndrome, and primary biliary cirrhosis. The majority of these manifestations were described prior to the advent of cART and have decreased in frequency since its widespread use. However, with increasing availability of cART, an immune reconstitution inflammatory syndrome (IRIS) has been increasingly observed in infected individuals, particularly those with low CD4+ T cell counts (see below). IRIS is an autoimmune-like phenomenon characterized by a paradoxical deterioration of clinical condition, which is usually compartmentalized to a particular organ system, in individuals in whom cART has recently been initiated. It is associated with a decrease in viral load and at least partial recovery of immune competence, which is usually associated with increases in CD4+ T cell counts. The immunopathogenesis of this syndrome is felt to be related to an increase in immune response against the presence of residual antigens that are usually microbial and is most commonly seen with underlying Mycobacterium tuberculosis and cryptococcosis. This syndrome is discussed in more detail below.
CYTOKINES AND OTHER SOLUBLE FACTORS IN HIV PATHOGENESIS
The immune system is homeostatically regulated by a complex network of immunoregulatory cytokines, which are pleiotropic and redundant and operate in an autocrine and paracrine manner. They are expressed continuously, even during periods of apparent quiescence of the immune system. On perturbation of the immune system by antigenic challenge, the expression of cytokines increases to varying degrees (Chap. 342). Cytokines that are important components of this immunoregulatory network are thought to play major roles in HIV disease, during both the early and chronic phases of infection. A potent proinflammatory “cytokine storm” is induced during the acute phase of HIV infection, likely a response by inflammatory cells to virus replicating at very high levels. Cytokines that are induced during this early phase include IFN-α, IL-15, and the CXC chemokine IP-10 (CXCL10), followed by IL-6, IL-12, and TNF-α, and a delayed peak of the anti-inflammatory cytokine IL-10. Soluble factors of innate immunity also are induced shortly after infection, including neopterin and β-microglobulin. Several of these early-expressed cytokines and factors are not downregulated following the early phase of HIV infection, as seen in other self-resolving viral infections, and persist during the chronic phase of infection and contribute to maintaining high levels of immune activation. Among the cytokines and factors associated with early innate immune responses, they are intended to contain viral replication, although paradoxically most are potent inducers of HIV expression/replication because of their ability to induce immune activation that leads to enhanced viral production and an increase in readily available target cells for HIV (activated CD4+ T cells). The induction of IFN-α, one of the first cytokines induced during primary HIV infection and an important element of innate immune sensing, is thought to play a particularly important role in HIV pathogenesis by inducing a large number of IFN-associated genes that activate the immune system, alter the homeostasis of CD4+ T cells, and influence the virus variants that are selected during the HIV transmission bottleneck. Other cytokines that are elevated during the chronic phase of HIV infection and linked to immune activation include IFN-γ, the CC-chemokine RANTES (CCL5), macrophage inflammatory protein (MIP)-1β (CCL4), and IL-18.
Several specific cytokines and soluble factors have been associated with HIV pathogenesis at various stages of disease, in various tissues or organs, and in the regulation of HIV replication. Plasma levels of IP-10 are predictive of disease progression, whereas the proinflammatory cytokine IL-6, soluble CD14 (sCD14), and coagulation marker D-dimer are associated with increased risk of all-cause mortality in HIV-infected individuals. In particular, IL-6, sCD14, and D-dimer are associated with increased risk of cardiovascular disease and other causes of death, even in individuals receiving cART. IL-18 has also been shown to play a role in the development of the HIV-associated lipodystrophy syndrome, whereas increased levels of transforming growth factor (TGF)-β are associated with the induction of collagen deposition in lymph nodes (see above). Elevated levels of TNF-α and IL-6 have been demonstrated in plasma and cerebrospinal fluid (CSF), and increased expression of TNF-α, IL-1β, IFN-γ, and IL-6 has been demonstrated in the lymph nodes of HIV-infected individuals. RANTES, MIP-1α (CCL3), and MIP-1β (CCL4) (Chap. 342) inhibit infection by and spread of R5 HIV-1 strains, while stromal cell–derived factor (SDF) 1 inhibits infection by and spread of X4 strains. The mechanisms whereby the CC-chemokines RANTES (CCL5), MIP-1α (CCL3), and MIP-1β (CCL4) inhibit infection of R5 strains of HIV, or SDF-1 blocks X4 strains of HIV, involve blocking of the binding of the virus to its co-receptors, the CC-chemokine receptor CCR5 and the CXC-chemokine receptor CXCR4, respectively. Other soluble factors that have not yet been fully characterized, such as soluble CD8 antiviral factor (CAF), also have been shown to suppress HIV replication, independent of co-receptor usage.
LYMPHOCYTE TURNOVER IN HIV INFECTION
The immune systems of patients with HIV infection are characterized by a profound increase in lymphocyte turnover that is immediately reduced with effective cART. Studies utilizing in vivo or in vitro labeling of lymphocytes in the S-phase of the cell cycle have demonstrated a tight correlation between the degree of lymphocyte turnover and plasma levels of HIV RNA. This increase in turnover is seen in CD4+ and CD8+ T lymphocytes as well as B lymphocytes and can be observed in peripheral blood and lymphoid tissue. Mathematical models derived from these data suggest that one can view the lymphoid pool as consisting of dynamically distinct subpopulations of cells that are differentially affected by HIV infection. A major consequence of HIV infection appears to be a shift in cells from a more quiescent pool to a pool with a higher turnover rate. It is likely that a consequence of a higher rate of turnover is a higher rate of cell death. It has been suggested that the more rapid decline in CD4+ compared with CD8+ T cells may be linked to alterations in inflammatory and homeostatic cytokines that cause increased activation-induced death without replenishment of CD4+ but not CD8+ T cells. (See Table 197-5 for additional mechanisms of depletion.)
TABLE 197-5Proposed Mechanisms of CD4+ T Cell Dysfunction and Depletion ||Download (.pdf) TABLE 197-5 Proposed Mechanisms of CD4+ T Cell Dysfunction and Depletion
|Direct Mechanisms ||Indirect Mechanisms |
|Loss of plasma membrane integrity due to viral budding ||Aberrant intracellular signaling events |
Accumulation of unintegrated viral DNA
Activation of DNA-dependent protein kinase during viral integration into host genome
|Interference with cellular RNA processing ||Innocent bystander killing of viral antigen–coated cells |
|Intracellular gp120-CD4 autofusion events ||Apoptosis, pyroptosis (caspase-1 associated inflammation), autophagy |
|Syncytia formation || |
Inhibition of lymphopoiesis from reduced survival cytokines and lymphoid tissue integrity
Activation-induced cell death
Elimination of HIV-infected cells by virus-specific immune responses
THE ROLE OF VIRAL RECEPTORS AND CO-RECEPTORS IN HIV PATHOGENESIS
As mentioned above, HIV-1 utilizes two major co-receptors along with CD4 to bind to, fuse with, and enter target cells; these co-receptors are CCR5 and CXCR4, which are also receptors for certain endogenous chemokines. Strains of HIV that utilize CCR5 as a co-receptor are referred to as R5 viruses. Strains of HIV that utilize CXCR4 are referred to as X4 viruses. Many virus strains are dual tropic in that they utilize both CCR5 and CXCR4; these are referred to as R5X4 viruses.
The natural chemokine ligands for the major HIV co-receptors can readily block entry of HIV. For example, the CC-chemokines RANTES (CCL5), MIP-1α (CCL3), and MIP-1β (CCL4), which are the natural ligands for CCR5, block entry of R5 viruses, whereas SDF-1, the natural ligand for CXCR4, blocks entry of X4 viruses. The mechanism of inhibition of viral entry is a steric inhibition of binding that is not dependent on signal transduction (Fig. 197-25).
Model for the role of co-receptors CXCR4 and CCR5 in the efficient binding and entry of X4 (A) and R5 (B) strains of HIV-1, respectively, into CD4+ target cells. Blocking of this initial event in the virus life cycle can be accomplished by inhibition of binding to the co-receptor by the normal ligand for the receptor in question. The ligand for CXCR4 is stromal cell–derived factor (SDF-1); the ligands for CCR5 are RANTES, MIP-1α, and MIP-1β.
The transmitting virus is almost invariably an R5 virus that predominates during the early stages of HIV disease. In the absence of cART or in cases of therapy failure, there is a transition to a predominantly X4 virus in approximately half of individuals infected with subtype B. The transition is often preceded by dual R5X4 strains, and detection of X4 variants is associated with a relatively rapid decline in CD4+ T cell counts, increased HIV plasma viremia, and progression of disease. However, the other half of infected individuals progress in their disease while maintaining predominance of an R5 virus, and individuals infected with subtype C rarely switch from CCR5 tropism to CXCR4 tropism. The reason for this difference is unclear.
The basis for the tropism of different envelope glycoproteins for either CCR5 or CXCR4 relates to the ability of the HIV envelope, including the third variable region (V3 loop) of gp120, to interact with these co-receptors. In this regard, binding of gp120 to CD4 induces a conformational change in gp120 that increases its affinity for the relevant co-receptor. Finally, R5 viruses are more efficient in infecting monocytes/macrophages and microglial cells of the brain (see “Neuropathogenesis in HIV Disease,” below).
THE INTEGRIN ALPHA 4 BETA 7
The integrin α4β7 is an accessory receptor for HIV. It is not essential for the binding and infection of a CD4+ T cell by HIV; however, it likely plays an important role in the transmission of HIV at mucosal surfaces such as the genital tract and gut and contributes somewhat to the pathogenesis of HIV disease. The integrin α4β7, which is the gut homing receptor for peripheral T cells, binds in its activated form to a specific tripeptide in the V2 loop of gp120, resulting in rapid activation of leukocyte function–associated antigen 1 (LFA-1), the central integrin in the establishment of virologic synapses, which facilitate efficient cell-to-cell spread of HIV. It has been demonstrated that α4β7high CD4+ T cells are more susceptible to productive infection than are α4β7low–neg CD4+ T cells because this cellular subset is enriched with metabolically active CD4+ T cells that are CCR5high. These cells are present at the gut and genital tract mucosal surfaces. Importantly, it has been demonstrated that the virus that is transmitted during sexual exposure binds much more efficiently to α4β7 than does the virus that diversifies from the transmitting virus over time by mutation, particularly involving the accumulation of glycogens on the surface of the HIV envelope (see “Early Events in HIV Infection: Primary Infection and Initial Dissemination of Virus,” above).
CD4+ T lymphocytes and to a lesser extent CD4+ cells of the myeloid lineage are the principal targets of HIV and are the only cells that can be productively infected with HIV. Circulating DCs have been reported to express low levels of CD4, although high expression of the restriction factor SAMHD1 in myeloid (mDC) and plasmacytoid (pDC) DCs limits HIV replication in these cells by depleting intracellular pools of dNTPs and directly degrading viral RNA. Epidermal Langerhans cells express CD4 and have been infected by HIV in vivo, although, they too restrict replication by high expression of the host restriction factor, langerin. As has been shown in vivo for DCs, FDCs, and B cells, Langerhans cells are more likely to bind and transfer virus to activated CD4+ T cells than to be productively infected themselves.
Of potential clinical relevance is the demonstration that thymic precursor cells, which were assumed to be negative for CD3, CD4, and CD8 molecules, actually do express low levels of CD4 and can be infected with HIV in vitro. In addition, human thymic epithelial cells transplanted into an immunodeficient mouse can be infected with HIV by direct inoculation of virus into the thymus. Since these cells may play a role in the normal regeneration of CD4+ T cells, it is possible that their infection and depletion contribute, at least in part, to the impaired ability of the CD4+ T cell pool to completely reconstitute itself in certain infected individuals in whom cART has suppressed plasma viremia to below the level of detection (see below). In addition, CD34+ monocyte precursor cells have been shown to be infected in vivo in patients with advanced HIV disease. It is likely that these cells express low levels of CD4, and therefore it is not essential to invoke CD4-independent mechanisms to explain the infection. The clinical relevance of this finding is unclear.
QUALITATIVE AND QUANTITATIVE ABNORMALITIES OF MONONUCLEAR CELLS
The primary immunopathogenic lesion in HIV infection involves CD4+ T cells, and the range of CD4+ T cell abnormalities in advanced HIV infection is broad. The defects are both quantitative and qualitative and ultimately impact virtually every limb of the immune system, indicating the critical dependence of the integrity of the immune system on the inducer/helper function of CD4+ T cells. In advanced HIV disease, most of the observed immune defects can ultimately be explained by the quantitative depletion of CD4+ T cells. However, T cell dysfunction can be demonstrated in patients early in the course of infection, even when the CD4+ T cell count is in the low-normal range. The degree and spectrum of dysfunctions increase as the disease progresses, reflecting the range of CD4+ T cell functional heterogeneity, especially in lymphoid tissues. One of the first sites of intense HIV replication is in the GALT where CD4+ TH17 cells reside; they are important for host defense against extracellular pathogens in the intestinal mucosa and help maintain the integrity of the gut epithelium. In HIV infection, they are depleted by direct and indirect effects of viral replication and cause loss of gut homeostasis and integrity, as well as a shift toward a TH1 phenotype. Studies have shown that even after many years of cART, normalization of the CD4+ T cells in the GALT remains incomplete. In lymph nodes, HIV perturbs another important subset of the CD4+ helper T lineage, namely TFH cells (see “Lymphoid Organs and HIV Pathogenesis,” above). TFH cells, which are derived either directly from naïve CD4+ T cells or from other TH precursors, migrate into B follicles during germinal center reactions and provide help to antigen-specific B cells through cell–cell interactions and secretion of cytokines to which B cells respond, the most important of which is IL-21. As with TH17 cells, TFH cells are highly susceptible to HIV infection. However, in contrast to TH17 and most other CD4+ T cell subsets, the number of TFH cells is increased in lymph nodes of HIV-infected individuals, especially those who are viremic. It is unclear whether this increase is helpful to responding B cells, although the likely outcome is that the increase in numbers is detrimental to the quality of the humoral immune response against HIV (see “Immune Response to HIV,” below). In addition, defects of central memory cells are a critical component of HIV immunopathogenesis. The progressive loss of antigen-specific CD4+ T cells has important implications for the control of HIV infection. In this regard, there is a correlation between the maintenance of HIV-specific CD4+ T cell proliferative responses and improved control of infection. Essentially every T cell function has been reported to be abnormal at some stage of HIV infection. Loss of polyfunctional HIV-specific CD4+ T cells, especially those that produce IL-2, occurs early in disease, whereas IFN-producing CD4+ T cells are maintained longer and do not correlate with control of HIV viremia. Other abnormalities include impaired expression of IL-2 receptors, defective IL-2 production, reduced expression of the IL-7 receptor (CD127), and a decreased proportion of CD4+ T cells that express CD28, a major co-stimulatory molecule necessary for the normal activation of T cells, which is also depleted as a result of aging. Cells lacking expression of CD28 do not respond normally to activation signals and may express markers of terminal activation including HLA-DR, CD38, and CD45RO. As mentioned above (“The Role of Immune Activation and Inflammation in HIV Pathogenesis”), a subset of CD4+ T cells referred to as T regulatory cells, or T-regs, may be involved in damping aberrant immune activation that propagates HIV replication. The presence of these T-reg cells correlates with lower viral loads and higher CD4+/CD8+ T cell ratios. A loss of this T-reg capability with advanced disease may be detrimental to the control of virus replication.
It is difficult to explain completely the profound immunodeficiency noted in HIV-infected individuals solely on the basis of direct infection and quantitative depletion of CD4+ T cells. This is particularly apparent during the early stages of HIV disease, when CD4+ T cell numbers may be only marginally decreased. In this regard, it is likely that CD4+ T cell dysfunction results from a combination of depletion of cells due to direct infection of the cell and a number of virus-related but indirect effects on the cell such as elimination of “innocent bystander cells” (Table 197-5). Several of these effects have been demonstrated ex vivo and/or by the analysis of cells isolated from the peripheral blood. Soluble viral proteins, particularly gp120, can bind with high affinity to the CD4 molecules on uninfected T cells and monocytes; in addition, virus and/or viral proteins can bind to DCs or FDCs. HIV-specific antibody can recognize these bound molecules and potentially collaborate in the elimination of the cells by ADCC. HIV envelope glycoproteins gp120 and gp160 manifest high-affinity binding to the CD4 molecule as well as to various chemokine receptors. Intracellular signals transduced by gp120 through both CD4 and CCR5/CXCR4 have been associated with a number of immunopathogenic processes including anergy, apoptosis, and abnormalities of cell trafficking. The molecular mechanisms responsible for these abnormalities include dysregulation of the T cell receptor–phosphoinositide pathway, p56lck activation, phosphorylation of focal adhesion kinase, activation of the MAP kinase and ras signaling pathways, and downregulation of the co-stimulatory molecules CD40 ligand and CD80.
The inexorable decline in CD4+ T cell counts that occurs in most HIV-infected individuals may result in part from the inability of the immune system to regenerate over an extended period of time the rapidly turning over CD4+ T cell pool efficiently enough to compensate for both HIV-mediated and naturally occurring attrition of cells. In this regard, the degree and duration of decline of CD4+ T cells at the time of initiation of therapy is an important predictor of the restoration of these cells. A person who maintains a very low CD4+ T cell count for a considerable period of time before the initiation of cART almost invariably has an incomplete reconstitution of such cells. At least two major mechanisms may contribute to the failure of the CD4+ T cell pool to reconstitute itself adequately over the course of HIV infection. The first is the destruction of lymphoid precursor cells, including thymic and bone marrow progenitor cells; the other is the gradual disruption of the lymphoid tissue architecture and microenvironment, which is essential for efficient regeneration of immunocompetent cells. Finally, during the advanced stages of CD4+ T lymphopenia, there are increased serum levels of the homeostatic cytokine IL-7. It was initially felt that this elevation was a homeostatic response to the lymphopenia; however, recent findings suggest that the increase in serum IL-7 was a result of reduced utilization of the cytokine related to the loss of cells expressing the IL-7 receptor, CD127, which serves as a normal physiologic regulator of IL-7 production.
A relative CD8+ T lymphocytosis is generally associated with high levels of HIV plasma viremia and likely reflects an immune response to the virus as well as dysregulated homeostasis associated with generalized immune activation. During the late stages of HIV infection, there may be a significant reduction in the numbers of CD8+ T cells despite the presence of high levels of viremia. HIV-specific CD8+ CTLs have been demonstrated in HIV-infected individuals early in the course of disease, and their emergence often coincides with a decrease in plasma viremia—an observation that is a factor in the proposal that virus-specific CTLs can control HIV disease for a finite period of time in a certain percentage of infected individuals. However, emergence of HIV escape mutants that ultimately evade these HIV-specific CD8+ T cells has been described in the majority of HIV-infected individuals who are not receiving cART. In addition, as the disease progresses, the functional capability of these cells gradually decreases, at least in part due to the persistent nature of HIV infection that causes functional exhaustion via the upregulation of inhibitory receptors such as PD-1 and TIGIT on HIV-specific CD8+ T cells (see “The Role of Immune Activation and Inflammation in HIV Pathogenesis,” above). As chronic immune activation persists, there are also systemic effects on CD8+ T cells, such that as a population they assume an abnormal phenotype characterized by expression of activation markers such as HLA-DR and CD38 with an absence of expression of the IL-2 receptor (CD25) and a reduced expression of the IL-7 receptor (CD127). In addition, CD8+ T cells lacking CD28 expression are increased in HIV disease, reflecting a skewed expansion of a less differentiated CD8+ T cell subset. This skewing of subsets is also associated with diminished polyfunctionality, a qualitative difference that distinguishes elite controllers from progressors. Elite controllers can also be distinguished from progressors by the maintenance in the former of a high proliferative capacity of their HIV-specific CD8+ T cells coupled to increases in perforin expression and elimination of infected targets, characteristics that are markedly diminished in advanced HIV disease. It has been reported that the phenotype of CD8+ T cells in HIV-infected individuals may be of prognostic significance. Those individuals whose CD8+ T cells developed a phenotype of HLA-DR+/CD38– following seroconversion had stabilization of their CD4+ T cell counts, whereas those whose CD8+ T cells developed a phenotype of HLA-DR+/CD38+ had a more aggressive course and a poorer prognosis. In addition to the defects in HIV-specific CD8+ CTLs, functional defects in other MHC-restricted CTLs, such as those directed against influenza and CMV, have been demonstrated. CD8+ T cells secrete a variety of soluble factors that inhibit HIV replication, including the CC-chemokines RANTES (CCL5), MIP-1α (CCL3), and MIP-1β (CCL4) as well as potentially a number of as yet unidentified factors. The presence of high levels of HIV viremia in vivo as well as exposure of CD8+ T cells in vitro to HIV envelope, both of which are associated with aberrant immune activation, have been shown to be associated with a variety of cellular functional abnormalities. Furthermore, since the integrity of CD8+ T cell function depends in part on adequate inductive signals from CD4+ T cells, the defect in CD8+ CTLs is likely compounded by the quantitative loss and qualitative dysfunction of CD4+ T cells.
The predominant defect in B cells from HIV-infected individuals is one of aberrant cellular activation, which is reflected by increased propensity to terminal differentiation and immunoglobulin secretion, as well as increased expression of markers of activation and exhaustion. As a result of activation and differentiation in vivo, B cells from HIV viremic patients manifest a decreased capacity to mount a proliferative response to ligation of the B cell antigen receptor and other B cell stimuli in vitro. B cells from HIV-infected individuals manifest enhanced spontaneous secretion of immunoglobulins in vitro, a process that reflects their highly differentiated state in vivo. There is also an increased incidence of EBV-related B cell lymphomas in HIV-infected individuals that are likely due to combined effects of defective T cell immune surveillance and increased B cell turnover that increases the risk of oncogenesis. Untransformed B cells cannot be infected with HIV, although HIV or its products can activate B cells directly. B cells from patients with high levels of viremia bind virions to their surface via the CD21 complement receptor. It is likely that in vivo activation of B cells by replication-competent or defective virus as well as viral products during the viremic state accounts at least in part for their activated phenotype. B cell subpopulations from HIV-infected individuals undergo a number of changes over the course of HIV disease, including the attrition of resting memory B cells and replacement with several aberrant memory and differentiated B cell subpopulations that collectively express reduced levels of CD21 and either increased expression of activation markers or inhibitory receptors associated with functional exhaustion. The more activated and differentiated B cells are also responsible for increased secretion of immunoglobulins and increased susceptibility to Fas-mediated apoptosis. In more advanced disease, there is also the appearance of immature B cells associated with CD4+ T cell lymphopenia. Despite increased frequencies of germinal center B cells and CD4+ TFH cells, both of which are required for effective humoral immunity, cognate B cell–CD4+ T cell interactions in lymphoid tissues are perturbed in HIV-infected individuals, especially those with persistent viremia. In vivo, the aberrant activated state of B cells manifests itself by hypergammaglobulinemia and by the presence of circulating immune complexes and autoantibodies. HIV-infected individuals respond poorly to primary and secondary immunizations with protein and polysaccharide antigens. Using immunization with influenza vaccine, it has been demonstrated that there is a memory B cell defect in HIV-infected individuals, particularly those with high levels of HIV viremia. There is also evidence that responses to HIV and non-HIV antigens in infected individuals, especially those who remain viremic, are enriched in abnormal subsets of B cells that either are highly prone to apoptosis or show signs of functional exhaustion. Taken together, these B cell defects are likely responsible at least in part for the inadequate humoral response to HIV as well as to decreased response to vaccinations and the increase in certain bacterial infections seen in advanced HIV disease in adults. In addition, they likely contribute to the inadequacy of host defenses against bacterial infections that play a role in the increased morbidity and mortality of HIV-infected children. The absolute number of circulating B cells also may be depressed in HIV infection; this phenomenon likely reflects increased activation-induced apoptosis as well as a redistribution of cells out of the circulation and into the lymphoid tissue—phenomena that are associated with ongoing viral replication.
Circulating monocytes are generally normal in number in HIV-infected individuals; however, there is evidence of increased activation within this lineage. The increased level of sCD14 and other biomarkers (see above) reported in HIV-infected individuals is an indirect marker of monocyte activation in vivo. A number of other abnormalities of circulating monocytes have been reported in HIV-infected individuals, many of which may be related directly or indirectly to aberrant in vivo immune activation. In this regard, increased levels of lipopolysaccharide (LPS) are found in the sera of HIV-infected individuals due, at least in part, to translocation across the gut mucosal barrier (see above). LPS is a highly inflammatory bacterial product that preferentially binds to macrophages through CD14 and Toll-like receptors, resulting in cellular activation. Functional abnormalities of monocyte/macrophages in HIV disease include decreased secretion of IL-1 and IL-12; increased secretion of cytokines such as IL-10 and IL-18 and markers of coagulation such as D-dimer; defects in antigen presentation and induction of T cell responses due to decreased MHC class II expression; and abnormalities of Fc receptor function, C3 receptor–mediated clearance, oxidative burst responses, and certain cytotoxic functions such as ADCC, possibly related to low levels of expression of Fc and complement receptors. Monocytes express the CD4 molecule and several co-receptors for HIV on their surface, and thus are potential targets of HIV infection. However, in vivo infection of circulating monocytes is difficult to demonstrate, although infection of tissue macrophages and macrophage-lineage cells in the brain (infiltrating macrophages or resident microglial cells) and lung (pulmonary alveolar macrophages) can be demonstrated easily. Tissue macrophages are an important source of HIV during the inflammatory response associated with opportunistic infections and can serve as persistent reservoirs of HIV infection, thus representing an obstacle to the eradication of HIV by antiretroviral drugs. Infection of monocyte precursors in the bone marrow may directly or indirectly be responsible for certain of the hematologic abnormalities in HIV-infected individuals. However, as with DCs, monocytes and macrophages express high levels of host restriction factors that likely help explain the low contribution of myeloid cells to the overall viral burden in HIV-infected individuals.
Dendritic and Langerhans Cells
DCs and Langerhans cells are not productively infected with HIV, but they are thought to play an important role in the initiation of HIV infection by virtue of the ability of HIV to bind to cell-surface C-type lectin receptors, particularly DC-SIGN (see above) and langerin. However, while langerin provides a host barrier for replication by trafficking HIV to acidic compartments for degradation, DC-SIGN retains HIV in early endosomal compartments. This allows efficient presentation of intact virus to CD4+ T cell targets that become infected; complexes of infected CD4+ T cells and DCs provide an optimal microenvironment for virus replication. Furthermore, pDCs secrete large amounts of IFN-α in response to viral infections and as such play an important role in innate sensing of HIV during early phase of infection. The numbers of circulating pDCs are decreased in HIV infection through mechanisms that remain unclear, although several studies have shown increased lymphoid tissue recruitment of DCs associated with lymphoid hyperplasia and inflammation. The mDCs or conventional DCs are also involved in the initiation of adaptive immunity in draining lymph nodes by presenting antigen to T cells and B cells, as well as by secreting cytokines such as IL-12, IL-15, and IL-18 that activate other immune cells. There are also indications that the relatively low infectibility of DCs may be associated with the expression of host restriction factors, including APOBEC3G and SAMHD1 (see above).
The role of NK cells is to provide immunosurveillance against virus-infected cells, certain tumor cells, and allogeneic cells (Chap. 342). There are no convincing data that HIV productively infects NK cells in vivo; however, functional abnormalities in NK cells have been observed throughout the course of HIV disease, and the severity of these abnormalities increases as disease progresses. NK cells are part of the innate immune system and act by direct killing of infected cells and secretion of antiviral cytokines and chemokines. In early HIV infection there is an increase in the activation of NK cells, and the capacity to secrete IFN-γ is maintained, although they manifest reduced cytotoxic function. During chronic HIV infection, both NK cell cytotoxicity and cytokine secretion become impaired. Given that HIV infection of target cells downregulates HLA-A and B, but not HLA-C and D molecules, this may explain in part the relative inability of NK cells to kill HIV-infected target cells. However, the NK cell impairments, especially in patients with high levels of virus replication, are associated with an expansion of an “anergic” CD56–/CD16+ NK cell subset. This abnormal subset of NK cells manifests an increased expression of inhibitory NK cell receptors (iNKRs) and a substantial decrease in expression of natural cytotoxicity receptors (NCRs) and shows a markedly impaired lytic activity. The overrepresentation of this abnormal subset of NK cells may explain in part the observed defects in NK cell function in HIV-infected individuals and likely begins to occur during primary infection. The relative expression of iNKRs and NCRs—as well as their ligands, which include HLA class I molecules—has an impact on the antiviral functions associated with NK cells, including direct killing and ADCC. Polymorphisms in iNKR and NCR alleles have been linked to HIV-1 disease outcomes. NK cells also serve as important sources of HIV-inhibitory CC-chemokines. NK cells isolated from HIV-infected individuals constitutively produce high levels of MIP-1α (CCL3), MIP-1β (CCL4), and RANTES (CCL5), although the impact of these chemokines on HIV replication in vivo is unclear. Finally, NK cell–DC interactions are important for normal immune function. NK cells and DCs reciprocally modulate each other’s activation and maturation. These interactions are markedly impaired in HIV-infected individuals with high levels of plasma viremia.
GENETIC FACTORS IN HIV-1 AND AIDS PATHOGENESIS
Candidate gene approaches and genome-wide association studies (GWAS) have identified polymorphisms in host genes that contribute to inter-individual variation in (1) the risk of acquiring HIV, (2) the steady-state levels of HIV that are established soon after infection (virologic set point), (3) the rate at which untreated HIV-infected patients progress to AIDS as well as risk of developing specific AIDS-defining illnesses (e.g., renal and neurologic diseases), and (4) the level of immune reconstitution (e.g., CD4+ counts) achieved after initiation of virally suppressive ART. The key polymorphisms that influence these four traits are summarized in Table 197-6, and their identification has greatly advanced our understanding of the genes that influence HIV-AIDS pathogenesis. Of particular interest are polymorphisms in two chromosomal regions, as they are associated with consistent effects on HIV acquisition, virologic set point, and/or rates of HIV disease progression: the region in chromosome 3 that includes the gene that encodes the HIV co-receptor CC chemokine receptor 5 (CCR5) and the major histocompatibility locus (MHC) in chromosome 6 (Fig. 197-26).
TABLE 197-6Host Genetic Factors That Influence Risk of HIV-1 Acquisition and Rates of HIV-1 Disease Progression ||Download (.pdf) TABLE 197-6 Host Genetic Factors That Influence Risk of HIV-1 Acquisition and Rates of HIV-1 Disease Progression
|Genea ||Genetic Variation ||Mechanismsb ||Genetic Effect on HIV-AIDSc |
|Genes in MHC Locus |
|HLA-B || |
B*27 and B*57
Presentation of specific HIV antigens
Restriction of specific HIV peptide presentation
Providing ligands for activating KIR
Slower progression to AIDS; lower viral load
Faster progression to AIDS; higher viral load
Slower progression to AIDS
|HLA class I allele || |
Homozygosity of HLA-class I alleles
Shared donor-recipient HLA alleles
Rare HLA alleles
Reduced repertoire for epitope recognition
Preadaptation of HIV strains
Limited adaptation of HIV strains; less frequent escape mutants
Faster progression to AIDS; increased risk of mother-to-child transmission
Faster disease progression to AIDS
Protection against HIV infection
|HLA class II allele ||HLA-DRB1 alleles ||Influencing protein specificity of CD4+ T cell responses to HIV Gag and Nef proteins || |
HLA-DRB1*15:02—lower viral load
HLA-DRB1*03:01—higher viral load
|HLA extended haplotype ||A1-B8-DR3-DQ2 (AH 8.1) ||Increased proinflammatory responses; higher TNF-α production ||Faster progression to AIDS |
|HLA-C ||35 kb upstream, rs9264942-C ||Increased expression of HLA-C ||Decreased viral load set point |
|HCP5 ||rs2395029-G ||Linkage disequilibrium with HLA-B*57:01 ||Lower viral load |
|MICA ||Noncoding SNP near MICA, rs4418214-T ||May affect HLA class I peptide presentation—linkage with protective HLA-B alleles ||Enriched in HIV-1 controllers |
|PSORS1C3 ||rs3131018-A ||May affect HLA class I peptide presentation ||Enriched in HIV-1 controllers |
|ZNRD1 ||rs9261174-C ||Possible interference in processing of HIV transcripts; influencing ZNRD1 expression; linkage disequilibrium with HLA-A10 ||Slower disease progression to AIDS |
|Chemokine Receptors |
|CCR5 || |
32-bp deletion in the ORF (Δ32), rs333
Promoter SNPs, haplotypes (HHA to HHG*2)
Truncated CCR5 protein
Altered CCR5 expression, e.g., HHE haplotype correlates with high CCR5 expression
Δ32/Δ32: resistance to acquiring HIV infection
Δ32/wild type: delays AIDS onset; improves immune reconstitution during ART
HHE/HHE: increased HIV/AIDS susceptibility
|CCR2 ||SNP in ORF (64 V→I), rs1799864 ||Possibly due to linkage with polymorphism in CCR5 promoter ||64I: delayed AIDS onset |
|CCRL2 || |
Coding SNP (167 Y→F)
Possibly due to linkage with CCR5 haplotype
Possibly due to linkage with CCR5 haplotype
167F is associated with accelerated progression to AIDS and more rapid development of PCP
Associated with high viral load set point
|CXCR6 ||rs2234358 G→T in the 3’UTR ||Trafficking of effector T cells and activation of NK T cells; minor HIV co-receptor ||Prevalence of rs2234358-T was lower in long-term nonprogressors and viremic controllers |
|CX3CR1 ||SNPs in ORF (249 V→I, rs3732379; and 280 T→M, rs3732378) ||280M reduces receptor expression and binding of fractalkine, the CX3CR1 ligand ||249I and 280M associated with faster AIDS onset in some Caucasian cohorts; inconsistent effects detected in other cohorts |
|DARC ||African-specific promoter SNP (–46T→C), rs2814778 ||–46C/C associates with low neutrophil counts; influences circulating chemokine levels; alters HIV binding to RBCs and transinfection of HIV-1 ||–46C/C: increased risk of acquiring HIV but slower HIV disease progression; Duffy-null-associated low neutrophil trait associated with increased HIV risk in persons of African descent |
|CCL3L, CCL4L ||Gene copy number of CCL3L and CCL4L ||High numbers of CCL3L and CCL4L gene-containing segmental duplications correlate with high CCL3L and CCL4L levels ||Gene copy number lower than population median associated with increased HIV/AIDS susceptibility and reduced immune reconstitution during ART |
|CCL5 ||Promoter SNPs ||Altered gene expression ||Altered HIV-AIDS susceptibility |
|CCL2 ||Promoter SNP (–2578 T→G), rs1024611 ||–2578G allele: increased CCL2 expression and monocyte recruitment ||–2578G/G associated with increased risk of developing HIV-1-associated dementia and rapid AIDS onset |
|IL-6 ||Promoter SNP (–174 G→C), rs1800795 ||–174G/G associated with increased IL-6 and CRP levels ||–174G/G associated with high risk of KS development and variable recovery of CD4 cells during ART |
|IL-7RA ||Coding SNP (244 T→I), rs6897932 ||244 I/I associated with increased signal transduction and proliferation in response to IL-7 ||244 I/I associated with faster CD4+ T cell recovery after ART initiation |
|IL-10 ||Promoter SNP (–592 C→A), rs1800872 ||–592A results in decreased IL-10 levels ||–592A associated with increased HIV-AIDS susceptibility |
|Innate Immunity Genes |
|MBL || |
Coding alleles (O)
X allele (promoter SNP –221)
Low plasma concentration and structural variation of MBL protein
Decreased levels of MBL protein
Slow progression to AIDS in heterozygous subjects (A/O)
Faster progression to AIDS in homozygous X/X subjects
|Apobec-3G ||ORF SNP (186 H→R), rs8177832 ||Reduced anti-HIV-1 activity ||186R associated with rapid AIDS onset in African Americans |
|Apobec-3F ||Haplotype tagged by ORF SNP (231 I→V), rs2076101 ||231V variant may influence Vif-mediated Apobec-3F degradation ||231V associated with lower VL, slower progression to AIDS and delayed progression to PCP |
|TLR7 ||ORF SNP (Gln11Leu), rs179008 ||Decreased expression of TLR7 leading to lack of recognition of HIV-infected cells ||Leu-containing protein associated with higher viral load and faster progression to AIDS |
|PARD3B ||rs11884476 (C→G), near exon 20 ||Direct interaction with HIV, signaling through SMAD family of proteins ||rs11884476-G associated with slower progression to AIDS |
|IFNL4 ||Frameshift mutation (TT→ΔG), rs368234815 ||Functional polymorphism in IFNL4 gene, possibly in linkage with IL28B variant and regulates IL-28B levels ||rs368234815-ΔG associated with higher prevalence of AIDS-defining illnesses and potentially increased HIV-1 infection risk |
|ApoE ||E4 allele ||E4 enhances HIV cell entry in vitro ||ApoE4/E4 associated with rapid AIDS onset and dementia |
|ApoL1/ MYH9 ||Several risk haplotypes, including G1 ||Unknown ||Increased risk for HIV-associated nephropathy |
|RYR3 ||ORF SNP (A →G), rs2229116 ||Unknown, potential impact on calcium signaling and homeostasis ||rs2229116-G associated with subclinical atherosclerosis |
|PROX1 ||rs17762192-G, 36kb upstream of PROX1 ||Unknown, presumably due to its impact on PROX1 expression, which is a negative regulator of IFN-γ ||rs17762192-G: reduced rate of disease progression |
|Gene–Gene Interaction |
|KIR+HLA || |
KIR3DS1 + HLA-Bw4-80Ile
HLA-C1 + KIR2DL3
Altered NK cell activity required to eliminate HIV-infected cells
Reduction of inhibitory KIR likely results in increased immune activation; impaired killing of latently infected cells; and a higher proviral burden
KIR3DS1 associated with HLA-Bw4-80Ile; +: delayed AIDS onset
HLA-C1+/KIR2DL3+: better immune recovery after viral load suppression on ART
|LILRB2+HLA ||LILRB2 + HLA class I ||Regulation of dendritic cells by LILRB2-HLA engagement ||Control of HIV-1 |
|CCL3L1+ CCR5 ||Low CCL3L1 gene copies + detrimental CCR5 genotypes ||Low CCL3L1 and high CCR5 expression ||Increased HIV/AIDS susceptibility and reduced immune reconstitution during ART |
CCR5 and MHC loci: two key regions that influence HIV-AIDS pathogenesis. Bottom: Manhattan plot of genome-wide association from >6000 HIV-infected Europeans. (Adapted from PJ McLaren et al: Proc Acad Natl Acad Sci 112:14658, 2015.) ∼8 million common variants were tested for their association with HIV viral load set point using linear regression. Genome-wide signals of association (p < 5 × 10–8, dotted line) were observed on chromosomes (Chr.) 6p21 in the MHC region and 3p21 in the CCR5 locus. Upper left: schema depicting composition of CCR5 haplotypes. (Adapted from E Gonzalez et al: Proc Natl Acad Sci USA 96:12004, 1999.) The 9 human haplotypes (HH) designated as HHA to HHG*2 were derived from the coding polymorphism of CCR2 64 V → I; 7 single nucleotide polymorphisms (SNPs) in the CCR5 promoter region as well as the Δ32 coding mutation in CCR5; wt, wild type. Carrington and colleagues refer to the CCR5-HHE haplotype as the P1 haplotype (MP Martin et al: Science 282:1907, 1998). Upper right: Representative haplotypes at Chr. 6p21 MHC region in Europeans. (Adapted from F Pereyra et al: Science 330:1551, 2010.) Haplotypes defined by the SNPs identified by genome-wide association studies, classic HLA alleles and amino acids in HLA-B and HLA-C that are associated with HIV viral control. Figure is not to scale and full references are in Table 197-6.
GENETICS OF CCR5: FROM BENCH TO BEDSIDE
While the discovery of CCR5 as a major co-receptor for cell entry of HIV-1 was established by in vitro studies, genetic association studies were required to establish its seminal role in HIV pathogenesis. Initial in vitro studies revealed that a 32-bp deletion (Δ32) in the coding region of CCR5 contributes to resistance to CCR5-using R5 strains of HIV. The CCR5 Δ32 allele encodes a truncated protein that is not expressed on the cell surface. Congruently, genotype-phenotype association studies in large cohorts demonstrated that individuals homozygous for the CCR5 Δ32 allele (Δ32/Δ32) lack CCR5 surface expression and are highly resistant to acquiring HIV infection; heterozygosity for the CCR5 Δ32 allele is associated with a lower risk of acquiring HIV.
The distribution of the CCR5 Δ32 allele is population specific. Approximately 1% of individuals of European ancestry are homozygous for the CCR5 Δ32 allele. Depending on the geographic region in Europe, up to 18% of individuals are heterozygous for the CCR5 Δ32 allele. The CCR5 Δ32 allele is rare in other populations. The evolutionary pressure that resulted in the emergence of the CCR5 Δ32 allele in the European population remains unknown and has been speculated to be secondary to an ancestral pandemic, such as the plague.
Subsequent studies identified single nucleotide polymorphisms (SNPs) in the promoter (regulatory) region of CCR5 that influence gene expression levels. Alleles bearing specific cassettes of linked polymorphisms (haplotypes) were identified and designated as human haplogroups A to G*2 (HHA to HHG*2) (Fig. 197-26). The CCR5 Δ32 polymorphism is found on the HHG*2 haplotype. CCR5 haplotypes A–D vs. E–G*2 differ by bearing GT versus AC at polymorphic sites rs1799987 and rs1799988 (Fig. 197-26). CCR5-HHA haplotype represents the ancestral haplotype (found in chimpanzees) and is associated with lower CCR5 gene expression, whereas the CCR5-HHE haplotype is associated with higher CCR5 expression. Methylation of DNA is a common epigenetic signaling mechanism that cells use to lock genes in the “off” position, and polymorphisms in CCR5 haplotypes may mediate their effects by influencing DNA methylation levels in the CCR5 locus. The CCR5-HHE and CCR5-HHA haplotypes are more sensitive and resistant, respectively, to T cell activation–induced demethylation of the CCR5 locus.
In worldwide populations, HHE and HHC are more prevalent, whereas the ancestral HHA haplotype is more common in persons of African ancestry. The associations of CCR5 haplotypes with HIV acquisition and/or HIV disease course are largely consistent with their effects on CCR5 gene expression. For example, homozygosity for the CCR5-HHE haplotype is associated with an increased risk of acquiring HIV, progressing rapidly to AIDS, and reduced immune recovery while the patient is on ART. The HHA haplotype is associated with slower disease progression in African populations and has been speculated to be a basis for why chimpanzees (who all carry the ancestral CCR5 HHA haplotype) naturally infected with simian immunodeficiency virus (SIV) may resist disease progression. The pairing of the HHC and CCR5 Δ32-bearing HHG*2 haplotypes (HHC/HHG*2 genotype) is associated with a lower risk of acquiring HIV infection and slower rate of HIV disease progression, whereas the pairing of the HHE haplotype with the HHG*2 haplotype is associated with the opposite effects. The CCR2-64I-bearing HHF*2 haplotype is associated with a slower HIV disease course.
Consistent with these genetic associations, polymorphisms in genes encoding ligands for CCR5 have also been demonstrated to associate with variable HIV susceptibility and disease progression rates. Examples include copy number variations of CCL3L1 and SNPs in CCL5. The sum of these studies established a pivotal role of CCR5 and its ligands in HIV-AIDS pathogenesis and, potentially, immune recovery.
The discovery that the CCR5 Δ32/Δ32 genotype is associated with strong resistance to HIV infection, and that uninfected Caucasians bearing this genotype did not appear to have impaired immunity, led to the development of two kinds of novel therapies. First, it spurred the development of a new class of therapies approved by the U.S. Food and Drug Administration (FDA), i.e., entry inhibitors (e.g., maraviroc) that block the interaction of CCR5 with the HIV envelope. Second, it led to the evaluation of novel experimental cellular therapies. An HIV-infected patient with acute myelogenous leukemia was given an allogeneic stem cell transplantation from an HLA-compatible person whose cells lacked expression of CCR5 due to the Δ32/Δ32 genotype. There has been no evidence of HIV-1 infection in the patient who underwent the transplant thus far (~10 years). This observation provided a “proof of concept” for an HIV cure and led to the development of additional novel cellular therapies involving autologous transplantation of CD4+ T cells in which the CCR5 gene is inactivated ex vivo using new gene editing procedures.
DISCOVERY OF HLA CLASS I ALLELES THAT ASSOCIATE WITH VIROLOGIC CONTROL OF HIV INFECTION
There is a strong association between variations within the HLA-B gene with protective (e.g., HLA-B*57 and B*27 alleles) or detrimental (e.g., HLA-B*35 allele) outcomes during HIV infection. Carriage of the HLA-B*57 and/or HLA-B*27 alleles is associated with slower disease progression. The beneficial effects of these alleles may relate in part to their consistent associations with a lower virologic set point as well as to higher cell-mediated immunity in HIV-infected persons. The protective effect of the HLA-B*57 and B*27 alleles on the HIV disease course is underscored by the finding that the prevalence of these alleles is higher among long-term nonprogressors and persons who control HIV replication spontaneously (elite controllers). In contrast, the HLA-B*35 allele has been associated with faster progression to AIDS and higher viral load. The prevalence of the HLA-B alleles differs between populations. HLA-B*57:01 in Europeans and HLA-B*57:03 in African Americans are the protective alleles. In some populations (e.g., Japanese) where the HLA-B*57/-B*27 alleles are absent, HLA-B*51 is associated with a protective phenotype.
Possession of the protective HLA-B alleles is associated with broader and stronger CD8+ T cell responses to HIV epitopes. The mechanisms underlying the differential effects of the HLA-B alleles on the course of HIV disease may relate to differences in the ability of antigen-presenting cells to present immunodominant HIV epitopes to T helper or cytotoxic T lymphocytes in the context of MHC-encoded molecules. This may result in differential immune responses that influence viral replication. In this regard, the HLA-B alleles that impact the course of HIV disease differ in their amino acid residues in the HLA-B peptide-binding groove; this may play a critical role in virologic control.
Investigators have also examined the influence of extended HLA haplotypes (linked alleles) on the course of HIV disease. The extended HLA ancestral haplotype (AH) 8.1 is defined by the presence of HLA-A1, HLA-B8, and HLA-DR3 alleles. AH 8.1 is the most common ancestral haplotype in Caucasians (present in 10%) and is associated with multiple autoimmune diseases in HIV-uninfected persons. These associations of AH 8.1 are thought to be due to a genetically determined hyperresponsiveness characterized by high TNF-α production and lack of complement C4A. Strong epidemiologic data indicate that carriage of AH 8.1 in HIV-infected persons is associated with a rapid decline in CD4+ T cells and faster progression to AIDS development. Gene–gene interactions between HLA alleles and other genes (e.g., killer cell immunoglobulin-like receptors) also may influence HIV disease progression rates.
POLYMORPHISMS IDENTIFIED BY GWAS THAT ASSOCIATE WITH HIV-1 ACQUSITION AND VIROLOGIC CONTROL
GWAS have not identified additional genetic variations that associate with risk of HIV-1 acquisition. By contrast, large-scale GWAS have identified SNPs, especially in the MHC, that influence HIV viral load, including in a large group of individuals termed “HIV controllers” who spontaneously (without ART) control viral replication. GWAS in HIV-infected persons of European ancestry identified four SNPs in genes in the HLA class I loci that associated with virologic control. These SNPs are within or in the vicinity of PSORS1C3, HLA-C, MICA, and HCP5 genes (Fig. 197-26). As noted in this figure, the individual effects of these alleles are difficult to discern because of linkage disequilibrium. The protective effects of the SNPs in HCP5 and MICA may relate to their linkage with known protective HLA-B alleles. The protective HCP5 allele is in linkage disequilibrium with the HLA-B*57:01 allele, and the protective MICA allele tags with the HLA-B*57:01 and B*27:05 alleles. The protective HLA-C SNP is associated with higher HLA-C expression, and this effect is thought to be due to the altered binding of a microRNA to the HLA-C mRNA. Higher HLA-C expression has been associated with beneficial HIV phenotypes. The mechanism associated with the SNP in PSORS1C3 is unknown. GWAS in African Americans identified a SNP that tags the HLA-B*57:03 allele that is known to associate with a lower virologic set point and slower disease course. Together, these GWAS data underscore the importance of variations in HLA class I loci in control of viral replication. A recent GWAS study suggested that an allele in the gene encoding CCRL2 influences the HIV viral load set point. CCRL2 is on chromosome 3p21 and resides ~30 kb downstream of the CCR5 loci; its effect could potentially be due to its linkage with the CCR5 haplotypes. Mathematical modeling revealed that variations in host genes may explain about 10% of the observed variability in HIV viral load, whereas viral genetic diversity may explain 29% of the variability.
GENETIC ASSOCIATIONS WITH SPECIFIC AIDS AND NON-AIDS CONDITIONS
Many of the non-AIDS events in HIV-infected individuals resemble those related to immune senescence and those found in the HIV-uninfected aging population. A functional SNP in the ryanodine receptor 3 (RYR3) gene was found to be associated with an increased risk of common carotid intima–media thickness (cIMT), which is a surrogate for subclinical atherosclerosis. Functional studies on RYR3 and its isoforms demonstrate a major role of these receptors in modulating endothelial function and atherogenesis via calcium signaling pathways, providing a biologically plausible mechanism by which the SNP in RYR3 may associate with increased cIMT risk.
HIV-1-associated nephropathy (HIVAN) is a form of focal sclerosing glomerulonephritis caused by direct infection of kidney epithelial cells with HIV. HIVAN is more common in persons of African descent. There is evidence that polymorphisms in the MYH9 gene and in the neighboring APOL1 gene are a strong determinant of susceptibility to HIVAN in African Americans. The effect of carrying two APOL1 risk alleles explains nearly 35% of HIVAN. The mechanisms by which MYH9/APOL1 variants predispose to HIVAN are currently unknown.
HIV-associated neurocognitive disorder
HIV-associated neurocognitive disorder (HAND) comprises a spectrum of neurocognitive deficits due to HIV infection. Variations in the apolipoprotein E (ApoE) gene have strong associations with Alzheimer’s disease in the HIV-uninfected population. In HIV-infected persons, possession of the ApoE4 allele has been associated with several cognitive outcomes, including dementia, peripheral neuropathy, and impairment in cognition and immediate and delayed verbal memory. Macrophage recruitment and activation play a central role in the development of many of the HAND syndromes. Variations in chemokines that play an influential role in macrophage activation and recruitment, namely CCL2 (MCP-1) and CCL3 (MIP-1α), have been shown to alter the risk of developing HAND. Variations in mitochondrial genes also have been associated with risk of AIDS and HAND. A GWAS identified a polymorphism in chromosome 14 in the T cell receptor α locus that may influence neurocognitive outcomes.
HIV-1 associated Pneumocystis pneumonia
Human Apobec3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades Apobec3 proteins. Association studies suggest a role of the genetic variation in the Apobec3 family in HIV disease. A common haplotype derived from 6 SNPs in the Apobec-3F gene and tagged by a codon-changing variant is associated with significantly lower viral load set point, slower rate of progression to AIDS, and delayed development of Pneumocystis pneumonia (PCP). In addition, a coding SNP in the CCRL2 gene is associated with accelerated progression to AIDS and more rapid development of PCP.
associations with ART-related adverse events
Abacavir, an effective antiretroviral agent, is associated with significant risk of hypersensitivity reactions (2–9% of cases). Interestingly, while the HLA-B*57:01 allele is associated with a slower HIV disease course, possession of this allele is associated with a higher risk of abacavir-associated hypersensitivity. Pharmacogenetic screening for the HLA-B*57:01 allele is recommended before initiation of abacavir treatment.
NEUROPATHOGENESIS IN HIV DISEASE
While there has been a remarkable decrease in the incidence of the severe forms of HIV encephalopathy among those with access to treatment in the era of effective cART, HIV-infected individuals can still experience milder forms of neurocognitive impairment despite adequate cART. Factors that contribute to the neurocognitive decline include lack of complete control of HIV replication in the brain; production of HIV proteins that may be neurotoxic; low CD4+ T cell nadir; chronic immune activation; comorbidities such as drug abuse, microvascular disease, older age, and diabetes; and the potential for neurotoxicity of certain antiretroviral drugs. HIV has been demonstrated in the brain and CSF of infected individuals with and without neuropsychiatric abnormalities. As opposed to lymphoid tissues, there are no resident lymphocytes in the brain. The main cell types that are infected in the brain in vivo are the perivascular macrophages and the microglial cells, which can sometimes form syncytia resulting in multinucleated giant cells; low-level viral replication is also seen in perivascular astrocytes. It has been proposed that monocytes that have already been infected in the blood can migrate into the brain, where they then reside as macrophages, or macrophages can be directly infected while residing within the brain. The precise mechanisms whereby HIV enters the brain are unclear; however, they are thought to relate, at least in part, to the ability of virus-infected and immune-activated macrophages to induce adhesion molecules such as E-selectin and vascular cell adhesion molecule 1 (VCAM-1) on brain endothelium. Other studies have demonstrated that HIV gp120 enhances the expression of intercellular adhesion molecule 1 (ICAM-1) in glial cells and HIV Tat protein can disrupt the tight junctions of the brain endothelial cells to facilitate entry of HIV-infected cells into the CNS. Virus isolates from the brain are preferentially R5 strains as opposed to X4 strains; in this regard, HIV-infected individuals who are heterozygous for CCR5-Δ32 appear to be relatively protected against the development of HIV encephalopathy. Once HIV enters the brain due to pressures of the local environment, it evolves to develop distinct sequences in the env, tat, and LTR genes. These unique sequences have been associated with neurocognitive dysfunction; however, it is unclear if they are causal (see below).
HIV-infected individuals may manifest white matter lesions as well as neuronal loss. The white matter lesions are due to axonal injury and a disruption of the blood-brain barrier and not due to demyelination. Given the absence of evidence of HIV infection of neurons, HIV-mediated effects on neurons are thought to involve indirect pathways whereby viral proteins, particularly gp120 and Tat, trigger the release of endogenous neurotoxins from macrophages and to a lesser extent from astrocytes. In addition, it has been demonstrated that both HIV-1 Nef and Tat can induce chemotaxis of leukocytes, including monocytes, into the CNS. Neurotoxins can be released from monocytes as a consequence of infection and/or immune activation. Monocyte-derived neurotoxic factors have been reported to kill neurons via a variety of mechanisms including activation of the N-methyl-D-aspartate (NMDA) receptors and induction of oxidative stress. In addition, HIV gp120 shed by virus-infected monocytes could cause neurotoxicity by antagonizing the function of vasoactive intestinal peptide (VIP), by elevating intracellular calcium levels, and by decreasing neurotrophic factor levels in the cerebral cortex. A variety of monocyte-derived cytokines can contribute directly or indirectly to the neurotoxic effects in HIV infection; these include TNF-α, IL-1, IL-6, TGF-β, IFN-γ, platelet-activating factor, and endothelin. Furthermore, among the CC-chemokines, elevated levels of monocyte chemotactic protein-1 (MCP-1 or CCL-2) in the brain and CSF have been shown to correlate best with the presence and degree of HIV encephalopathy in ART-naïve patients. In addition, infection and/or activation of monocyte-lineage cells can result in increased production of eicosanoids, quinolinic acid, nitric oxide, excitatory amino acids such as L-cysteine and glutamate, arachidonic acid, platelet activating factor, free radicals, TNF-α, and TGF-β, which may contribute to neurotoxicity. Astrocytes may play diverse roles in HIV neuropathogenesis. Reactive gliosis or astrocytosis has been demonstrated in the brains of HIV-infected individuals, and TNF-α and IL-6 have been shown to induce astrocyte proliferation. In addition, astrocyte-derived IL-6 can induce HIV expression in infected cells in vitro. Furthermore, it has been suggested that astrocytes may downregulate macrophage-produced neurotoxins. Evidence of neuronal injury can be demonstrated by measuring neurofilament levels in CSF. Treatment with cART leads to improvement in neuropsychiatric manifestations and a decrease in these cytokine levels in CSF, suggesting that they are driven by the virus or by its products. However, even in patients on long-term cART, there may be evidence of persistently activated lymphocytes in the CSF. It is unclear if these lymphocytes may contribute to neuronal injury in the brain or are critical for controlling the CNS viral reservoir. However, some individuals may develop a subacute encephalitis due to an IRIS reaction (see below). This often occurs weeks or a few months after initiation of cART in individuals with low CD4+ T cell counts. It is thought that the recovery of CD4+ T cells causes a lymphocyte response to the CNS HIV reservoir. The contribution of host genetic factors to development of neuropsychiatric manifestations of HIV infection has not been well studied. However, evidence supports the role of several genetic factors including the E4 allele for apoE in an increased risk of HIV-associated neurocognitive disorders and peripheral neuropathy.
It has also been suggested that the CNS may serve as a relatively sequestered site for a reservoir of latently infected cells that might be a barrier for the eradication of virus by cART (see “The HIV Reservoir: Obstacles to the Eradication of Virus,” above).
PATHOGENESIS OF KAPOSI’S SARCOMA
There are at least four distinct epidemiologic forms of KS: (1) the classic form that occurs in older men of predominantly Mediterranean or eastern European Jewish backgrounds with no recognized contributing factors; (2) the equatorial African form that occurs in all ages, also without any recognized precipitating factors; (3) the form associated with organ transplantation and its attendant iatrogenic immunosuppressed state; and (4) the form associated with HIV-1 infection. In the latter two forms, KS is an opportunistic disease; in HIV-infected individuals, unlike typical opportunistic infections, its occurrence is not strictly related to the level of depression of CD4+ T cell counts. The pathogenesis of KS is complex; fundamentally, it is an angioproliferative disease that is not a true neoplastic sarcoma, at least not in its early stages. It is a manifestation of excessive proliferation of spindle cells that are believed to be of vascular origin and have features in common with endothelial and smooth-muscle cells. In HIV disease the development of KS is dependent on the interplay of a variety of factors including HIV-1 itself, human herpes virus 8 (HHV-8), immune activation, and cytokine secretion. A number of epidemiologic and virologic studies have clearly linked HHV-8, which is also referred to as Kaposi’s sarcoma–associated herpesvirus (KSHV), to KS not only in HIV-infected individuals but also in individuals with the other forms of KS. HHV-8 is a γ-herpesvirus related to EBV and herpesvirus saimiri. It encodes a homologue to human IL-6 and, in addition to KS, has been implicated in the pathogenesis of body cavity lymphoma, multiple myeloma, and monoclonal gammopathy of undetermined significance. Sequences of HHV-8 are found universally in the lesions of KS, and patients with KS are virtually all seropositive for HHV-8. HHV-8 DNA sequences can be found in the B cells of 30–50% of patients with KS and 7% of patients with AIDS without clinically apparent KS.
Between 1% and 2% of eligible blood donors are positive for antibodies to HHV-8, while the prevalence of HHV-8 seropositivity in HIV-infected men is 30–35%. The prevalence of HHV-8 seropositivity in HIV-infected women is ~4%. This finding is reflective of the lower incidence of KS in women. It has been debated whether HHV-8 is actually the transforming agent in KS; the bulk of the cells in the tumor lesions of KS are not neoplastic cells. However, it has been demonstrated that endothelial cells can be transformed in vitro by HHV-8. In this regard, HHV-8 possesses a number of genes, including homologues of the IL-8 receptor, Bcl-2, and cyclin D, that can potentially transform the host cell. Despite the complexity of the pathogenic events associated with the development of KS in HIV-infected individuals, HHV-8 is the etiologic agent of this disease. The initiation and/or propagation of KS requires an activated state and is mediated, at least in part, by cytokines. A number of factors, including TNF-α, IL-1β, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), basic fibroblast growth factor, and oncostatin M, function in an autocrine and paracrine manner to sustain the growth and chemotaxis of the KS spindle cells. In this regard, KSHV-derived IL-6 has been demonstrated to induce proliferation of lymphoma cells and to inhibit the cytostatic effects of IFN-α on KSHV-infected lymphoma cells.
As detailed above and below, following the initial burst of viremia during primary infection, HIV-infected individuals mount robust immune responses that in most cases substantially curtail the levels of plasma viremia and likely contribute to delaying the ultimate development of clinically apparent disease for a median of 10 years in untreated individuals. This immune response contains elements of both humoral and cell-mediated immunity involving both adaptive and innate immune responses (Table 197-7; Fig. 197-27). It is directed against multiple antigenic determinants of the HIV virion as well as against viral proteins expressed on the surface of infected cells. Ironically, those CD4+ T cells with T cell receptors specific for HIV are theoretically those CD4+ T cells most likely to be activated—and thus to serve as early targets for productive HIV infection and the cell death or dysfunction associated with infection. Thus, an early consequence of HIV infection is interference with and decrease of the helper T cell population needed to generate an effective immune response.
TABLE 197-7Elements of the Immune Response to HIV ||Download (.pdf) TABLE 197-7 Elements of the Immune Response to HIV
Helper CD4+ T lymphocytes
Class I MHC–restricted cytotoxic CD8+ T lymphocytes
CD8+ T cell–mediated inhibition (noncytolytic)
Natural killer cells
Schematic representation of the different immunologic effector mechanisms thought to be active in the setting of HIV infection. Detailed descriptions are given in the text. ADCC, antibody-dependent cellular cytotoxicity; MHC, major histocompatibility complex; TCR, T cell receptor.
Although a great deal of investigation has been directed toward delineating and better understanding the components of this immune response, it remains unclear which immunologic effector mechanisms are most important in delaying progression of infection and which, if any, play a role in the pathogenesis of HIV disease. This lack of knowledge has also hampered the ability to develop an effective vaccine for HIV disease.
Antibodies to HIV usually appear within 3–6 weeks and almost invariably within 12 weeks of primary infection (Fig. 197-28); rare exceptions are in individuals who have defects in the ability to produce HIV-specific antibodies. Detection of these antibodies forms the basis of most diagnostic screening tests for HIV infection. The appearance of HIV-binding antibodies detected by ELISA and western blot assays occurs prior to the appearance of neutralizing antibodies; the latter generally appear following the initial decreases in plasma viremia and are more closely related to the appearance of HIV-specific CD8+ T lymphocytes. The first antibodies detected are those directed against the immunodominant region of the envelope gp41, followed by the appearance of antibodies to the structural or gag protein p24 and the gag precursor p55. Antibodies to p24 gag are followed by the appearance of antibodies to the outer envelope glycoprotein (gp120), the gag protein p17, and the products of the pol gene (p31 and p66). In addition, one may see antibodies to the low-molecular-weight regulatory proteins encoded by the HIV genes vpr, vpu, vif, rev, tat, and nef. On rare occasion, levels of HIV-specific antibodies may decline during treatment of acute HIV infection.
Relationship between initial HIV viremia and the development of antibodies to HIV. Within 3 to 6 weeks of initial HIV infection, non-neutralizing antibodies to HIV appear. These antibodies are capable of mediating antibody-dependent cellular cytotoxicity (ADCC). The decline in plasma viremia generally correlates with the appearance of cytotoxic T lymphocytes (CTL). After approximately 3 months, autologous neutralizing antibodies (NAbs) capable of neutralizing prior circulating strains of HIV appear. After 2 or more years, broadly reactive NAbs appear. (Adapted from JT Mascola, DC Montefiori: Annu Rev Immunol 28:413, 2010.)
While antibodies to multiple antigens of HIV are produced, the precise functional significance of these different antibodies is unclear. The only viral proteins that elicit neutralizing antibodies are the envelope proteins gp120 and gp41. Antibodies directed toward the envelope proteins of HIV have been characterized both as being protective and as possibly contributing to the pathogenesis of HIV disease. Among the protective antibodies are those that function to neutralize HIV directly and prevent the spread of infection to additional cells, as well as those that participate in ADCC. The first neutralizing antibodies are directed against the autologous infecting virus and appear after approximately 12 to 24 weeks of infection. Due to its high rate of mutation the virus is usually able to quickly escape these (and subsequent) neutralizing antibodies. One important mechanism of immune escape is the addition of N-linked glycosylation sites, forming a glycan shield that interferes with envelope recognition by these initial antibodies.
A number of broad and potent HIV-neutralizing envelope-specific antibodies have been isolated from HIV-infected individuals in studies designed to better understand the host response to HIV infection. Approximately 20% of patients develop antibodies capable of neutralizing highly diverse strains. These usually appear 2 or more years following infection in the face of continual viremia. These studies have revealed at least five major sites within the HIV envelope trimer that are able to elicit broadly neutralizing antibodies. These sites include antibodies directed toward the CD4 binding site (CD4bs) of gp120, those binding glycan-dependent epitopes in the V1/V2 region of gp120, those near the base of the V3 region of gp120, those binding to the gp120/gp41 bridge, and those binding to the membrane-proximal region of gp41 (Fig. 197-29). Several of these antibodies contain unique features including high levels of somatic hypermutation, selective germline gene usage (especially for CD4bs antibodies), and long heavy chain complementary determining regions (especially CDRH3). Of note, while these antibodies are broadly neutralizing in vitro, their precise in vivo significance is unclear and the patients from whom they were derived demonstrate evidence of ongoing viral replication unless treated with cART.
Known targets of broadly neutralizing antibodies against HIV-1. (Adapted from PD Kwong, JR Mascola: Immunity 37:412, 2012.)
The other major class of protective antibodies are those that participate in ADCC, a form of cell-mediated immunity (Chap. 342) in which NK cells that bear Fc receptors are armed with specific anti-HIV antibodies that bind to the NK cells via their Fc portion. These armed NK cells then bind to and destroy cells expressing HIV antigens. The levels of anti-envelope antibodies capable of mediating ADCC are highest in the earlier stages of HIV infection. Antibodies to both gp120 and gp41 have been shown to participate in ADCC-mediated killing of HIV-infected cells. In vitro, IL-2 can augment ADCC-mediated killing.
In addition to playing a role in host defense, HIV-specific antibodies have also been implicated in disease pathogenesis. Antibodies directed to gp41, when present in low titer, have been shown in vitro to be capable of facilitating infection of cells through an Fc receptor–mediated mechanism known as antibody enhancement. Thus, the same regions of the envelope protein of HIV that give rise to antibodies capable of mediating ADCC can also elicit the production of antibodies that can facilitate infection of cells in vitro. In addition, it has been postulated that anti-gp120 antibodies that participate in the ADCC killing of HIV-infected cells might also kill uninfected CD4+ T cells if the uninfected cells had bound free gp120, a phenomenon referred to as bystander killing.
One of the most primitive components of the humoral immune system is the complement system (Chap. 342). This element of innate immunity consists of ~30 proteins that are found circulating in blood or associated with cell membranes. While HIV alone is capable of directly activating the complement cascade, the resulting lysis is weak due to the presence of host cell regulatory proteins captured in the virion envelope during budding. It is possible that complement-opsonized HIV virions have increased infectivity in a manner analogous to antibody-mediated enhancement.
Given that T cell–mediated immunity is known to play a major role in host defense against most viral infections (Chap. 342), it is generally thought to be an important component of the host immune response to HIV. T cell immunity can be divided into two major categories: that mediated by helper/inducer CD4+ T cells and that mediated by cytotoxic/immunoregulatory CD8+ T cells.
HIV-specific CD4+ T cells can be detected in the majority of HIV-infected patients through the use of flow cytometry to measure intracellular cytokine production in response to MHC class II tetramers pulsed with HIV peptides or through lymphocyte proliferation assays utilizing HIV antigens such as p24. These cells likely play a critical role in the orchestration of the immune response to HIV by providing help to HIV-specific B cells and CD8+ T cells. They may also be capable of directly killing HIV-infected cells. HIV-specific CD4+ T cells may be preferential targets of HIV infection by HIV-infected antigen-presenting cells during the generation of an immune response to HIV (Fig. 197-27). However, they also are likely to undergo clonal expansions in response to HIV antigens and thus survive as a population of cells. No clear correlations exist between levels of HIV-specific CD4+ T lymphocytes and plasma HIV RNA levels; however, in the setting of high viral loads, CD4+ T cell responses to HIV antigens appear to shift from one of proliferation and IL-2 production to one of IFN-γ production. Thus, while a reverse correlation exists between the level of p24-specific proliferation and levels of plasma HIV viremia, the nature of the causal relationship between these parameters is unclear.
MHC class I–restricted, HIV-specific CD8+ T cells have been identified in the peripheral blood of patients with HIV-1 infection. These cells include CTLs that produce perforins and T cells that can be induced by HIV antigens to express an array of cytokines such as IFN-γ, IL-2, MIP-1β, and TNF-α. CTLs have been identified in the peripheral blood of patients within weeks of HIV infection and prior to the appearance of plasma virus. The selective pressure they exert on the evolution of the population of circulating viruses reflects their potential role in control of HIV infection. These CD8+ T lymphocytes, through their HIV-specific antigen receptors, bind to and cause the lytic destruction of target cells bearing autologous MHC class I molecules presenting HIV antigens. Two types of CTL activity can be demonstrated in the peripheral blood or lymph node mononuclear cells of HIV-infected individuals. The first type directly lyses appropriate target cells in culture without prior in vitro stimulation (spontaneous CTL activity). The other type of CTL activity reflects the precursor frequency of CTLs (CTLp); this type of CTL activity can be demonstrated by stimulation of CD8+ T cells in vitro with a mitogen such as phytohemagglutinin or anti-CD3 antibody.
In addition to CTLs, CD8+ T cells capable of being induced by HIV antigens to express cytokines such as IFN-γ also appear in the setting of HIV-1 infection. It is not clear whether these are the same or different effector pools compared with those cells mediating cytotoxicity; in addition, the relative roles of each in host defense against HIV are not fully understood. It does appear that these CD8+ T cells are driven to in vivo expansion by HIV antigen. There is a direct correlation between levels of CD8+ T cells capable of producing IFN-γ in response to HIV antigens and plasma levels of HIV-1 RNA. Thus, while these cells are clearly induced by HIV-1 infection, their overall ability to control infection remains unclear. Multiple HIV antigens, including Gag, Env, Pol, Tat, Rev, and Nef, can elicit CD8+ T cell responses. Among patients who control viral replication in the absence of antiretroviral drugs are a subset of patients referred to as elite nonprogressors (see “Long-Term Survivors, Long-Term Nonprogressors, and Elite Controllers,” above) whose peripheral blood contains a population of CD8+ T cells that undergo substantial in vitro proliferation and perforin expression in response to HIV antigens. It is possible that these cells play an important role in HIV-specific host defense.
At least three other forms of cell-mediated immunity to HIV have been described: non-cytolytic CD8+ T cell–mediated suppression of HIV replication, ADCC, and NK cell activity. Non-cytolytic CD8+ T cell–mediated suppression of HIV replication refers to the ability of CD8+ T cells from an HIV-infected patient to inhibit the replication of HIV in tissue culture without killing infected targets. There is no requirement for HLA compatibility between the CD8+ T cells and the HIV-infected cells. This effector mechanism is thus nonspecific and appears to be mediated by soluble factor(s) including the CC-chemokines RANTES (CCL5), MIP-1α (CCL3), and MIP-1β (CCL4). These CC-chemokines are potent suppressors of HIV replication and operate at least in part via blockade of the HIV co-receptor (CCR5) for R5 (macrophage-tropic) strains of HIV-1 (see above). ADCC, as described above in relation to humoral immunity, involves the killing of HIV-expressing cells by NK cells armed with specific antibodies directed against HIV antigens. Finally, NK cells alone have been shown to be capable of killing HIV-infected target cells in tissue culture. This primitive cytotoxic mechanism of host defense is directed toward nonspecific surveillance for neoplastic transformation and viral infection through recognition of altered class I MHC molecules.
DIAGNOSIS AND LABORATORY MONITORING OF HIV INFECTION
The establishment of HIV as the causative agent of AIDS and related syndromes early in 1984 was followed by the rapid development of sensitive screening tests for HIV infection. By March 1985, blood donors in the United States were routinely screened for antibodies to HIV. In 1996, blood banks in the United States added the p24 antigen capture assay to the screening process to help identify the rare infected individuals who were donating blood in the time (up to 3 months) between infection and the development of antibodies. In 2002, the ability to detect early infection with HIV was further enhanced by the licensure of nucleic acid testing (NAT) as a routine part of blood donor screening. These refinements decreased the interval between infection and detection (window period) from 22 days for antibody testing to 16 days with p24 antigen testing and subsequently to 12 days with NAT. The development of sensitive assays for monitoring levels of plasma viremia ushered in a new era of being able to monitor the progression of HIV disease more closely. Utilization of these tests, coupled with the measurement of levels of CD4+ T lymphocytes in peripheral blood, is essential in the management of patients with HIV infection.
DIAGNOSIS OF HIV INFECTION
The CDC has recommended that screening for HIV infection be performed as a matter of routine health care. The diagnosis of HIV infection depends on the demonstration of antibodies to HIV and/or the direct detection of HIV or one of its components. As noted above, antibodies to HIV generally appear in the circulation 3–12 weeks following infection.
The standard blood screening tests for HIV infection are based on the detection of antibodies to HIV. A common platform is the ELISA, also referred to as an enzyme immunoassay (EIA). This solid-phase assay is an extremely good screening test with a sensitivity of >99.5%. Most diagnostic laboratories use commercial kits that contain antigens from both HIV-1 and HIV-2 and thus are able to detect antibodies to either. These kits use both natural and recombinant antigens and are continuously updated to increase their sensitivity to newly discovered species, such as group O viruses (Fig. 197-1). The fourth-generation EIA tests combine detection of antibodies to HIV with detection of the p24 antigen of HIV. EIA tests are generally scored as positive (highly reactive), negative (nonreactive), or indeterminate (partially reactive). While the EIA is an extremely sensitive test, it is not optimal with regard to specificity. This is particularly true in studies of low-risk individuals, such as volunteer blood donors. In this latter population, only 10% of EIA-positive individuals are subsequently confirmed to have HIV infection. Among the factors associated with false-positive EIA tests are antibodies to class II antigens (such as may be seen following pregnancy, blood transfusion, or transplantation), autoantibodies, hepatic disease, recent influenza vaccination, and acute viral infections. For these reasons, anyone suspected of having HIV infection based on a positive or inconclusive fourth-generation EIA result should have the result confirmed with a more specific assay such as an HIV-1- or HIV-2-specific antibody immunoassay, a western blot, or a plasma HIV RNA level. One can estimate whether an individual has a recent infection with HIV-1 by comparing the results on a standard EIA test that will score positive for all infected individuals with the results on an assay modified to be less sensitive (“detuned assay”) that will score positive for individuals with established HIV infection and negative for individuals with recent infection. In rare instances, an HIV-infected individual treated early in the course of infection may revert to a negative EIA. This does not indicate clearing of infection; rather, it signifies levels of ongoing exposure to virus or viral proteins insufficient to maintain a measurable antibody response. When these individuals have discontinued therapy, viruses and antibodies have reappeared.
While current CDC recommendations indicate that a positive fourth-generation assay confirmed by a second HIV-1- or HIV-2-specific immunoassay is adequate for diagnosis, many feel it is prudent to confirm diagnosis with a second platform test such as the western blot or HIV plasma RNA level. The western blot (Fig. 197-30) assay takes advantage of the fact that multiple HIV antigens of different, well-characterized molecular weights elicit the production of specific antibodies. These antigens can be separated on the basis of molecular weight, and antibodies to each component can be detected as discrete bands on the western blot. A negative western blot is one in which no bands are present at molecular weights corresponding to HIV gene products. In a patient with a positive or indeterminate EIA and a negative western blot, one can conclude with certainty that the EIA reactivity was a false positive. On the other hand, a western blot demonstrating antibodies to products of all three of the major genes of HIV (gag, pol, and env) is conclusive evidence of infection with HIV. Criteria established by the FDA in 1993 state that a western blot result is considered positive if antibodies exist to two of the three HIV proteins: p24, gp41, and gp120/160. Using these criteria, ~10% of all blood donors deemed positive for HIV-1 infection lacked an antibody band to the pol gene product p31. Some 50% of these blood donors were subsequently found to be false positives. Thus, the absence of the p31 band should increase the suspicion that one may be dealing with a false-positive test result. In this setting it is prudent to obtain additional confirmation with an RNA-based test for HIV-1 and/or a follow-up western blot. By definition, western blot patterns of reactivity that do not fall into the positive or negative categories are considered “indeterminate.” There are two possible explanations for an indeterminate western blot result. The most likely explanation in a low-risk individual is that the patient being tested has antibodies that cross-react with one of the proteins of HIV. The most common patterns of cross-reactivity are antibodies that react with p24 and/or p55. The least likely explanation in this setting is that the individual is infected with HIV and is in the process of mounting a classic antibody response. In either instance, the western blot should be repeated in 1 month to determine whether the indeterminate pattern is a pattern in evolution. In addition, one may attempt to confirm a diagnosis of HIV infection with one of the tests for HIV RNA (discussed below). While the western blot is an excellent confirmatory test for HIV infection in patients with a positive or indeterminate EIA, it is a poor screening test. Among individuals with a negative EIA and PCR for HIV, 20–30% may show one or more bands on western blot. While these bands are usually faint and represent cross-reactivity, their presence creates a situation in which other diagnostic modalities (such as DNA PCR, RT-PCR, or p24 antigen capture) must be employed to ensure that the bands do not indicate early HIV infection.
Western blot assay for detection of antibodies to HIV. A. Schematic representation of how a western blot is performed. B. Examples of patterns of western blot reactivity. In each instance the western blot strip contains antigens to HIV-1. The serum from the patient immunized to the HIV-1 envelope gp160 contains only antibodies to the HIV-1 envelope proteins. The serum from the patient with HIV-2 infection cross-reacts with both reverse transcriptase and gag gene products of HIV-1.
A guideline for the use of these serologic tests in attempting to make a diagnosis of HIV infection is depicted in Fig. 197-31. In patients in whom HIV infection is suspected, the appropriate initial test is the EIA. If the result is negative, unless there is strong reason to suspect early HIV infection (as in a patient exposed within the previous 3 months), the diagnosis is ruled out and retesting should be performed only as clinically indicated. If the EIA is indeterminate or positive, the test should be repeated. If the repeat is negative on two occasions, one can assume that the initial positive reading was due to a technical error in the performance of the assay and that the patient is negative. If the repeat is indeterminate or positive, one should proceed to the HIV-1 western blot. If the western blot is positive, the diagnosis is HIV-1 infection. If the western blot is negative, the EIA can be assumed to have been a false positive for HIV-1 and the diagnosis of HIV-1 infection is ruled out. It would also be prudent at this point to perform specific serologic testing for HIV-2 following the same type of algorithm. If the western blot for HIV-1 is indeterminate, it should be repeated in 4–6 weeks; in addition, one may proceed to a specific HIV-1 or HIV-2 antibody differentiation assay, HIV-1 RNA assay, or HIV-1 DNA PCR. If the HIV RNA assays are negative and there is no progression in the western blot, a diagnosis of HIV-1 is ruled out. If either HIV-1 RNA assay is positive and/or the HIV-1 western blot shows progression, a tentative diagnosis of HIV-1 infection can be made and later confirmed with a follow-up western blot demonstrating a positive pattern. In addition to these standard laboratory-based assays for detecting antibodies to HIV, a series of point-of-care tests can provide results in 1–60 min. Among the most popular of these is the OraQuick Rapid HIV-1 antibody test that can be run on blood, plasma, or saliva. The sensitivity and specificity of this test is ~99% when run on whole blood. Specificity remains the same but sensitivity drops to 98% when the test is run on saliva. While negative results from this test are adequate to rule out a diagnosis of HIV infection, a positive finding should be considered preliminary and confirmed with standard serologic testing, as described above. Two rapid test kits are licensed for home use. They are the OraQuick HIV test and the Home Access HIV-1 test system. A positive result with either of these tests should be followed with confirmatory testing by a healthcare professional.
Serologic tests for the diagnosis of HIV-1 or HIV-2 infection. A. Algorithm including the use of a western blot. *Stable indeterminate western blot 4–6 weeks later makes HIV infection unlikely. However, it should be repeated twice at 3-month intervals to rule out HIV infection. Alternatively, one may test for HIV-1 p24 antigen or HIV RNA. EIA, enzyme immunoassay. B. CDC algorithm not including the use of a western blot. (Adapted from stacks.cdc.gov/view/cdc/23446.)
A variety of laboratory tests are available for the direct detection of HIV or its components (Table 197-8). These tests may be of considerable help in making a diagnosis of HIV infection when the antibody determination assays or western blot results are indeterminate. In addition, the tests detecting levels of HIV RNA can be used to determine prognosis and to assess the response to antiretroviral therapies. The simplest, least expensive, and most rarely used of the direct detection tests is the p24 antigen capture assay. This is an EIA-type assay in which the solid phase consists of antibodies to the p24 antigen of HIV. It detects the viral protein p24 in the blood of HIV-infected individuals where it exists either as free antigen or complexed to anti-p24 antibodies. Overall, ~30% of individuals with untreated HIV infection have detectable levels of free p24 antigen. This increases to ~50% when samples are treated with a weak acid to dissociate antigen-antibody complexes. Throughout the course of HIV infection, an equilibrium exists between p24 antigen and anti-p24 antibodies. During the first few weeks of infection, before an immune response develops, there is a brisk rise in p24 antigen levels. After the development of anti-p24 antibodies, these levels decline. Late in the course of infection, when circulating levels of virus are high, p24 antigen levels also increase, particularly when detected by techniques involving dissociation of antigen-antibody complexes. The p24 antigen capture assay has its greatest use as a screening test for HIV infection in patients suspected of having the acute HIV syndrome (see below), as high levels of p24 antigen are present prior to the development of antibodies. Its use as a stand-alone test for routine blood donor screening for HIV infection has been replaced by use of NAT or “fourth-generation” assays that combine antigen and antibody testing. The ability to measure and monitor levels of HIV RNA in the plasma of patients with HIV infection has been of extraordinary value in furthering our understanding of the pathogenesis of HIV infection, in monitoring the response to cART, and in providing a diagnostic tool in settings where measurements of anti-HIV antibodies may be misleading, such as in acute infection and neonatal infection. Four assays are predominantly used for this purpose. They are reverse transcriptase PCR (RT-PCR; Amplicor and RealTime); branched DNA (bDNA; VERSANT); transcription-mediated amplification (TMA; APTIMA); and nucleic acid sequence–based amplification (NASBA; NucliSENS). These tests are of value in making a diagnosis of HIV infection, in establishing initial prognosis, and in monitoring the effects of therapy. In addition to the commercially available tests for measuring HIV RNA, DNA PCR assays are also employed by research laboratories for making a diagnosis of HIV infection by amplifying HIV proviral DNA from peripheral blood mononuclear cells. The commercially available RNA detection tests have a sensitivity of 40–80 copies of HIV RNA per milliliter of plasma. Research laboratory–based RNA assays can detect as few as one HIV RNA copy per milliliter, while the DNA PCR tests can detect proviral DNA at a frequency of one copy per 10,000–100,000 cells. Thus, these tests are extremely sensitive. One frequent consequence of a high degree of sensitivity is some loss of specificity, and false-positive results have been reported with each of these techniques. For this reason, a positive EIA with a confirmatory western blot or HIV RNA assay remains the “gold standard” for a diagnosis of HIV infection, and the interpretation of other test results must be done with this in mind.
TABLE 197-8Characteristics of Tests for Direct Detection of HIV ||Download (.pdf) TABLE 197-8 Characteristics of Tests for Direct Detection of HIV
|Test ||Technique ||Sensitivitya ||Cost/Testb |
|Immune complex–dissociated p24 antigen capture assay ||Measurement of levels of HIV-1 core protein in an EIA-based format following dissociation of antigen-antibody complexes by weak acid treatment ||Positive in 50% of patients; detects down to 15 pg/mL of p24 protein ||$1–2 |
|HIV RNA by PCR ||Target amplification of HIV-1 RNA via reverse transcription followed by PCR ||Reliable to 40 copies/mL of HIV RNA ||$75–150 |
|HIV RNA by bDNA ||Measurement of levels of particle-associated HIV RNA in a nucleic acid capture assay employing signal amplification ||Reliable to 50 copies/mL of HIV RNA ||$75–150 |
|HIV RNA by TMA ||Target amplification of HIV-1 RNA via reverse transcription followed by T7 RNA polymerase ||Reliable to 100 copies/mL of HIV RNA ||$225 |
|HIV RNA by NASBA ||Isothermal nucleic acid amplification with internal controls ||Reliable to 80 copies/mL of HIV RNA ||$75–150 |
In the RT-PCR technique, following DNAse treatment, a cDNA copy is made of all RNA species present in plasma. Because HIV is an RNA virus, this will result in the production of DNA copies of the HIV genome in amounts proportional to the amount of HIV RNA present in plasma. This cDNA is then amplified and characterized using standard PCR techniques, employing primer pairs that can distinguish genomic cDNA from messenger cDNA. The bDNA assay involves the use of a solid-phase nucleic acid capture system and signal amplification through successive nucleic acid hybridizations to detect small quantities of HIV RNA. Both tests can achieve a tenfold increase in sensitivity to 40–50 copies of HIV RNA per milliliter with a preconcentration step in which plasma undergoes ultracentrifugation to pellet the viral particles. In the TMA assay, a cDNA copy of viral RNA is made using primers that contain a promoter sequence for T7 RNA polymerase. T7 polymerase is then added to produce multiple copies of RNA amplicon from the DNA template. It is qualified at 100 copies/mL. The NASBA technique involves the isothermal amplification of a sequence within the gag region of HIV in the presence of internal standards and employs the production of multiple RNA copies through the action of T7-RNA polymerase. The resulting RNA species are quantitated through hybridization with a molecular beacon DNA probe that is quenched in the absence of hybridization. The lower limit of detection for the NucliSENS assay is 80 copies/mL.
In addition to being a diagnostic and prognostic tool, RT-PCR and DNA-PCR are also useful for amplifying defined areas of the HIV genome for sequence analysis and have become an important technique for studies of sequence diversity and microbial resistance to antiretroviral agents. In patients with a positive or indeterminate EIA test and an indeterminate western blot, and in patients in whom serologic testing may be unreliable (such as patients with hypogammaglobulinemia or advanced HIV disease), these tests for quantitating HIV RNA in plasma or detecting proviral DNA in peripheral blood mononuclear cells are valuable tools for making a diagnosis of HIV infection; however, they should be used for diagnosis only when standard serologic testing has failed to provide a definitive result.
LABORATORY MONITORING OF PATIENTS WITH HIV INFECTION
The epidemic of HIV infection and AIDS has provided the clinician with new challenges for integrating clinical and laboratory data to effect optimal patient management. The close relationship between clinical manifestations of HIV infection and CD4+ T cell count has made measurement of CD4+ T cell numbers a routine part of the evaluation of HIV-infected individuals. The discovery of HIV as the cause of AIDS led to the development of sensitive tests that allow one to monitor the levels of HIV in the blood. Determinations of peripheral blood CD4+ T cell counts and measurements of the plasma levels of HIV RNA provide a powerful set of tools for determining prognosis and monitoring response to therapy.
The CD4+ T cell count is the laboratory test generally accepted as the best indicator of the immediate state of immunologic competence of the patient with HIV infection. This measurement, which can be made directly or calculated as the product of the percentage of CD4+ T cells (determined by flow cytometry) and the total lymphocyte count (determined by the white blood cell count [WBC] multiplied by the lymphocyte differential percentage), has been shown to correlate very well with the level of immunologic competence. Patients with CD4+ T cell counts <200/μL are at high risk of disease from P. jirovecii, while patients with CD4+ T cell counts <50/μL are also at high risk of disease from CMV, mycobacteria of the M. avium complex (MAC), and/or T. gondii (Fig. 197-32). Once the CD4+ T cell count is <200/μL, patients should be placed on a regimen for P. jirovecii prophylaxis, and once the count is <50/μL, primary prophylaxis for MAC infection is indicated. As with any laboratory measurement, one may wish to obtain two determinations prior to any significant changes in patient management based on CD4+ T cell count alone. Patients with HIV infection should have CD4+ T cell measurements performed at the time of diagnosis and every 3–6 months thereafter. More frequent measurements should be made if a declining trend is noted. For patients who have been on cART for at least 2 years with HIV RNA levels persistently <50 copies/mL and CD4 counts >500/μl, the monitoring of the CD4 count is felt by many to be optional. There are a handful of clinical situations in which the CD4+ T cell count may be misleading. Patients with HTLV-1/HIV co-infection may have elevated CD4+ T cell counts that do not accurately reflect their degree of immune competence. In patients with hypersplenism or those who have undergone splenectomy, and in patients receiving medications that suppress the bone marrow such as IFN-α, the CD4+ T cell percentage may be a more reliable indication of immune function than the CD4+ T cell count. A CD4+ T cell percentage of 15 is comparable to a CD4+ T cell count of 200/μL.
Relationship between CD4+ T cell counts and the development of opportunistic diseases. Boxplot of the median (line inside the box), first quartile (bottom of the box), third quartile (top of the box), and mean (asterisk) CD4+ lymphocyte count at the time of the development of opportunistic disease. Can, candidal esophagitis; CMV, cytomegalovirus infection; Crp, cryptosporidiosis; Cry, cryptococcal meningitis; DEM, AIDS dementia complex; HSV, herpes simplex virus infection; HZos, herpes zoster; KS, Kaposi’s sarcoma; MAC, Mycobacterium avium complex bacteremia; NHL, non-Hodgkin’s lymphoma; PCP, primary Pneumocystis jirovecii pneumonia; PCP2, secondary P. jirovecii pneumonia; PML, progressive multifocal leukoencephalopathy; Tox, Toxoplasma gondii encephalitis; WS, wasting syndrome. (From RD Moore, RE Chaisson: Ann Intern Med 124:633, 1996.)
Facilitated by highly sensitive techniques for the precise quantitation of small amounts of nucleic acids, the measurement of serum or plasma levels of HIV RNA has become an essential component in the monitoring of patients with HIV infection. As discussed in “Diagnosis of HIV Infection,” above, the most commonly used technique is the RT-PCR assay. This assay generates data in the form of number of copies of HIV RNA per milliliter of serum or plasma and can reliably detect as few as 40 copies of HIV RNA per milliliter of plasma. Research-based assays can detect down to one copy per milliliter. While it is common practice to describe levels of HIV RNA below these cut-offs as “undetectable,” this is a term that should be avoided as it is imprecise and leaves the false impression that the level of virus is 0. By utilizing more sensitive, nested PCR techniques and by studying tissue levels of virus as well as plasma levels, HIV RNA can be detected in virtually every patient with HIV infection. The one notable exception to this is a patient who underwent cytoreductive therapy followed by a bone marrow transplant from a CCR5Δ32 homozygous donor.
Measurements of changes in HIV RNA levels over time have been of great value in delineating the relationship between levels of virus and rates of disease progression (Fig. 197-22), the rates of viral turnover, the relationship between immune system activation and viral replication, and the time to development of drug resistance. HIV RNA measurements are greatly influenced by the state of activation of the immune system and may fluctuate greatly in the setting of secondary infections or immunization. For these reasons, decisions based on HIV RNA levels should never be made on a single determination. Measurements of plasma HIV RNA levels should be made at the time of HIV diagnosis and every 3–6 months thereafter in the untreated patient. Following the initiation of therapy or any change in therapy, plasma HIV RNA levels should be monitored approximately every 4 weeks until the effectiveness of the therapeutic regimen is determined by the development of a new steady-state level of HIV RNA. In most instances of effective antiretroviral therapy the plasma level of HIV RNA will drop to <50 copies/mL within 6 months of the initiation of treatment. During therapy, levels of HIV RNA should be monitored every 3–6 months to evaluate the continuing effectiveness of therapy.
The availability of multiple antiretroviral drugs as treatment options has generated a great deal of interest in the potential for measuring the sensitivity of an individual’s HIV viral quasispecies to different antiretroviral agents. HIV resistance testing can be done through either genotypic or phenotypic measurements. In the genotypic assays, sequence analyses of the HIV genomes obtained from patients are compared with sequences of viruses with known antiretroviral resistance profiles. In the phenotypic assays, the in vivo growth of viral isolates obtained from the patient is compared with the growth of reference strains of the virus in the presence or absence of different antiretroviral drugs. A modification of this phenotypic approach utilizes a comparison of the enzymatic activities of the reverse transcriptase, protease, or integrase genes obtained by molecular cloning of patients’ isolates to the enzymatic activities of genes obtained from reference strains of HIV in the presence or absence of different drugs targeted to these genes. These tests are quite good in identifying those antiretroviral agents that have been utilized in the past and suggesting agents that may be of future value in a given patient. Resistance testing is recommended at the time of initial diagnosis and, if therapy is not initiated at that time, at the time of initiation of cART. Drug resistance testing is also indicated in the setting of virologic failure and should be performed while the patient is still on the failing regimen because of the propensity for the pool of HIV quasispecies to rapidly revert to wild-type in the absence of the selective pressures of cART. In the hands of experts, resistance testing enhances the short-term ability to decrease viral load by ~0.5 log compared with changing drugs merely on the basis of drug history. In addition to the use of resistance testing to help in the selection of new drugs in patients with virologic failure, it may also be of value in selecting an initial regimen for treatment of therapy-naïve individuals. This is particularly true in geographic areas with a high level of background resistance. The patient needs to have an HIV-1 RNA level above 500–1000 copies/mL for an accurate resistance determination. Resistance assays lose their consistency at lower levels of plasma viremia.
Co-Receptor Tropism Assays
Following the licensure of maraviroc as the first CCR5 antagonist for the treatment of HIV infection (see below), it became necessary to be able to determine whether a patient’s virus was likely to respond to this treatment. Patients tend to have CCR5-tropic virus early in the course of infection, with a trend toward CXCR4 viruses later in disease. The antiretroviral agent maraviroc is effective only against CCR5-tropic viruses. Because the genotypic determinants of cellular tropism are poorly defined, a phenotypic assay is necessary to determine this property of HIV. Two commercial assays, the Trofile assay (Monogram Biosciences) and the Phenoscript assay (VIRalliance), are available to make this determination. These assays clone the envelope regions of the patient’s virus into an indicator virus that is then used to infect target cells expressing either CCR5 or CXCR4 as their co-receptor. These assays take weeks to perform and are expensive. Another, less costly option is to obtain a genotypic assay of the V3 region of HIV-1 and then employ a computer algorithm to predict viral tropism from the sequence. While this approach is less expensive than the classic phenotypic assay, there are fewer data to validate its predictive value.
A variety of other laboratory tests have been studied as potential markers of HIV disease activity. Among these are quantitative culture of replication-competent HIV from plasma, peripheral blood mononuclear cells, or resting memory CD4+ T cells; circulating levels of β2-microglobulin, soluble IL-2 receptor, IgA, acid-labile endogenous IFN, or TNF-α; and the presence or absence of activation markers such as CD38, HLA-DR, and PD-1 on CD4+ or CD8+ T cells. Nonspecific serologic markers of inflammation and/or coagulation such as IL-6, D-dimer, and sCD14 have been shown to have a high correlation with all-cause mortality (Table 197-9). While these measurements have value as markers of disease activity and help to increase our understanding of the pathogenesis of HIV disease, they do not currently play a major role in the monitoring of patients with HIV infection.
TABLE 197-9Association Between High-Sensitivity CRP, Il-6, and D-Dimer with All-Cause Mortality in Patients with HIV Infection ||Download (.pdf) TABLE 197-9 Association Between High-Sensitivity CRP, Il-6, and D-Dimer with All-Cause Mortality in Patients with HIV Infection
| ||Unadjusted ||Adjusted |
|Marker ||Odds Ratio (Fourth/First) ||p ||Odds Ratio (Fourth/First) ||p |
|Hs-CRP ||2.0 ||.05 ||2.8 ||.03 |
|IL-6 ||8.3 ||<.0001 ||11.8 ||<.0001 |
|D-dimer ||12.4 ||<.0001 ||26.5 ||<.0001 |
The clinical consequences of HIV infection encompass a spectrum ranging from an acute syndrome associated with primary infection to a prolonged asymptomatic state to advanced disease. It is best to regard HIV disease as beginning at the time of primary infection and progressing through various stages. As mentioned above, active virus replication and progressive immunologic impairment occur throughout the course of HIV infection in most patients. With the exception of the rare, true, “elite” virus controllers or long-term nonprogressors (see “Long-Term Survivors, Long-Term Nonprogressors, and Elite Controllers,” above), HIV disease in untreated patients inexorably progresses even during the clinically latent stage. Since the mid-1990s, cART has had a major impact on preventing and reversing the progression of disease over extended periods of time in a substantial proportion of adequately treated patients. Today, a person diagnosed with HIV infection and treated with cART has a close to normal life expectancy.
It is estimated that 50–70% of individuals with HIV infection experience an acute clinical syndrome ~3–6 weeks after primary infection (Fig. 197-33). Varying degrees of clinical severity have been reported, and although it has been suggested that symptomatic seroconversion leading to the seeking of medical attention indicates an increased risk for an accelerated course of disease, there does not appear to be a correlation between the level of the initial burst of viremia in acute HIV infection and the subsequent course of disease. The typical clinical findings in the acute HIV syndrome are listed in Table 197-10; they occur along with a burst of plasma viremia. It has been reported that several symptoms of the acute HIV syndrome (fever, skin rash, pharyngitis, and myalgia) occur less frequently in those infected by injection drug use compared with those infected by sexual contact. The syndrome is typical of an acute viral syndrome and has been likened to acute infectious mononucleosis. Symptoms usually persist for one to several weeks and gradually subside as an immune response to HIV develops and the levels of plasma viremia decrease. Opportunistic infections have been reported during this stage of infection, reflecting the immunodeficiency that results from reduced numbers of CD4+ T cells and likely also from the dysfunction of CD4+ T cells owing to viral protein and endogenous cytokine-induced perturbations of cells (Table 197-5) associated with the extremely high levels of plasma viremia. The Fiebig staging system has been used to describe the different stages of acute HIV infection, ranging from Stage 1 (HIV RNA positive alone) to Stage VI (HIV RNA and full western blot positive). A number of immunologic abnormalities accompany the acute HIV syndrome, including multiphasic perturbations of the numbers of circulating lymphocyte subsets. The number of total lymphocytes and T cell subsets (CD4+ and CD8+) are initially reduced. An inversion of the CD4+/CD8+ T cell ratio occurs later because of a rise in the number of CD8+ T cells. In fact, there may be a selective and transient expansion of CD8+ T cell subsets, as determined by T cell receptor analysis (see above). The total circulating CD8+ T cell count may remain elevated or return to normal; however, CD4+ T cell levels usually remain somewhat depressed, although there may be a slight rebound toward normal. Lymphadenopathy occurs in ~70% of individuals with primary HIV infection. Most patients recover spontaneously from this syndrome and many are left with only a mildly depressed CD4+ T cell count that remains stable for a variable period before beginning its progressive decline; in some individuals, the CD4+ T cell count returns to the normal range. Approximately 10% of patients manifest a fulminant course of immunologic and clinical deterioration after primary infection, even after the disappearance of initial symptoms. In most patients, primary infection with or without the acute syndrome is followed by a prolonged period of clinical latency or smoldering low disease activity.
TABLE 197-10Clinical Findings in the Acute HIV Syndrome ||Download (.pdf) TABLE 197-10 Clinical Findings in the Acute HIV Syndrome
|General ||Neurologic |
| Fever || Meningitis |
| Pharyngitis || Encephalitis |
| Lymphadenopathy || Peripheral neuropathy |
| Headache/retroorbital pain || Myelopathy |
| Arthralgias/myalgias ||Dermatologic |
| Lethargy/malaise || Erythematous maculopapular rash |
| Anorexia/weight loss || Mucocutaneous ulceration |
| Nausea/vomiting/diarrhea || |
The acute HIV syndrome. See text for detailed description. (Adapted from G Pantaleo et al: N Engl J Med 328:327, 1993. Copyright 1993 Massachusetts Medical Society. All rights reserved.)
THE ASYMPTOMATIC STAGE—CLINICAL LATENCY
Although the length of time from initial infection to the development of clinical disease varies greatly, the median time for untreated patients is ~10 years. As emphasized above, HIV disease with active virus replication is ongoing and progressive during this asymptomatic period. The rate of disease progression is directly correlated with HIV RNA levels. Patients with high levels of HIV RNA in plasma progress to symptomatic disease faster than do patients with low levels of HIV RNA (Fig. 197-22). Some patients referred to as long-term nonprogressors show little if any decline in CD4+ T cell counts over extended periods of time. These patients generally have extremely low levels of HIV RNA; a subset, referred to as elite nonprogressors, exhibits HIV RNA levels <50 copies/mL. Certain other patients remain entirely asymptomatic despite the fact that their CD4+ T cell counts show a steady progressive decline to extremely low levels. In these patients, the appearance of an opportunistic disease may be the first manifestation of HIV infection. During the asymptomatic period of HIV infection, the average rate of CD4+ T cell decline is ~50/μL per year in an untreated patient. When the CD4+ T cell count falls to <200/μL, the resulting state of immunodeficiency is severe enough to place the patient at high risk for opportunistic infections and neoplasms and, hence, for clinically apparent disease.
Symptoms of HIV disease can appear at any time during the course of HIV infection. Generally speaking, the spectrum of illnesses that one observes changes as the CD4+ T cell count declines. The more severe and life-threatening complications of HIV infection occur in patients with CD4+ T cell counts <200/μL. A diagnosis of AIDS is made in any individual age 6 years and older with HIV infection and a CD4+ T cell count <200/μL (Stage 3, Table 197-2) and in anyone with HIV infection who develops one of the HIV-associated diseases considered to be indicative of a severe defect in cell-mediated immunity (Table 197-1). While the causative agents of the secondary infections are characteristically opportunistic organisms such as P. jirovecii, atypical mycobacteria, CMV, and other organisms that do not ordinarily cause disease in the absence of a compromised immune system, they also include several common bacterial and mycobacterial pathogens. Following the widespread use of cART and implementation of guidelines for the prevention of opportunistic infections (Table 197-11), the incidence of these secondary infections has decreased dramatically (Fig. 197-34). Overall, the clinical spectrum of HIV disease is constantly changing as patients live longer and new and better approaches to treatment and prophylaxis are developed. In addition to the classic AIDS-defining illnesses, patients with HIV infection also have an increase in several serious non-AIDS illnesses, including non-AIDS related cancers and cardiovascular, renal, and hepatic disease. Non-AIDS events dominate the disease burden for patients with HIV infection receiving cART (Table 197-4). In developed countries, AIDS-related illnesses are responsible for only ~25% of deaths in patients with HIV infection. A similar percentage of deaths are due to non-AIDS-defining malignancies, with cardiovascular disease and liver disease each accounting for approximately 15% of deaths. The physician providing care to a patient with HIV infection must be well versed in general internal medicine as well as HIV-related opportunistic diseases. In general, it should be stressed that a key element of treatment of symptomatic complications of HIV disease, whether they are primary or secondary, is achieving good control of HIV replication through the use of cART and instituting primary and secondary prophylaxis for opportunistic infections as indicated.
TABLE 197-11NIH/CDC/IDSA 2013 Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIV ||Download (.pdf) TABLE 197-11 NIH/CDC/IDSA 2013 Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIV
|Pathogen ||Indications ||First Choice(s) ||Alternatives |
|Recommended as Standard of Care for Primary and Secondary Prophylaxis |
|Pneumocystis jirovecii || |
CD4+ T cell count <200/μL
Prior bout of PCP
(TMP-SMX), 1 DS tablet qd PO
TMP-SMX, 1 SS tablet qd PO
Dapsone 50 mg bid PO or 100 mg/d PO
Dapsone 50 mg/d PO +
Pyrimethamine 50 mg/week PO +
Leucovorin 25 mg/week PO
(Dapsone 200 mg PO +
Pyrimethamine 75 mg PO +
Leucovorin 25 mg weekly PO)
Aerosolized pentamidine, 300 mg via Respirgard II nebulizer every month
Atovaquone 1500 mg/d PO
TMP-SMX 1 DS tablet 3×/week PO
| ||May stop prophylaxis if CD4+ T cell count >200/μL for ≥3 months || || |
|Mycobacterium tuberculosis Isoniazid sensitive || |
Skin test >5 mm
Positive IFN-γ release assay
Prior positive test without treatment
Close contact with case of active pulmonary TB
Same with high probability of exposure to drug-resistant TB
(Isoniazid 300 mg PO +
Pyridoxine 25 mg PO) qd × 9 months
Isoniazid 900 mg PO twice weekly
+ Pyridoxine 25 mg PO daily
× 9 months
|Rifabutin (dose adjusted based on cART regimen) or rifampin 600 mg PO qd × 4 months |
|Drug resistant ||Consult local public health authorities || || |
|Mycobacterium-avium complex ||CD4+ T cell count <50/μL || |
Azithromycin 1200 mg weekly PO or 600 mg twice weekly PO
Clarithromycin 500 mg bid PO
|Rifabutin (dose adjusted based on cART regimen) |
| ||Prior documented disseminated disease || |
Clarithromycin 500 mg bid PO +
Ethambutol 15 (mg/kg)/d PO
Azithromycin 500–600 mg/d PO +
Ethambutol 15 (mg/kg)/d PO
| ||May stop prophylaxis if CD4+ T cell count >100/μL for ≥6 months || || |
|Toxoplasma gondii ||TOXO IgG antibody positive and CD4+ T cell count <100/μL ||TMP-SMX 1 DS tablet PO qd || |
TMP-SMX 1 DS 3× weekly PO
TMP-SMX, 1 SS PO daily
Dapsone 50 mg/d PO +
Pyrimethamine 50 mg weekly PO +
Leucovorin 25 mg weekly PO
(Dapsone 200 mg PO +
Pyrimethamine 75 mg PO +
Leucovorin 25 mg PO) weekly
Atovaquone 1500 mg PO daily ±
(Pyrimethamine 25 mg PO +
Leucovorin 10 mg PO) daily
| ||Prior toxoplasmic encephalitis and CD4+ T cell count <200/μL || |
Sulfadiazine 2000–4000 mg in 2–4 divided doses daily PO +
Pyrimethamine 25–50 mg/d PO +
Leucovorin 10–25 mg/d PO
Clindamycin 600 mg q8h PO +
Pyrimethamine 25–50 mg/d PO +
Leucovorin 10–25 mg/d PO
TMP-SMX 1 DS tablet bid
Atovaquone 750–1500 mg PO bid ±
(Pyrimethamine 25 mg/d PO +
Leucovorin 10 mg/d PO) or Sulfadiazine 2000–4000 mg/d (in 2–4 divided doses) PO
|Toxoplasma gondii ||May stop prophylaxis if CD4+ T cell count >200/μL for ≥3 months || || |
|Varicella zoster virus ||Significant exposure to chickenpox or shingles in a patient with no history of immunization or prior exposure to either ||Varicella zoster immune globulin, IM, within 10 d of exposure (800-843-7477) || |
Acyclovir 800 mg PO 5 × day for 5–7 days
Valacyclovir 1 g PO tid for 5–7 days
|Cryptococcus neoformans ||Prior documented disease ||Fluconazole 200 mg/d PO ||Itraconazole 200 mg/d PO |
| ||May stop prophylaxis if CD4+ T cell count >100/μL, no evidence of active fungal infection, and HIV RNA levels <500 copies/mL for >3 months || || |
|Histoplasma capsulatum ||Prior documented disease or CD4+ T cell count <150μL and high risk (endemic area or occupational exposure) ||Itraconazole 200 mg bid PO ||Fluconazole 400 mg/d PO |
| ||May stop prophylaxis after 1 year if CD4+ T cell count >150/μL and patient on cART for ≥6 months || || |
|Coccidioides immitis ||Prior documented disease or positive serology and CD4+ T cell count <250/μL if from a disease endemic area. (For this indication prophylaxis can be stopped if CD4+ T cell count ≥250 for 6 months.) ||Fluconazole 400 mg/d PO || |
|Penicillium marneffei || |
Prior documented disease
Patients with CD4+T cell counts <100 who live or stay in northern Thailand, Southern China, or Vietnam
|Itraconazole 200 mg/d PO ||Fluconazole 400 mg PO once weekly |
| ||May stop secondary prophylaxis in patients on ARV therapy with CD4+ T cell count >100/μL for ≥6 months || || |
|Salmonella species ||Prior recurrent bacteremia ||Ciprofloxacin 500 mg bid PO for ≥6 months || |
|Bartonella ||Prior infection || |
Doxycycline 200 mg/d PO
Azithromycin 1200 mg weekly PO
Clarithromycin 500 mg bid PO
| ||May stop if CD4+ T cell count >200/μL for >3 months || || |
|Cytomegalovirus ||Prior end-organ disease ||Valganciclovir 900 mg bid PO || |
Cidofovir 5 mg/kg every other week IV +
Foscarnet 90–120 (mg/kg)/d IV
| || |
May stop prophylaxis if CD4+ T cell count >100/μL for 6 months and no evidence of active CMV disease
Restart if prior retinitis and CD4+ T cells <100/μL
| || |
|Immunizations Generally Recommended |
|Hepatitis B virus ||All susceptible (anti-HBc- and anti-HBs-negative) patients ||Hepatitis B vaccine: 3 doses || |
|Hepatitis A virus ||All susceptible (anti-HAV-negative) patients ||Hepatitis A vaccine: 2 doses || |
|Influenza virus ||All patients annually ||Inactivated trivalent influenza virus vaccine 1 dose yearly || |
Oseltamivir 75 mg PO qd
Rimantadine or amantadine 100 mg PO bid (influenza A only)
|Streptococcus pneumoniae ||All patients, preferably before CD4+ T cell count ≤200/μL ||Pneumococcal conjugated vaccine (13) 0.5 mL IM × 1 followed in 8 weeks or more by pneumococcal polysaccharide vaccine (23) if CD4+ T cell count >200/μL || |
| ||Patients initially immunized at a CD4+ T cell count <100/μL whose CD4+ T cell count then increases to>200/μL ||Reimmunize || |
|Human papillomavirus ||All patients 13–26 years of age ||HPV vaccine; 3 doses || |
|Recommended for Prevention of Severe or Frequent Recurrences |
|Herpes simplex ||Frequent/severe recurrences || |
Valacyclovir 500 mg bid PO
Acyclovir 400 mg bid PO
Famciclovir 500 mg bid PO
|Candida ||Frequent/severe recurrences ||Fluconazole 100–200 mg/d PO ||Posaconazole 400 mg bid PO |
A. Decrease in the incidence of opportunistic infections and Kaposi’s sarcoma in HIV-infected individuals with CD4+ T cell counts <100/μL from 1992 through 1998. (Adapted and updated from FJ Palella et al: N Engl J Med 338:853, 1998, and JE Kaplan et al: Clin Infect Dis 30[S1]:S5, 2000, with permission.) B. Quarterly incidence rates of cytomegalovirus (CMV), Pneumocystis jirovecii pneumonia (PCP), and Mycobacterium avium complex (MAC) from 1995 to 2001. (From FJ Palella et al: AIDS 16:1617, 2002.)
Diseases of the Respiratory System
Acute bronchitis and sinusitis are prevalent during all stages of HIV infection. The most severe cases tend to occur in patients with lower CD4+ T cell counts. Sinusitis presents as fever, nasal congestion, and headache. The diagnosis is made by CT or MRI. The maxillary sinuses are most commonly involved; however, disease is also frequently seen in the ethmoid, sphenoid, and frontal sinuses. While some patients may improve without antibiotic therapy, radiographic improvement is quicker and more pronounced in patients who have received antimicrobial therapy. It is postulated that this high incidence of sinusitis results from an increased frequency of infection with encapsulated organisms such as H. influenzae and Streptococcus pneumoniae. In patients with low CD4+ T cell counts one may see mucormycosis infections of the sinuses. In contrast to the course of this infection in other patient populations, mucormycosis of the sinuses in patients with HIV infection may progress more slowly. In this setting aggressive, frequent local debridement in addition to local and systemic amphotericin B may result in effective treatment.
Pulmonary disease is one of the most frequent complications of HIV infection. The most common manifestation of pulmonary disease is pneumonia. Three of the 10 most common AIDS-defining illnesses are recurrent bacterial pneumonia, tuberculosis, and pneumonia due to the unicellular fungus P. jirovecii. Other major causes of pulmonary infiltrates include other mycobacterial infections, other fungal infections, nonspecific interstitial pneumonitis, KS, and lymphoma.
Bacterial pneumonia is seen with an increased frequency in patients with HIV infection, with 0.8–2.0 cases per 100 person-years. Patients with HIV infection are particularly prone to infections with encapsulated organisms. S. pneumoniae (Chap. 141) and H. influenzae (Chap. 152) are responsible for most cases of bacterial pneumonia in patients with AIDS. This may be a consequence of altered B cell function and/or defects in neutrophil function that may be secondary to HIV disease (see above). Pneumonias due to S. aureus (Chap. 142) and P. aeruginosa (Chap. 159) also are reported to occur with an increased frequency in patients with HIV infection. S. pneumoniae (pneumococcal) infection may be the earliest serious infection to occur in patients with HIV disease. This can present as pneumonia, sinusitis, and/or bacteremia. Patients with untreated HIV infection have a sixfold increase in the incidence of pneumococcal pneumonia and a 100-fold increase in the incidence of pneumococcal bacteremia. Pneumococcal disease may be seen in patients with relatively intact immune systems. In one study, the baseline CD4+ T cell count at the time of a first episode of pneumococcal pneumonia was ~300/μL. Of interest is the fact that the inflammatory response to pneumococcal infection appears proportional to the CD4+ T cell count. Due to this high risk of pneumococcal disease, immunization with the conjugated pneumococcal vaccine followed by booster immunization with the 23-valent pneumococcal polysaccharide vaccine is one of the generally recommended prophylactic measures for patients with HIV infection. This is likely most effective if given while the CD4+ T cell count is >200/μL and, if given to patients with lower CD4+ T cell counts, should be repeated once the count has been above 200 for 6 months. Although clear guidelines do not exist, it also makes sense to repeat immunization every 5 years. The incidence of bacterial pneumonia is cut in half when patients quit smoking.
Pneumocystis pneumonia (PCP), once the hallmark of AIDS, has dramatically declined in incidence following the development of effective prophylactic regimens and the widespread use of cART. It is, however, still the single most common cause of pneumonia in patients with HIV infection in the United States and can be identified as a likely etiologic agent in 25% of cases of pneumonia in patients with HIV infection, with an incidence in the range of 2–3 cases per 100 person-years. Approximately 30% of cases of HIV-associated PCP occur in patients who are unaware of their HIV status. The risk of PCP is greatest among those who have experienced a previous bout of PCP and those who have CD4+ T cell counts of <200/μL. Overall, 79% of patients with PCP have CD4+ T cell counts <100/μL and 95% of patients have CD4+ T cell counts <200/μL. Recurrent fever, night sweats, thrush, and unexplained weight loss also are associated with an increased incidence of PCP. For these reasons, it is strongly recommended that all patients with CD4+ T cell counts <200/μL (or a CD4 percentage <15) receive some form of PCP prophylaxis. The incidence of PCP is approaching zero in patients with known HIV infection receiving appropriate cART and prophylaxis. In the United States, primary PCP is now occurring at a median CD4+ T cell count of 36/μL, while secondary PCP is occurring at a median CD4+ T cell count of 10/μL. Patients with PCP generally present with fever and a cough that is usually nonproductive or productive of only scant amounts of white sputum. They may complain of a characteristic retrosternal chest pain that is worse on inspiration and is described as sharp or burning. HIV-associated PCP may have an indolent course characterized by weeks of vague symptoms and should be included in the differential diagnosis of fever, pulmonary complaints, or unexplained weight loss in any patient with HIV infection and <200 CD4+ T cells/μL. The most common finding on chest x-ray is either a normal film, if the disease is suspected early, or a faint bilateral interstitial infiltrate. The classic finding of a dense perihilar infiltrate is unusual in patients with AIDS. In patients with PCP who have been receiving aerosolized pentamidine for prophylaxis, one may see an x-ray picture of upper lobe cavitary disease, reminiscent of TB. Other less common findings on chest x-ray include lobar infiltrates and pleural effusions. Thin-section CT may demonstrate a patchy ground-glass appearance. Routine laboratory evaluation is usually of little help in the differential diagnosis of PCP. A mild leukocytosis is common, although this may not be obvious in patients with prior neutropenia. Elevation of lactate dehydrogenase is common. Arterial blood-gases may indicate hypoxemia with a decline in Pao2 and an increase in the arterial-alveolar (a–A) gradient. Arterial blood-gas measurements not only aid in making the diagnosis of PCP but also provide important information for staging the severity of the disease and directing treatment (see below). A definitive diagnosis of PCP requires demonstration of the organism in samples obtained from induced sputum, bronchoalveolar lavage, transbronchial biopsy, or open-lung biopsy. PCR has been used to detect specific DNA sequences for P. jirovecii in clinical specimens where histologic examinations have failed to make a diagnosis.
In addition to pneumonia, a number of other clinical problems have been reported in HIV-infected patients as a result of infection with P. jirovecii. Otic involvement may be seen as a primary infection, presenting as a polypoid mass involving the external auditory canal. In patients receiving aerosolized pentamidine for prophylaxis against PCP, one may see a variety of extrapulmonary manifestations of P. jirovecii. These include ophthalmic lesions of the choroid, a necrotizing vasculitis that resembles Buerger disease, bone marrow hypoplasia, and intestinal obstruction. Other organs that have been involved include lymph nodes, spleen, liver, kidney, pancreas, pericardium, heart, thyroid, and adrenals. Organ infection may be associated with cystic lesions that may appear calcified on CT or ultrasound.
The standard treatment for PCP or disseminated pneumocystosis is trimethoprim-sulfamethoxazole (TMP-SMX). A high (20–85%) incidence of side effects, particularly skin rash and bone marrow suppression, is seen with TMP-SMX in patients with HIV infection. Alternative treatments for mild to moderate PCP include dapsone/trimethoprim, clindamycin/primaquine, and atovaquone. IV pentamidine is the treatment of choice for severe disease in the patient unable to tolerate TMP-SMX. For patients with a Pao2 <70 mmHg or with an a–A gradient >35 mmHg, adjunct glucocorticoid therapy should be used in addition to specific antimicrobials. Overall, treatment should be continued for 21 days and followed by secondary prophylaxis. Prophylaxis for PCP is indicated for any HIV-infected individual who has experienced a prior bout of PCP, any patient with a CD4+ T cell count of <200/μL or a CD4 percentage <15, any patient with unexplained fever for >2 weeks, and any patient with a recent history of oropharyngeal candidiasis. The preferred regimen for prophylaxis is TMP-SMX, one double-strength tablet daily. This regimen also provides protection against toxoplasmosis and some bacterial respiratory pathogens. For patients who cannot tolerate TMP-SMX, alternatives for prophylaxis include dapsone plus pyrimethamine plus leucovorin, aerosolized pentamidine administered by the Respirgard II nebulizer, and atovaquone. Primary or secondary prophylaxis for PCP can be discontinued in those patients treated with cART who maintain good suppression of HIV (<50 copies/mL) and CD4+ T cell counts >200/μL for at least 3 months.
M. tuberculosis, once thought to be on its way to extinction in the United States, experienced a resurgence associated with the HIV epidemic (Chap. 173). Worldwide, approximately one-third of all AIDS-related deaths are associated with TB, and TB is the primary cause of death for 10–15% of patients with HIV infection. In the United States ~5% of AIDS patients have active TB. Patients with HIV infection are more likely to have active TB by a factor of 100 when compared with an HIV-negative population. For an asymptomatic HIV-negative person with a positive purified protein derivative (PPD) skin test, the risk of reactivation TB is around 1% per year. For the patient with untreated HIV infection, a positive PPD skin test, and no signs or symptoms of TB, the rate of reactivation TB is 7–10% per year. Untreated TB can accelerate the course of HIV infection. Levels of plasma HIV RNA increase in the setting of active TB and decline in the setting of successful TB treatment. Active TB is most common in patients 25–44 years of age, in African Americans and Hispanics, in patients in New York City and Miami, and in patients in developing countries. In these demographic groups, 20–70% of the new cases of active TB are in patients with HIV infection. The epidemic of TB embedded in the epidemic of HIV infection probably represents the greatest health risk to the general public and the health care profession associated with the HIV epidemic. In contrast to infection with atypical mycobacteria such as MAC, active TB often develops relatively early in the course of HIV infection and may be an early clinical sign of HIV disease. In one study, the median CD4+ T cell count at presentation of TB was 326/μL. The clinical manifestations of TB in HIV-infected patients are quite varied and generally show different patterns as a function of the CD4+ T cell count. In patients with relatively high CD4+ T cell counts, the typical pattern of pulmonary reactivation occurs: patients present with fever, cough, dyspnea on exertion, weight loss, night sweats, and a chest x-ray revealing cavitary apical disease of the upper lobes. In patients with lower CD4+ T cell counts, disseminated disease is more common. In these patients the chest x-ray may reveal diffuse or lower-lobe bilateral reticulonodular infiltrates consistent with miliary spread, pleural effusions, and hilar and/or mediastinal adenopathy. Infection may be present in bone, brain, meninges, GI tract, lymph nodes (particularly cervical lymph nodes), and viscera. Some patients with advanced HIV infection and active TB may have no symptoms of illness, and thus screening for TB should be part of the initial evaluation of every patient with HIV infection. Approximately 60–80% of HIV-infected patients with TB have pulmonary disease, and 30–40% have extrapulmonary disease. Respiratory isolation and a negative-pressure room should be used for patients in whom a diagnosis of pulmonary TB is being considered. This approach is critical to limit nosocomial and community spread of infection. Culture of the organism from an involved site provides a definitive diagnosis. Blood cultures are positive in 15% of patients. This figure is higher in patients with lower CD4 +T cell counts. In the setting of fulminant disease one cannot rely on the accuracy of a negative PPD skin test to rule out a diagnosis of TB. In addition, IFN-γ release assays may be difficult to interpret due to high backgrounds as a consequence of HIV-associated immune activation. TB is one of the conditions associated with HIV infection for which cure is possible with appropriate therapy. Therapy for TB is generally the same in the HIV-infected patient as in the HIV-negative patient (Chap. 173). Due to the possibility of multidrug-resistant or extensively drug-resistant TB, drug susceptibility testing should be performed to guide therapy. Due to pharmacokinetic interactions, adjusted doses of rifabutin and/or changes in cART are required when treating TB in the setting of HIV infection. Treatment is most effective in programs that involve directly observed therapy. Initiation of cART and/or anti-TB therapy may be associated with clinical deterioration due to immune reconstitution inflammatory syndrome (IRIS) reactions. These are most common in patients initiating both treatments at the same time, may occur as early as 1 week after initiation of cART therapy, and are seen more frequently in patients with advanced HIV disease. For these reasons it is recommended that initiation of cART be delayed in antiretroviral-naïve patients with CD4 counts >50 cells/μL until 2–4 weeks following the initiation of treatment for TB. For patients with lower CD4 counts the benefits of more immediate cART outweigh the risks of IRIS, and cART should be started as soon as possible in those patients. Effective prevention of active TB can be a reality if the health care professional is aggressive in looking for evidence of latent or active TB by making sure that all patients with HIV infection receive a PPD skin test or evaluation with an IFN-γ release assay. Anergy testing is not of value in this setting. Since these tests rely on the host mounting an immune response to M. tuberculosis, patients with CD4+ T cell counts <200 cells/μL should be retested if their CD4+ T cell counts rise to persistently above 200. Patients at risk of continued exposure to TB should be tested annually. HIV-infected individuals with a skin-test reaction of >5 mm, those with a positive IFN-γ release assay, or those who are close household contacts of persons with active TB should receive treatment with 9 months of isoniazid and pyridoxine.
Atypical mycobacterial infections are also seen with an increased frequency in patients with HIV infection. Infections with at least 12 different mycobacteria have been reported, including M. bovis and representatives of all four Runyon groups. The most common atypical mycobacterial infection is with M. avium or M. intracellulare species—the Mycobacterium avium complex (MAC). Infections with MAC are seen mainly in patients in the United States and are rare in Africa. It has been suggested that prior infection with M. tuberculosis decreases the risk of MAC infection. MAC infections probably arise from organisms that are ubiquitous in the environment, including both soil and water. There is little evidence for person-to-person transmission of MAC infection. The presumed portals of entry are the respiratory and GI tracts. MAC infection is a late complication of HIV infection, occurring predominantly in patients with CD4+ T cell counts of <50/μL. The average CD4+ T cell count at the time of diagnosis is 10/μL. The most common presentation is disseminated disease with fever, weight loss, and night sweats. At least 85% of patients with MAC infection are mycobacteremic, and large numbers of organisms can often be demonstrated on bone marrow biopsy. The chest x-ray is abnormal in ~25% of patients, with the most common pattern being that of a bilateral, lower-lobe infiltrate suggestive of miliary spread. Alveolar or nodular infiltrates and hilar and/or mediastinal adenopathy also can occur. Other clinical findings include endobronchial lesions, abdominal pain, diarrhea, and lymphadenopathy. Anemia and elevated liver alkaline phosphatase are common. The diagnosis is made by the culture of blood or involved tissue. The finding of two consecutive sputum samples positive for MAC is highly suggestive of pulmonary infection. Cultures may take 2 weeks to turn positive. Therapy consists of a macrolide, usually clarithromycin, with ethambutol. Some physicians elect to add a third drug from among rifabutin, ciprofloxacin, or amikacin in patients with extensive disease. Therapy is continued until resolution of clinical signs and symptoms, negative cultures, and CD4+ T cell counts >100/μL for 3–6 months in the setting of cART. Primary prophylaxis for MAC is indicated in patients with HIV infection and CD4+ T cell counts <50/μL (Table 197-11). This may be discontinued in patients in whom cART induces a sustained suppression of viral replication and an increase in CD4+ T cell count to >100/μL for ≥6 months.
Rhodococcus equi is a gram-positive, pleomorphic, acid-fast, non-spore-forming bacillus that can cause pulmonary and/or disseminated infection in patients with advanced HIV infection. Fever and cough are the most common presenting signs. Radiographically one may see cavitary lesions and consolidation. Blood cultures are often positive. Treatment is based on antimicrobial sensitivity testing.
Fungal infections of the lung, in addition to PCP, can be seen in patients with AIDS. Patients with pulmonary cryptococcal disease present with fever, cough, dyspnea, and, in some cases, hemoptysis. A focal or diffuse interstitial infiltrate is seen on chest x-ray in >90% of patients. In addition, one may see lobar disease, cavitary disease, pleural effusions, and hilar or mediastinal adenopathy. More than half of patients are fungemic, and 90% of patients have concomitant CNS infection. Coccidioides immitis is a mold that is endemic in the southwest United States. It can cause a reactivation pulmonary syndrome in patients with HIV infection. Most patients with this condition will have CD4+ T cell counts <250/μL. Patients present with fever, weight loss, cough, and extensive, diffuse reticulonodular infiltrates on chest x-ray. One may also see nodules, cavities, pleural effusions, and hilar adenopathy. While serologic testing is of value in the immunocompetent host, serologies are negative in 25% of HIV-infected patients with coccidioidal infection. Invasive aspergillosis is not an AIDS-defining illness and is generally not seen in patients with AIDS in the absence of neutropenia or administration of glucocorticoids. When it does occur, Aspergillus infection may have an unusual presentation in the respiratory tract of patients with AIDS, where it gives the appearance of a pseudomembranous tracheobronchitis. Primary pulmonary infection of the lung may be seen with histoplasmosis. The most common pulmonary manifestation of histoplasmosis, however, is in the setting of disseminated disease, presumably due to reactivation. In this setting respiratory symptoms are usually minimal, with cough and dyspnea occurring in 10–30% of patients. The chest x-ray is abnormal in ~50% of patients, showing either a diffuse interstitial infiltrate or diffuse small nodules, and the urine will often be positive for Histoplasma antigen.
Two forms of idiopathic interstitial pneumonia have been identified in patients with HIV infection: lymphoid interstitial pneumonitis (LIP) and nonspecific interstitial pneumonitis (NIP). LIP, a common finding in children, is seen in about 1% of adult patients with untreated HIV infection. This disorder is characterized by a benign infiltrate of the lung and is thought to be part of the polyclonal activation of lymphocytes seen in the context of HIV and EBV infections. Transbronchial biopsy is diagnostic in 50% of the cases, with an open-lung biopsy required for diagnosis in the remainder of cases. This condition is generally self-limited and no specific treatment is necessary. Severe cases have been managed with brief courses of glucocorticoids. Although rarely a clinical problem since the use of cART, evidence of NIP may be seen in up to half of all patients with untreated HIV infection. Histologically, interstitial infiltrates of lymphocytes and plasma cells in a perivascular and peribronchial distribution are present. When symptomatic, patients present with fever and nonproductive cough occasionally accompanied by mild chest discomfort. Chest x-ray is usually normal or may reveal a faint interstitial pattern. Similar to LIP, NIP is a self-limited process for which no therapy is indicated other than appropriate management of the underlying HIV infection. HIV-related pulmonary arterial hypertension (HIV-PAH) is seen in ~0.5% of HIV-infected individuals. Patients may present with an array of symptoms including shortness of breath, fatigue, syncope, chest pain, and signs of right-sided heart failure. Chest x-ray reveals dilated pulmonary vessels and right-sided cardiomegaly with right ventricular hypertrophy seen on electrocardiogram. cART does not appear to be of clear benefit, and the prognosis is quite poor with a median survival in the range of 2 years.
Neoplastic diseases of the lung including KS and lymphoma are discussed below in the section on neoplastic diseases.
Diseases of the Cardiovascular System
Heart disease is a relatively common postmortem finding in HIV-infected patients (25–75% in autopsy series). The most common form of heart disease is coronary heart disease. In one large series the overall rate of myocardial infarction (MI) was 3.5/1000 patient-years, 28% of these events were fatal, and MI was responsible for 7% of all deaths in the cohort. In patients with HIV infection, cardiovascular disease may be associated with classic risk factors such as smoking, a direct consequence of HIV infection, or a complication of cART. Patients with HIV infection have higher levels of triglycerides, lower levels of high-density lipoprotein cholesterol, and a higher prevalence of smoking than cohorts of individuals without HIV infection. The finding that the rate of cardiovascular disease events was lower in patients on antiretroviral therapy than in those randomized to undergo a treatment interruption identified a clear association between HIV replication and risk of cardiovascular disease. In one study, a baseline CD4+ T cell count of <500/μL was found to be an independent risk factor for cardiovascular disease comparable in magnitude to that attributable to smoking. While the precise pathogenesis of this association remains unclear, it is likely related to the immune activation and increased propensity for coagulation seen as a consequence of HIV replication. Exposure to HIV protease inhibitors and certain reverse transcriptase inhibitors has been associated with increases in total cholesterol and/or risk of MI. Any increases in the risk of death from MI resulting from the use of certain antiretrovirals must be balanced against the marked increases in overall survival brought about by these drugs.
Another form of heart disease associated with HIV infection is a dilated cardiomyopathy associated with congestive heart failure (CHF) referred to as HIV-associated cardiomyopathy. This generally occurs as a late complication of HIV infection and, histologically, displays elements of myocarditis. For this reason some have advocated treatment with IV immunoglobulin (IVIg). HIV can be directly demonstrated in cardiac tissue in this setting, and there is debate over whether it plays a direct role in this condition. Patients present with typical findings of CHF including edema and shortness of breath. Patients with HIV infection may also develop cardiomyopathy as side effects of IFN-α or nucleoside analogue therapy. These are reversible once therapy is stopped. KS, cryptococcosis, Chagas’ disease, and toxoplasmosis can involve the myocardium, leading to cardiomyopathy. In one series, most patients with HIV infection and a treatable myocarditis were found to have myocarditis associated with toxoplasmosis. Most of these patients also had evidence of CNS toxoplasmosis. Thus, MRI or double-dose contrast CT scan of the brain should be included in the workup of any patient with advanced HIV infection and cardiomyopathy.
A variety of other cardiovascular problems are found in patients with HIV infection. Pericardial effusions may be seen in the setting of advanced HIV infection. Predisposing factors include TB, CHF, mycobacterial infection, cryptococcal infection, pulmonary infection, lymphoma, and KS. While pericarditis is quite rare, in one series 5% of patients with HIV disease had pericardial effusions that were considered to be moderate or severe. Tamponade and death have occurred in association with pericardial KS, presumably owing to acute hemorrhage. Nonbacterial thrombotic endocarditis has been reported and should be considered in patients with unexplained embolic phenomena. IV pentamidine, when given rapidly, can result in hypotension as a consequence of cardiovascular collapse.
Diseases of the Oropharynx and Gastrointestinal System
Oropharyngeal and GI diseases are common features of HIV infection. They are most frequently due to secondary infections. In addition, oral and GI lesions may occur with KS and lymphoma.
Oral lesions, including thrush, hairy leukoplakia, and aphthous ulcers (Fig. 197-35), are particularly common in patients with untreated HIV infection. Thrush, due to Candida infection, and oral hairy leukoplakia, presumed due to EBV, are usually indicative of fairly advanced immunologic decline; they generally occur in patients with CD4+ T cell counts of <300/μL. In one study, 59% of patients with oral candidiasis went on to develop AIDS in the next year. Thrush appears as a white, cheesy exudate, often on an erythematous mucosa in the posterior oropharynx. While most commonly seen on the soft palate, early lesions are often found along the gingival border. The diagnosis is made by direct examination of a scraping for pseudohyphal elements. Culturing is of no diagnostic value, as patients with HIV infection may have a positive throat culture for Candida in the absence of thrush. Oral hairy leukoplakia presents as white, frondlike lesions, generally along the lateral borders of the tongue and sometimes on the adjacent buccal mucosa (Fig. 197-35). Despite its name, oral hairy leukoplakia is not considered a premalignant condition. Lesions are associated with florid replication of EBV. While usually more disconcerting as a sign of HIV-associated immunodeficiency than a clinical problem in need of treatment, severe cases have been reported to respond to topical podophyllin or systemic therapy with anti-herpesvirus agents. Aphthous ulcers of the posterior oropharynx also are seen with regularity in patients with untreated HIV infection (Fig. 197-35). These lesions are of unknown etiology and can be quite painful and interfere with swallowing. Topical anesthetics provide immediate symptomatic relief of short duration. The fact that thalidomide is an effective treatment for this condition suggests that the pathogenesis may involve the action of tissue-destructive cytokines. Palatal, glossal, or gingival ulcers may also result from cryptococcal disease or histoplasmosis.
Various oral lesions in HIV-infected individuals. A. Thrush. B. Hairy leukoplakia. C. Aphthous ulcer. D. Kaposi’s sarcoma.
Esophagitis (Fig. 197-36) may present with odynophagia and retrosternal pain. Upper endoscopy is generally required to make an accurate diagnosis. Esophagitis may be due to Candida, CMV, or HSV. While CMV tends to be associated with a single large ulcer, HSV infection is more often associated with multiple small ulcers. The esophagus may also be the site of KS and lymphoma. Like the oral mucosa, the esophageal mucosa may have large, painful ulcers of unclear etiology that may respond to thalidomide. While achlorhydria is a common problem in patients with HIV infection, other gastric problems are generally rare. Among the neoplastic conditions involving the stomach are KS and lymphoma.
Barium swallow of a patient with Candida esophagitis. The flow of barium along the mucosal surface is grossly irregular.
Infections of the small and large intestine leading to diarrhea, abdominal pain, and occasionally fever are among the most significant GI problems in HIV-infected patients. They include infections with bacteria, protozoa, and viruses.
Bacteria may be responsible for secondary infections of the GI tract. Infections with enteric pathogens such as Salmonella, Shigella, and Campylobacter are more common in men who have sex with men and are often more severe and more apt to relapse in patients with HIV infection. Patients with untreated HIV have approximately a 20-fold increased risk of infection with S. typhimurium. They may present with a variety of nonspecific symptoms including fever, anorexia, fatigue, and malaise of several weeks’ duration. Diarrhea is common but may be absent. Diagnosis is made by culture of blood and stool. Long-term therapy with ciprofloxacin is the recommended treatment. HIV-infected patients also have an increased incidence of S. typhi infection in areas of the world where typhoid is a problem. Shigella spp., particularly S. flexneri, can cause severe intestinal disease in HIV-infected individuals. Up to 50% of patients will develop bacteremia. Campylobacter infections occur with an increased frequency in patients with HIV infection. While C. jejuni is the strain most frequently isolated, infections with many other strains have been reported. Patients usually present with crampy abdominal pain, fever, and bloody diarrhea. Infection may also present as proctitis. Stool examination reveals the presence of fecal leukocytes. Systemic infection can occur, with up to 10% of infected patients exhibiting bacteremia. Most strains are sensitive to erythromycin. Abdominal pain and diarrhea may be seen with MAC infection.
Fungal infections may also be a cause of diarrhea in patients with HIV infection. Histoplasmosis, coccidioidomycosis, and penicilliosis have all been identified as a cause of fever and diarrhea in patients with HIV infection. Peritonitis has been seen with C. immitis.
Cryptosporidia, microsporidia, and Isospora belli (Chap. 224) are the most common opportunistic protozoa that infect the GI tract and cause diarrhea in HIV-infected patients. Cryptosporidial infection may present in a variety of ways, ranging from a self-limited or intermittent diarrheal illness in patients in the early stages of HIV infection to a severe, life-threatening diarrhea in severely immunodeficient individuals. In patients with untreated HIV infection and CD4+ T cell counts of <300/μL, the incidence of cryptosporidiosis is ~1% per year. In 75% of cases the diarrhea is accompanied by crampy abdominal pain, and 25% of patients have nausea and/or vomiting. Cryptosporidia may also cause biliary tract disease in the HIV-infected patient, leading to cholecystitis with or without accompanying cholangitis and pancreatitis secondary to papillary stenosis. The diagnosis of cryptosporidial diarrhea is made by stool examination or biopsy of the small intestine. The diarrhea is noninflammatory, and the characteristic finding is the presence of oocysts that stain with acid-fast dyes. Therapy is predominantly supportive, and marked improvements have been reported in the setting of effective cART. Treatment with up to 2000 mg/d of nitazoxanide (NTZ) is associated with improvement in symptoms or a decrease in shedding of organisms in about half of patients. Its overall role in the management of this condition remains unclear. Patients can minimize their risk of developing cryptosporidiosis by avoiding contact with human and animal feces, by not drinking untreated water from lakes or rivers, and by not eating raw shellfish.
Microsporidia are small, unicellular, obligate intracellular parasites that reside in the cytoplasm of enteric cells (Chap. 224). The main species causing disease in humans is Enterocytozoon bieneusi. The clinical manifestations are similar to those described for cryptosporidia and include abdominal pain, malabsorption, diarrhea, and cholangitis. The small size of the organism may make it difficult to detect; however, with the use of chromotrope-based stains, organisms can be identified in stool samples by light microscopy. Definitive diagnosis generally depends on electron-microscopic examination of a stool specimen, intestinal aspirate, or intestinal biopsy specimen. In contrast to cryptosporidia, microsporidia have been noted in a variety of extraintestinal locations, including the eye, brain, sinuses, muscle, and liver, and they have been associated with conjunctivitis and hepatitis. The most effective way to deal with microsporidia in a patient with HIV infection is to restore the immune system by treating the HIV infection with cART. Albendazole, 400 mg bid, has been reported to be of benefit in some patients.
I. belli is a coccidian parasite (Chap. 224) most commonly found as a cause of diarrhea in patients from tropical and subtropical regions. Its cysts appear in the stool as large, acid-fast structures that can be differentiated from those of cryptosporidia on the basis of size, shape, and number of sporocysts. The clinical syndromes of Isospora infection are identical to those caused by cryptosporidia. The important distinction is that infection with Isospora is generally relatively easy to treat with TMP-SMX. While relapses are common, a thrice-weekly regimen of TMP-SMX appears adequate to prevent recurrence.
CMV colitis was once seen as a consequence of advanced immunodeficiency in 5–10% of patients with AIDS. It is much less common with the advent of cART. CMV colitis presents as diarrhea, abdominal pain, weight loss, and anorexia. The diarrhea is usually nonbloody, and the diagnosis is achieved through endoscopy and biopsy. Multiple mucosal ulcerations are seen at endoscopy, and biopsies reveal characteristic intranuclear and cytoplasmic inclusion bodies. Secondary bacteremias may result as a consequence of thinning of the bowel wall. Treatment is with either ganciclovir or foscarnet for 3–6 weeks. Relapses are common, and maintenance therapy is typically necessary in patients whose HIV infection is poorly controlled. Patients with CMV disease of the GI tract should be carefully monitored for evidence of CMV retinitis.
In addition to disease caused by specific secondary infections, patients with HIV infection may also experience a chronic diarrheal syndrome for which no etiologic agent other than HIV can be identified. This entity is referred to as AIDS enteropathy or HIV enteropathy. It is most likely a direct result of HIV infection in the GI tract. Histologic examination of the small bowel in these patients reveals low-grade mucosal atrophy with a decrease in mitotic figures, suggesting a hyporegenerative state. Patients often have decreased or absent small-bowel lactase and malabsorption with accompanying weight loss.
The initial evaluation of a patient with HIV infection and diarrhea should include a set of stool examinations, including culture, examination for ova and parasites, and examination for Clostridium difficile toxin. Approximately 50% of the time this workup will demonstrate infection with pathogenic bacteria, mycobacteria, or protozoa. If the initial stool examinations are negative, additional evaluation, including upper and/or lower endoscopy with biopsy, will yield a diagnosis of microsporidial or mycobacterial infection of the small intestine ~30% of the time. In patients for whom this diagnostic evaluation is nonrevealing, a presumptive diagnosis of HIV enteropathy can be made if the diarrhea has persisted for >1 month. An algorithm for the evaluation of diarrhea in patients with HIV infection is given in Fig. 197-37.
Algorithm for the evaluation of diarrhea in a patient with HIV infection. HIV-associated enteropathy is a diagnosis of exclusion and can be made only after other, generally treatable, forms of diarrheal illness have been ruled out.
Rectal lesions are common in HIV-infected patients, particularly the perirectal ulcers and erosions due to the reactivation of HSV (Fig. 197-38). These lesions may appear quite atypical, as denuded skin without vesicles. They typically respond well to treatment with valacyclovir, famciclovir, or foscarnet. Other rectal lesions encountered in patients with HIV infection include condylomata acuminata, KS, and intraepithelial neoplasia (see below).
Severe, erosive perirectal herpes simplex in a patient with AIDS.
Diseases of the hepatobiliary system are a major problem in patients with HIV infection. It has been estimated that approximately 15% of the deaths of patients with HIV infection are related to liver disease. While this is predominantly a reflection of the problems encountered in the setting of co-infection with hepatitis B or C, it is also a reflection of the hepatic injury, ranging from hepatic steatosis to hypersensitivity reactions to immune reconstitution, that can be seen in the context of cART.
The prevalence of co-infection with HIV and hepatitis viruses varies by geographic region. In the United States, ~90% of HIV-infected individuals have evidence of infection with HBV; 6–14% have chronic HBV infection; 5–50% of patients are co-infected with HCV; and co-infections with hepatitis D, E, and/or G viruses are common. Among IV drug users with HIV infection, rates of HCV infection range from 70% to 95%. HIV infection has a significant impact on the course of hepatitis virus infection. It is associated with approximately a threefold increase in the development of persistent hepatitis B surface antigenemia. Patients infected with both HBV and HIV have decreased evidence of inflammatory liver disease. The presumption that this is due to the immunosuppressive effects of HIV infection is supported by the observations that this situation can be reversed, and one may see the development of more severe hepatitis following the initiation of effective cART. In studies of the impact of HIV on HBV infection, four- to tenfold increases in liver-related mortality rates have been noted in patients with HIV and active HBV infection compared to rates in patients with either infection alone. There is, however, only a slight increase in overall mortality rate in HIV-infected individuals who are also hepatitis B surface antigen (HBsAg)–positive. IFN-α is less successful as treatment for HBV in patients with HIV co-infection. Lamivudine, emtricitabine, adefovir/tenofovir/entecavir, and telbivudine alone or in combination are useful in the treatment of hepatitis B in patients with HIV infection. It is important to remember that all the above-mentioned drugs also have activity against HIV and should not be used alone in patients with HIV infection, in order to avoid the emergence of quasispecies of HIV resistant to these drugs. For this reason, the treatment of hepatitis B infection in a patient with HIV infection should always be done in the setting of cART. HCV infection is more severe in the patient with HIV infection; it does not appear to affect overall mortality rates in HIV-infected individuals when other variables such as age, baseline CD4+ T cell count, and use of cART are taken into account. In the setting of HIV and HCV co-infection, levels of HCV are approximately tenfold higher than in the HIV-negative patient with HCV infection. There is a 50% higher overall mortality rate with a five-fold increased risk of death due to liver disease in patients chronically infected with both HCV and HIV. Use of directly acting agents for the treatment of HCV leads to cure rates approaching 100%, even in patients with HIV co-infection. Successful treatment of HCV in HIV-infected patients decreases mortality. Hepatitis A virus infection is not seen with an increased frequency in patients with HIV infection. It is recommended that all patients with HIV infection who have not experienced natural infection be immunized with hepatitis A and/or hepatitis B vaccines. Infection with hepatitis G virus, also known as GB virus C, is seen in ~50% of patients with HIV infection. For reasons that are currently unclear, there are data to suggest that patients with HIV infection co-infected with this virus have a decreased rate of progression to AIDS.
A variety of other infections also may involve the liver. Granulomatous hepatitis may be seen as a consequence of mycobacterial or fungal infections, particularly MAC infection. Hepatic masses may be seen in the context of TB, peliosis hepatis, or fungal infection. Among the fungal opportunistic infections, C. immitis and Histoplasma capsulatum are those most likely to involve the liver. Biliary tract disease in the form of papillary stenosis or sclerosing cholangitis has been reported in the context of cryptosporidiosis, CMV infection, and KS. When no diagnosis can be made, the term AIDS cholangiopathy is used. Hemophagocytic lymphohistiocytosis of the liver has been seen in the setting of Hodgkin’s disease and may occur prior to diagnosis of the underlying neoplasm.
Many of the drugs used to treat HIV infection are metabolized by the liver and can cause liver injury. Fatal hepatic reactions have been reported with a wide array of antiretrovirals including nucleoside analogues, nonnucleoside analogues, and protease inhibitors. Nucleoside analogues work by inhibiting DNA synthesis. This can result in toxicity to mitochondria, which can lead to disturbances in oxidative metabolism. This may manifest as hepatic steatosis and, in severe cases, lactic acidosis and fulminant liver failure. It is important to be aware of this condition and to watch for it in patients with HIV infection receiving nucleoside analogues. It is reversible if diagnosed early and the offending agent(s) discontinued. Nevirapine has been associated with at times fatal fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure. Indinavir may cause mild to moderate elevations in serum bilirubin in 10–15% of patients in a syndrome similar to Gilbert’s syndrome. A similar pattern of hepatic injury may be seen with atazanavir. In the patient receiving cART with an unexplained increase in hepatic transaminases, strong consideration should be given to drug toxicity.
Pancreatic injury is most commonly a consequence of drug toxicity, notably that secondary to pentamidine or dideoxynucleosides. While up to half of patients in some series have biochemical evidence of pancreatic injury, <5% of patients show any clinical evidence of pancreatitis that is not linked to a drug toxicity.
Diseases of the Kidney and Genitourinary Tract
Diseases of the kidney or genitourinary tract may be a direct consequence of HIV infection, due to an opportunistic infection or neoplasm, or related to drug toxicity. Overall, microalbuminuria is seen in ~20% of untreated HIV-infected patients; significant proteinuria is seen in closer to 2%. The presence of microalbuminuria has been associated with an increase in all-cause mortality rate. HIV-associated nephropathy (HIVAN) was first described in IDUs and was initially thought to be IDU nephropathy in patients with HIV infection; it is now recognized as a true direct complication of HIV infection. Although the majority of patients with this condition have CD4+ T cell counts <200/μL, HIV-associated nephropathy can be an early manifestation of HIV infection and is also seen in children. Over 90% of reported cases have been in African-American or Hispanic individuals; the disease is not only more prevalent in these populations but also more severe and is the third leading cause of end-stage renal failure among African Americans age 20–64 in the United States. Proteinuria is the hallmark of this disorder. Edema and hypertension are rare. Ultrasound examination reveals enlarged, hyperechogenic kidneys. A definitive diagnosis is obtained through renal biopsy. Histologically, focal segmental glomerulosclerosis is present in 80%, and mesangial proliferation in 10–15% of cases. Prior to effective antiretroviral therapy, this disease was characterized by relatively rapid progression to end-stage renal disease. Patients with HIV-associated nephropathy should be treated for their HIV infection. Treatment with angiotensin-converting enzyme (ACE) inhibitors and/or prednisone, 60 mg/d, also has been reported to be of benefit in some cases. The incidence of this disease in patients receiving adequate cART has not been well defined; however, the impression is that it has decreased in frequency and severity. It is the leading cause of end-stage renal disease in patients with HIV infection.
Among the drugs commonly associated with renal damage in patients with HIV disease are pentamidine, amphotericin, adefovir, cidofovir, tenofovir, and foscarnet. TMP-SMX may compete for tubular secretion with creatinine and cause an increase in the serum creatinine level. The pharmacokinetic booster cobicistat, a component of several fixed-drug cART formulations, inhibits renal tubular secretion of creatinine leading to increased serum creatinine levels without a true decline in glomerular filtration rate. Sulfadiazine may crystallize in the kidney and result in an easily reversible form of renal shutdown, while indinavir or atazanavir may form renal calculi. Adequate hydration is the mainstay of treatment and prevention for these latter two conditions.
Genitourinary tract infections are seen with a high frequency in patients with HIV infection; they present with skin lesions, dysuria, hematuria, and/or pyuria and are managed in the same fashion as in patients without HIV infection. Infections with HSV are covered below (“Dermatologic Diseases”). Infections with T. pallidum, the etiologic agent of syphilis, play an important role in the HIV epidemic. In HIV-negative individuals, genital syphilitic ulcers as well as the ulcers of chancroid are major predisposing factors for heterosexual transmission of HIV infection. While most HIV-infected individuals with syphilis have a typical presentation, a variety of formerly rare clinical problems may be encountered in the setting of dual infection. Among them are lues maligna, an ulcerating lesion of the skin due to a necrotizing vasculitis; unexplained fever; nephrotic syndrome; and neurosyphilis. The most common presentation of syphilis in the HIV-infected patient is that of condylomata lata, a form of secondary syphilis. Neurosyphilis may be asymptomatic or may present as acute meningitis, neuroretinitis, deafness, or stroke. The rate of neurosyphilis may be as high as 1% in patients with HIV infection, and one should consider a lumbar puncture to look for neurosyphilis in all patients with HIV infection and secondary syphilis. As a consequence of the immunologic abnormalities seen in the setting of HIV infection, diagnosis of syphilis through standard serologic testing may be challenging. On the one hand, a significant number of patients have false-positive Venereal Disease Research Laboratory (VDRL) tests due to polyclonal B cell activation. On the other hand, the development of a new positive VDRL may be delayed in patients with new infections, and the anti–fluorescent treponemal antibody (anti-FTA) test may be negative due to immunodeficiency. Thus, dark-field examination of appropriate specimens should be performed in any patient in whom syphilis is suspected, even if the patient has a negative VDRL. Similarly, any patient with a positive serum VDRL test, neurologic findings, and an abnormal spinal fluid examination should be considered to have neurosyphilis and treated accordingly, regardless of the CSF VDRL result. In any setting, patients treated for syphilis need to be carefully monitored to ensure adequate therapy. Approximately one-third of patients with HIV infection will experience a Jarisch-Herxheimer reaction upon initiation of therapy for syphilis.
Vulvovaginal candidiasis is a common problem in women with HIV infection. Symptoms include pruritus, discomfort, dyspareunia, and dysuria. Vulvar infection may present as a morbilliform rash that may extend to the thighs. Vaginal infection is usually associated with a white discharge, and plaques may be seen along an erythematous vaginal wall. Diagnosis is made by microscopic examination of the discharge for pseudohyphal elements in a 10% potassium hydroxide solution. Mild disease can be treated with topical therapy. More serious disease can be treated with fluconazole. Other causes of vaginitis include Trichomonas and mixed bacteria.
Diseases of the Endocrine System and Metabolic Disorders
A variety of endocrine and metabolic disorders are seen in the context of HIV infection. These may be a direct consequence of HIV infection, secondary to opportunistic infections or neoplasms, or related to medication side effects. Between 33% and 75% of patients with HIV infection receiving thymidine analogues or protease inhibitors as a component of cART develop a syndrome often referred to as lipodystrophy, consisting of elevations in plasma triglycerides, total cholesterol, and apolipoprotein B, as well as hyperinsulinemia and hyperglycemia. Many of the patients have been noted to have a characteristic set of body habitus changes associated with fat redistribution, consisting of truncal obesity coupled with peripheral wasting (Fig. 197-39). Truncal obesity is apparent as an increase in abdominal girth related to increases in mesenteric fat, a dorsocervical fat pad (“buffalo hump”) reminiscent of patients with Cushing’s syndrome, and enlargement of the breasts. The peripheral wasting, or lipoatrophy, is particularly noticeable in the face and buttocks and by the prominence of the veins in the legs. These changes may develop at any time ranging from ~6 weeks to several years following the initiation of cART. Approximately 20% of the patients with HIV-associated lipodystrophy meet the criteria for the metabolic syndrome as defined by The International Diabetes Federation or The U.S. National Cholesterol Education Program Adult Treatment Panel III. The lipodystrophy syndrome has been reported in association with regimens containing a variety of different drugs, and while initially reported in the setting of protease inhibitor therapy, it appears that similar changes can also be induced by protease-sparing regimens. It has been suggested that the lipoatrophy changes are particularly severe in patients receiving the thymidine analogues stavudine and zidovudine. Current treatment guidelines avoid these drugs and recommend drugs with fewer of these side effects. National Cholesterol Education Program (NCEP) guidelines should be followed in the management of these lipid abnormalities (Chap. 400), and consideration should be given to changing the components of cART with avoidance of thymidine analogues (azidothymidine and stavudine) and offending protease inhibitors. Due to concerns regarding drug interactions, the most commonly utilized lipid-lowering agents in this setting are gemfibrozil and atorvastatin. In addition, lactic acidosis is associated with cART. This is most commonly seen with nucleoside analogue reverse transcriptase inhibitors and can be fatal.
Characteristics of lipodystrophy. A. Truncal obesity and buffalo hump. B. Facial wasting. C. Accumulation of intraabdominal fat on CT scan.
Patients with advanced HIV disease may develop hyponatremia due to the syndrome of inappropriate antidiuretic hormone (vasopressin) secretion (SIADH) as a consequence of increased free-water intake and decreased free-water excretion. SIADH is usually seen in conjunction with pulmonary or CNS disease. Low serum sodium may also be due to adrenal insufficiency; a concomitant high serum potassium should alert one to this possibility. Hyperkalemia may be secondary to adrenal insufficiency; HIV nephropathy; or medications, particularly trimethoprim and pentamidine. Hypokalemia may be seen in the setting of tenofovir or amphotericin therapy. Adrenal gland disease may be due to mycobacterial infections, CMV disease, cryptococcal disease, histoplasmosis, or ketoconazole toxicity. Iatrogenic Cushing’s syndrome with suppression of the hypothalamic-pituitary-adrenal axis may be seen with the use of local glucocorticoids (injected or inhaled) in patients receiving ritonavir. This is due to inhibition of the hepatic enzyme CYP3A4 by ritonavir leading to prolongation of the glucocorticoid half-life.
Thyroid function may be altered in 10–15% of patients with HIV infection. Both hypo- and hyperthyroidism may be seen. The predominant abnormality is subclinical hypothyroidism. In the setting of cART, up to 10% of patients have been noted to have elevated thyroid-stimulating hormone levels, suggesting that this may be a manifestation of immune reconstitution. Immune-reconstitution Graves’ disease may occur as a late (9–48 months) complication of cART. In advanced HIV disease, infection of the thyroid gland may occur with opportunistic pathogens, including P. jirovecii, CMV, mycobacteria, Toxoplasma gondii, and Cryptococcus neoformans. These infections are generally associated with a nontender, diffuse enlargement of the thyroid gland. Thyroid function is usually normal. Diagnosis is made by fine-needle aspirate or open biopsy.
Depending on the severity of disease, HIV infection is associated with hypogonadism in 20–50% of men. While this is generally a complication of underlying illness, testicular dysfunction may also be a side effect of ganciclovir therapy. In some surveys, up to two-thirds of patients report decreased libido and one-third complain of erectile dysfunction. Androgen-replacement therapy should be considered in patients with symptomatic hypogonadism. HIV infection does not seem to have a significant effect on the menstrual cycle outside the setting of advanced disease.
Immunologic and Rheumatologic Diseases
Immunologic and rheumatologic disorders are common in patients with HIV infection and range from excessive immediate-type hypersensitivity reactions (Chap. 347) to an increase in the incidence of reactive arthritis (Chap. 355) to conditions characterized by a diffuse infiltrative lymphocytosis. The occurrence of these phenomena is an apparent paradox in the setting of the profound immunodeficiency and immunosuppression that characterizes HIV infection and reflects the complex nature of the immune system and its regulatory mechanisms.
Drug allergies are the most significant allergic reactions occurring in HIV-infected patients and appear to become more common as the disease progresses. They occur in up to 65% of patients who receive therapy with TMP-SMX for PCP. In general, these drug reactions are characterized by erythematous, morbilliform eruptions that are pruritic, tend to coalesce, and are often associated with fever. Nonetheless, ~33% of patients can be maintained on the offending therapy, and thus these reactions are not an immediate indication to stop the drug. Anaphylaxis is extremely rare in patients with HIV infection, and patients who have a cutaneous reaction during a single course of therapy can still be considered candidates for future treatment or prophylaxis with the same agent. The one exception to this is the nucleoside analogue abacavir, where fatal hypersensitivity reactions have been reported with rechallenge. This hypersensitivity is strongly associated with the HLA-B5701 haplotype, and a hypersensitivity reaction to abacavir is an absolute contraindication to future therapy. For other agents, including TMP-SMX, desensitization regimens are moderately successful. While the mechanisms underlying these allergic-type reactions remain unknown, patients with HIV infection have been noted to have elevated IgE levels that increase as the CD4+ T cell count declines. The numerous examples of patients with multiple drug reactions suggest that a common pathway is involved.
HIV infection shares many similarities with a variety of autoimmune diseases, including a substantial polyclonal B cell activation that is associated with a high incidence of antiphospholipid antibodies, such as anticardiolipin antibodies, VDRL antibodies, and lupus-like anticoagulants. In addition, HIV-infected individuals have an increased incidence of antinuclear antibodies. Despite these serologic findings, there is no evidence that HIV-infected individuals have an increase in two of the more common autoimmune diseases, i.e., systemic lupus erythematosus and rheumatoid arthritis. In fact, it has been observed that these diseases may be somewhat ameliorated by the concomitant presence of HIV infection, suggesting that an intact CD4+ T cell limb of the immune response plays an integral role in the pathogenesis of these conditions. Similarly, there are anecdotal reports of patients with common variable immunodeficiency (Chap. 344), characterized by hypogammaglobulinemia, who have had a normalization of Ig levels following the development of HIV infection, suggesting a possible role for overactive CD4+ T cell immunity in certain forms of that syndrome. The one autoimmune disease that may occur with an increased frequency in patients with HIV infection is a variant of primary Sjögren’s syndrome (Chap. 354). Patients with HIV infection may develop a syndrome consisting of parotid gland enlargement, dry eyes, and dry mouth that is associated with lymphocytic infiltrates of the salivary gland and lung. One also can see peripheral neuropathy, polymyositis, renal tubular acidosis, and hepatitis. In contrast to Sjögren’s syndrome, in which the lymphocytic infiltrates are composed predominantly of CD4+ T cells, in patients with HIV infection the infiltrates are composed predominantly of CD8+ T cells. In addition, while patients with Sjögren’s syndrome are mainly women who have autoantibodies to Ro and La and who frequently have HLA-DR3 or B8 MHC haplotypes, HIV-infected individuals with this syndrome are usually African-American men who do not have anti-Ro or anti-La and who most often are HLA-DR5. This syndrome appears to be less common with the increased use of effective cART. The term diffuse infiltrative lymphocytosis syndrome (DILS) is used to describe this entity and to distinguish it from Sjögren’s syndrome.
Approximately one-third of HIV-infected individuals experience arthralgias; furthermore, 5–10% are diagnosed as having some form of reactive arthritis, such as Reiter’s syndrome or psoriatic arthritis as well as undifferentiated spondyloarthropathy (Chap. 355). These syndromes occur with increasing frequency as the competency of the immune system declines. This association may be related to an increase in the number of infections with organisms that may trigger a reactive arthritis with progressive immunodeficiency or to a loss of important regulatory T cells. Reactive arthritides in HIV-infected individuals generally respond well to standard treatment; however, therapy with methotrexate has been associated with an increase in the incidence of opportunistic infections and should be used with caution and only in severe cases.
HIV-infected individuals also experience a variety of joint problems without obvious cause that are referred to generically as HIV- or AIDS-associated arthropathy. This syndrome is characterized by subacute oligoarticular arthritis developing over a period of 1–6 weeks and lasting 6 weeks to 6 months. It generally involves the large joints, predominantly the knees and ankles, and is nonerosive with only a mild inflammatory response. X-rays are nonrevealing. Nonsteroidal anti-inflammatory drugs are only marginally helpful; however, relief has been noted with the use of intraarticular glucocorticoids. A second form of arthritis also thought to be secondary to HIV infection is called painful articular syndrome. This condition, reported as occurring in as many as 10% of AIDS patients, presents as an acute, severe, sharp pain in the affected joint. It affects primarily the knees, elbows, and shoulders; lasts 2–24 h; and may be severe enough to require narcotic analgesics. The cause of this arthropathy is unclear; however, it is thought to result from a direct effect of HIV on the joint. This condition is reminiscent of the fact that other lentiviruses, in particular the caprine arthritis-encephalitis virus, are capable of directly causing arthritis.
A variety of other immunologic or rheumatologic diseases have been reported in HIV-infected individuals, either de novo or in association with opportunistic infections or drugs. Using the criteria of widespread musculoskeletal pain of at least 3 months’ duration and the presence of at least 11 of 18 possible tender points by digital palpation, 11% of an HIV-infected cohort containing 55% IDUs were diagnosed as having fibromyalgia (Chap. 366). While the incidence of frank arthritis was less in this population than in other studied populations that consisted predominantly of men who have sex with men, these data support the concept that there are musculoskeletal problems that occur as a direct result of HIV infection. In addition there have been reports of leukocytoclastic vasculitis in the setting of zidovudine therapy. CNS angiitis and polymyositis also have been reported in HIV-infected individuals. Septic arthritis is surprisingly rare, especially given the increased incidence of staphylococcal bacteremias seen in this population. When septic arthritis has been reported, it has usually been due to Staphylococcus aureus, systemic fungal infection with C. neoformans, Sporothrix schenckii, or H. capsulatum or to systemic mycobacterial infection with M. tuberculosis, M. haemophilum, M. avium, or M. kansasii.
Patients with HIV infection treated with cART have been found to have an increased incidence of osteonecrosis or avascular necrosis of the hip and shoulders. In a study of asymptomatic patients, 4.4% were found to have evidence of osteonecrosis on MRI. While precise cause-and-effect relationships have been difficult to establish, this complication has been associated with the use of lipid-lowering agents, systemic glucocorticoids, and testosterone; bodybuilding exercise; alcohol consumption; and the presence of anticardiolipin antibodies. Osteoporosis has been reported in 7% of women with HIV infection, with 41% of women demonstrating some degree of osteopenia. Several studies have documented decreases in bone mineral density of 2–6% in the first 2 years following the initiation of cART. This may be particularly apparent with tenofovir-containing regimens.
Immune Reconstitution Inflammatory Syndrome (IRIS)
Following the initiation of effective cART, a paradoxical worsening of preexisting, untreated, or partially treated opportunistic infections may be noted. One may also see exacerbations of pre-existing autoimmune conditions or the development of new autoimmune conditions following the initiation of antiretrovirals (Table 197-12). IRIS related to a known pre-existing infection or neoplasm is referred to as paradoxical IRIS, while IRIS associated with a previously undiagnosed condition is referred to as unmasking IRIS. The term immune reconstitution disease (IRD) is sometimes used to distinguish IRIS manifestations related to opportunistic diseases from IRIS manifestations related to autoimmune diseases. IRD is particularly common in patients with underlying untreated mycobacterial or fungal infections. Some form of IRIS is seen in 10–30% of patients, depending on the clinical setting, and is most common in patients starting therapy with CD4+ T cell counts <50 cells/μL who have a precipitous drop in HIV RNA levels following the initiation of cART. Signs and symptoms may appear anywhere from 2 weeks to 2 years after the initiation of cART and can include localized lymphadenitis, prolonged fever, pulmonary infiltrates, hepatitis, increased intracranial pressure, uveitis, sarcoidosis, and Graves’ disease. The clinical course can be protracted, and severe cases can be fatal. The underlying mechanism appears to be related to a phenomenon similar to type IV hypersensitivity reactions and reflects the immediate improvements in immune function that occur as levels of HIV RNA drop and the immunosuppressive effects of HIV infection are controlled. In severe cases, the use of immunosuppressive drugs such as glucocorticoids may be required to blunt the inflammatory component of these reactions while specific antimicrobial therapy takes effect.
TABLE 197-12Characteristics of Immune Reconstitution Inflammatory Syndrome (IRIS) ||Download (.pdf) TABLE 197-12 Characteristics of Immune Reconstitution Inflammatory Syndrome (IRIS)
|Paradoxical worsening of an existing clinical condition or abrupt appearance of a new clinical finding (unmasking) is seen following the initiation of antiretroviral therapy |
|Occurs weeks to months following the initiation of antiretroviral therapy |
|Is most common in patients starting therapy with a CD4+ T cell count <50/μL who experience a precipitous drop in viral load |
|Is frequently seen in the setting of tuberculosis; particularly when cART is starting soon after initiation of anti-TB therapy |
|Can be fatal |
Diseases of the Hematopoietic System
Disorders of the hematopoietic system including lymphadenopathy, anemia, leukopenia, and/or thrombocytopenia are common throughout the course of HIV infection and may be the direct result of HIV, manifestations of secondary infections and neoplasms, or side effects of therapy (Table 197-13). Direct histologic examination and culture of lymph node or bone marrow tissue are often diagnostic. A significant percentage of bone marrow aspirates from patients with HIV infection have been reported to contain lymphoid aggregates, the precise significance of which is unknown. Initiation of cART will lead to reversal of most hematologic complications that are the direct result of HIV infection.
TABLE 197-13Causes of Bone Marrow Suppression in Patients with HIV Infection ||Download (.pdf) TABLE 197-13 Causes of Bone Marrow Suppression in Patients with HIV Infection
Some patients, otherwise asymptomatic, may develop persistent generalized lymphadenopathy as an early clinical manifestation of HIV infection. This condition is defined as the presence of enlarged lymph nodes (>1 cm) in two or more extrainguinal sites for >3 months without an obvious cause. The lymphadenopathy is due to marked follicular hyperplasia in the node in response to HIV infection. The nodes are generally discrete and freely movable. This feature of HIV disease may be seen at any point in the spectrum of immune dysfunction and is not associated with an increased likelihood of developing AIDS. Paradoxically, a loss in lymphadenopathy or a decrease in lymph node size outside the setting of cART may be a prognostic marker of disease progression. In patients with CD4+ T cell counts >200/μL, the differential diagnosis of lymphadenopathy includes KS, TB, Castleman’s disease, and lymphoma. In patients with more advanced disease, lymphadenopathy may also be due to atypical mycobacterial infection, toxoplasmosis, systemic fungal infection, or bacillary angiomatosis. While indicated in patients with CD4+ T cell counts <200/μL, lymph node biopsy is not indicated in patients with early-stage disease unless there are signs and symptoms of systemic illness, such as fever and weight loss, or unless the nodes begin to enlarge, become fixed, or coalesce. Monoclonal gammopathy of unknown significance (MGUS) (Chap. 107), defined as the presence of a serum monoclonal IgG, IgA, or IgM in the absence of a clear cause, has been reported in 3% of patients with HIV infection. The overall clinical significance of this finding in patients with HIV infection is unclear, although it has been associated with other viral infections, non-Hodgkin’s lymphoma, and plasma cell malignancy.
Anemia is the most common hematologic abnormality in HIV-infected patients and, in the absence of a specific treatable cause, is independently associated with a poor prognosis. While generally mild, anemia can be quite severe and require chronic blood transfusions. Among the specific reversible causes of anemia in the setting of HIV infection are drug toxicity, systemic fungal and mycobacterial infections, nutritional deficiencies, and parvovirus B19 infections. Zidovudine may block erythroid maturation prior to its effects on other marrow elements. A characteristic feature of zidovudine therapy is an elevated mean corpuscular volume (MCV). Another drug used in patients with HIV infection that has a selective effect on the erythroid series is dapsone. This drug can cause a serious hemolytic anemia in patients who are deficient in glucose-6-phosphate dehydrogenase and can create a functional anemia in others through induction of methemoglobinemia. Folate levels are usually normal in HIV-infected individuals; however, vitamin B12 levels may be depressed as a consequence of achlorhydria or malabsorption. True autoimmune hemolytic anemia is rare, although ~20% of patients with HIV infection may have a positive direct antiglobulin test as a consequence of polyclonal B cell activation. Infection with parvovirus B19 may also cause anemia. It is important to recognize this possibility given the fact that it responds well to treatment with IVIg. Erythropoietin levels in patients with HIV infection and anemia are generally lower than expected given the degree of anemia. Treatment with erythropoietin may result in an increase in hemoglobin levels. An exception to this is a subset of patients with zidovudine-associated anemia in whom erythropoietin levels may be quite high.
During the course of HIV infection, neutropenia may be seen in approximately half of patients. In most instances it is mild; however, it can be severe and can put patients at risk of spontaneous bacterial infections. This is most frequently seen in patients with severely advanced HIV disease and in patients receiving any of a number of potentially myelosuppressive therapies. In the setting of neutropenia, diseases that are not commonly seen in HIV-infected patients, such as aspergillosis or mucormycosis, may occur. Both granulocyte colony-stimulating factor (G-CSF) and GM-CSF increase neutrophil counts in patients with HIV infection regardless of the cause of the neutropenia. Earlier concerns about the potential of these agents to also increase levels of HIV were not confirmed in controlled clinical trials.
Thrombocytopenia may be an early consequence of HIV infection. Approximately 3% of patients with untreated HIV infection and CD4+ T cell counts ≥400/μL have platelet counts <150,000/μL. For untreated patients with CD4+ T cell counts <400/μL, this incidence increases to 10%. In patients receiving antiretrovirals, thrombocytopenia is associated with hepatitis C, cirrhosis, and ongoing high-level HIV replication. Thrombocytopenia is rarely a serious clinical problem in patients with HIV infection and generally responds well to successful cART. Clinically, it resembles the thrombocytopenia seen in patients with idiopathic thrombocytopenic purpura (Chap. 111). Immune complexes containing anti-gp120 antibodies and anti-anti-gp120 antibodies have been noted in the circulation and on the surface of platelets in patients with HIV infection. Patients with HIV infection have also been noted to have a platelet-specific antibody directed toward a 25-kDa component of the surface of the platelet. Other data suggest that the thrombocytopenia in patients with HIV infection may be due to a direct effect of HIV on megakaryocytes. Whatever the cause, it is very clear that the most effective medical approach to this problem has been the use of cART. For patients with platelet counts <20,000/μL, a more aggressive approach combining IVIg or anti-Rh Ig for an immediate response and cART for a more lasting response is appropriate. Rituximab has been used with some success in otherwise refractory cases. Splenectomy is a rarely needed option and is reserved for patients refractory to medical management. Because of the risk of serious infection with encapsulated organisms, all patients with HIV infection about to undergo splenectomy should be immunized with pneumococcal polysaccharide. It should be noted that, in addition to causing an increase in the platelet count, removal of the spleen will result in an increase in the peripheral blood lymphocyte count, making CD4+ T cell counts unreliable markers of immunocompetence. In this setting, the clinician should rely on the CD4+ T cell percentage for making diagnostic decisions with respect to the likelihood of opportunistic infections. A CD4+ T cell percentage of 15 is approximately equivalent to a CD4+ T cell count of 200/μL. In patients with early HIV infection, thrombocytopenia has also been reported as a consequence of classic thrombotic thrombocytopenic purpura (Chap. 111). This clinical syndrome, consisting of fever, thrombocytopenia, hemolytic anemia, and neurologic and renal dysfunction, is a rare complication of early HIV infection. As in other settings, the appropriate management is the use of salicylates and plasma exchange. Other causes of thrombocytopenia include lymphoma, mycobacterial infections, and fungal infections.
The incidence of venous thromboembolic disease such as deep-vein thrombosis or pulmonary embolus is approximately 1% per year in patients with HIV infection. This is approximately 10 times higher than that seen in an age-matched population. Factors associated with an increased risk of clinical thrombosis include age over 45, history of an opportunistic infection, lower CD4 count, and estrogen use. Abnormalities of the coagulation cascade, including decreased protein S activity, increases in factor VIII, anticardiolipin antibodies, PAR-1 expression on T cells, or lupus-like anticoagulant, have been reported in more than 50% of patients with HIV infection. The clinical significance of this increased propensity toward thromboembolic disease is likely reflected in the observation that elevations in D-dimer are strongly associated with all-cause mortality in patients with HIV infection (Table 197-9).
Dermatologic problems occur in >90% of patients with HIV infection. From the macular, roseola-like rash seen with the acute seroconversion syndrome to extensive end-stage KS, cutaneous manifestations of HIV disease can be seen throughout the course of HIV infection. Among the more common nonneoplastic problems are seborrheic dermatitis, folliculitis, and opportunistic infections. Extrapulmonary pneumocystosis may cause a necrotizing vasculitis. Neoplastic conditions are covered in a separate section below.
Seborrheic dermatitis occurs in 3% of the general population and in up to 50% of patients with HIV infection. Seborrheic dermatitis increases in prevalence and severity as the CD4+ T cell count declines. In HIV-infected patients, seborrheic dermatitis may be aggravated by concomitant infection with Pityrosporum, a yeastlike fungus; use of topical antifungal agents has been recommended in cases refractory to standard topical treatment.
Folliculitis is among the most prevalent dermatologic disorders in patients with HIV infection and is seen in ~20% of patients. It is more common in patients with CD4+ T cell counts <200 cells/μL. Pruritic papular eruption is one of the most common pruritic rashes in patients with HIV infection. It appears as multiple papules on the face, trunk, and extensor surfaces and may improve with cART. Eosinophilic pustular folliculitis is a rare form of folliculitis that is seen with increased frequency in patients with HIV infection. It presents as multiple, urticarial perifollicular papules that may coalesce into plaquelike lesions. Skin biopsy reveals an eosinophilic infiltrate of the hair follicle, which in certain cases has been associated with the presence of a mite. Patients typically have an elevated serum IgE level and may respond to treatment with topical anthelmintics. Pruritus is a common symptom in patients with HIV infection and can lead to prurigo nodularis. Patients with HIV infection have also been reported to develop a severe form of Norwegian scabies with hyperkeratotic psoriasiform lesions.
Both psoriasis and ichthyosis, although they are not reported to be increased in frequency, may be particularly severe when they occur in patients with HIV infection. Preexisting psoriasis may become guttate in appearance and more refractory to treatment in the setting of HIV infection.
Reactivation herpes zoster (shingles) is seen in 10–20% of patients with HIV infection. This reactivation syndrome of varicella-zoster virus indicates a modest decline in immune function and may be the first indication of clinical immunodeficiency. In one series, patients who developed shingles did so an average of 5 years after HIV infection. In a cohort of patients with HIV infection and localized zoster, the subsequent rate of the development of AIDS was 1% per month. In that study, AIDS was more likely to develop if the outbreak of zoster was associated with severe pain, extensive skin involvement, or involvement of cranial or cervical dermatomes. The clinical manifestations of reactivation zoster in HIV-infected patients, although indicative of immunologic compromise, are not as severe as those seen in other immunodeficient conditions. Thus, while lesions may extend over several dermatomes, involve the spinal cord, and/or be associated with frank cutaneous dissemination, visceral involvement has not been reported. In contrast to patients without a known underlying immunodeficiency state, patients with HIV infection tend to have recurrences of zoster with a relapse rate of ~20%. Valacyclovir, acyclovir, or famciclovir is the treatment of choice. Foscarnet may be of value in patients with acyclovir-resistant virus.
Infection with herpes simplex virus in HIV-infected individuals is associated with recurrent orolabial, genital, and perianal lesions as part of recurrent reactivation syndromes (Chap. 187). As HIV disease progresses and the CD4+ T cell count declines, these infections become more frequent and severe. Lesions often appear as beefy red, are exquisitely painful, and have a tendency to occur high in the gluteal cleft (Fig. 197-37). Perirectal HSV may be associated with proctitis and anal fissures. HSV should be high in the differential diagnosis of any HIV-infected patient with a poorly healing, painful perirectal lesion. In addition to recurrent mucosal ulcers, recurrent HSV infection in the form of herpetic whitlow can be a problem in patients with HIV infection, presenting with painful vesicles or extensive cutaneous erosion. Valacyclovir, acyclovir, or famciclovir is the treatment of choice in these settings. It is noteworthy that even subclinical reactivation of herpes simplex may be associated with increases in plasma HIV RNA levels.
Diffuse skin eruptions due to Molluscum contagiosum may be seen in patients with advanced HIV infection. These flesh-colored, umbilicated lesions resemble those of Penicillium marnefei or Cryptococcosis. They tend to regress with effective cART and can also be treated with local therapy. Similarly, condyloma acuminatum lesions may be more severe and more widely distributed in patients with low CD4+ T cell counts. Imiquimod cream may be helpful in some cases. Atypical mycobacterial infections may present as erythematous cutaneous nodules, as may fungal infections, Bartonella, Acanthamoeba, and KS. Cutaneous infections with Aspergillus have been noted at the site of IV catheter placement.
The skin of patients with HIV infection is often a target organ for drug reactions (Chap. 56). Although most skin reactions are mild and not necessarily an indication to discontinue therapy, patients may have particularly severe cutaneous reactions, including erythroderma, Stevens-Johnson syndrome, and toxic epidermal necrolysis, as a reaction to drugs—particularly sulfa drugs, nonnucleoside reverse transcriptase inhibitors, abacavir, amprenavir, darunavir, fosamprenavir, and tipranavir. Similarly, patients with HIV infection are often quite photosensitive and burn easily following exposure to sunlight or as a side effect of radiation therapy (Chap. 57).
HIV infection and its treatment may be accompanied by cosmetic changes of the skin that are not of great clinical importance but may be troubling to patients. Yellowing of the nails and straightening of the hair, particularly in African-American patients, have been reported as a consequence of HIV infection. Zidovudine therapy has been associated with elongation of the eyelashes and the development of a bluish discoloration to the nails, again more common in African-American patients. Therapy with clofazimine may cause a yellow-orange discoloration of the skin and urine.
Clinical disease of the nervous system accounts for a significant degree of morbidity in a high percentage of patients with HIV infection (Table 197-14). The neurologic problems that occur in HIV-infected individuals may be either primary to the pathogenic processes of HIV infection or secondary to opportunistic infections or neoplasms. Among the more frequent opportunistic diseases that involve the CNS are toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, and primary CNS lymphoma. Other less common problems include mycobacterial infections; syphilis; and infection with CMV, herpes zoster, HTLV-1, Trypanosoma cruzi, or Acanthamoeba. Overall, secondary diseases of the CNS have been reported to occur in approximately one-third of patients with AIDS. These data antedate the widespread use of cART, and this frequency is considerably lower in patients receiving effective antiretroviral drugs. Primary processes related to HIV infection of the nervous system are reminiscent of those seen with other lentiviruses, such as the maedi-visna virus of sheep.
TABLE 197-14Neurologic Diseases in Patients with HIV Infection ||Download (.pdf) TABLE 197-14 Neurologic Diseases in Patients with HIV Infection
Primary CNS lymphoma
Neurologic problems directly attributable to HIV occur throughout the course of infection and may be inflammatory, demyelinating, or degenerative in nature. The term HIV-associated neurocognitive disorders (HAND) is used to describe a spectrum of disorders that range from asymptomatic neurocognitive impairment (ANI) to minor neurocognitive disorder (MND) to clinically severe dementia. The most severe form, HIV-associated dementia (HAD), also referred to as the AIDS dementia complex, or HIV encephalopathy, is considered an AIDS-defining illness. Most HIV-infected patients have some neurologic problem during the course of their disease. Even in the setting of suppressive cART, approximately 50% of HIV-infected individuals can be shown to have mild to moderate neurocognitive impairment using sensitive neuropsychiatric testing. As noted in the section on pathogenesis, damage to the CNS may be a direct result of viral infection of the CNS macrophages or glial cells or may be secondary to the release of neurotoxins and potentially toxic cytokines such as IL-1β, TNF-α, IL-6, and TGF-β. It has been reported that HIV-infected individuals with the E4 allele for apoE are at increased risk for AIDS encephalopathy and peripheral neuropathy. Virtually all patients with HIV infection have some degree of nervous system involvement with the virus. This is evidenced by the fact that CSF findings are abnormal in ~90% of untreated patients, even during the asymptomatic phase of HIV infection. CSF abnormalities include pleocytosis (50–65% of patients), detection of viral RNA (~75%), elevated CSF protein (35%), and evidence of intrathecal synthesis of anti-HIV antibodies (90%). It is important to point out that evidence of infection of the CNS with HIV does not imply impairment of cognitive function. The neurologic function of an HIV-infected individual should be considered normal unless clinical signs and symptoms suggest otherwise.
Aseptic meningitis may be seen in any but the very late stages of HIV infection. In the setting of acute primary infection, patients may experience a syndrome of headache, photophobia, and meningismus. Rarely, an acute encephalopathy due to encephalitis may occur. Cranial nerve involvement may be seen, predominantly cranial nerve VII but occasionally V and/or VIII. CSF findings include a lymphocytic pleocytosis, elevated protein level, and normal glucose level. This syndrome, which cannot be clinically differentiated from other viral meningitides (Chap. 134), usually resolves spontaneously within 2–4 weeks; however, in some patients, signs and symptoms may become chronic. Aseptic meningitis may occur any time in the course of HIV infection; however, it is rare following the development of AIDS. This suggests that clinical aseptic meningitis in the context of HIV infection is an immune-mediated disease.
Cryptococcus is the leading infectious cause of meningitis in patients with AIDS (Chap. 210). While the vast majority of these are due to C. neoformans, up to 12% may be due to C. gattii. Cryptococcal meningitis is the initial AIDS-defining illness in ~2% of patients and generally occurs in patients with CD4+ T cell counts <100/μL. Cryptococcal meningitis is particularly common in untreated patients with AIDS in Africa, occurring in ~5% of patients. Most patients present with a picture of subacute meningoencephalitis with fever, nausea, vomiting, altered mental status, headache, and meningeal signs. The incidence of seizures and focal neurologic deficits is low. The CSF profile may be normal or may show only modest elevations in WBC or protein levels and decreases in glucose. The opening pressure in the CSF is usually elevated. In addition to meningitis, patients may develop cryptococcomas and cranial nerve involvement. Approximately one-third of patients also have pulmonary disease. Uncommon manifestations of cryptococcal infection include skin lesions that resemble molluscum contagiosum, lymphadenopathy, palatal and glossal ulcers, arthritis, gastroenteritis, myocarditis, and prostatitis. The prostate gland may serve as a reservoir for smoldering cryptococcal infection. The diagnosis of cryptococcal meningitis is made by identification of organisms in spinal fluid with india ink examination or by the detection of cryptococcal antigen. Blood cultures for fungus are often positive. A biopsy may be needed to make a diagnosis of CNS cryptococcoma. Treatment is with IV amphotericin B 0.7 mg/kg daily, or liposomal amphotericin 4–6 mg/kg daily, with flucytosine 25 mg/kg qid for at least 2 weeks if possible, continuing with amphotericin alone ideally until the CSF culture turns negative. Decreases in renal function in association with amphotericin can lead to increases in flucytosine levels and subsequent bone marrow suppression. Amphotericin is followed by fluconazole 400 mg/d PO for 8 weeks, and then fluconazole 200 mg/d until the CD4+ T cell count has increased to >200 cells/μL for 6 months in response to cART. Repeated lumbar puncture may be required to manage increased intracranial pressure. Symptoms may recur with initiation of cART as an immune reconstitution syndrome (see above). Other fungi that may cause meningitis in patients with HIV infection are C. immitis and H. capsulatum. Meningoencephalitis has also been reported due to Acanthamoeba or Naegleria.
HIV-associated dementia consists of a constellation of signs and symptoms of CNS disease. While this is generally a late complication of HIV infection that progresses slowly over months, it can be seen in patients with CD4+ T cell counts >350 cells/μL. A major feature of this entity is the development of dementia, defined as a decline in cognitive ability from a previous level. It may present as impaired ability to concentrate, increased forgetfulness, difficulty reading, or increased difficulty performing complex tasks. Initially these symptoms may be indistinguishable from findings of situational depression or fatigue. In contrast to “cortical” dementia (such as Alzheimer’s disease), aphasia, apraxia, and agnosia are uncommon, leading some investigators to classify HIV encephalopathy as a “subcortical dementia” characterized by defects in short-term memory and executive function (see below). In addition to dementia, patients with HIV encephalopathy may also have motor and behavioral abnormalities. Among the motor problems are unsteady gait, poor balance, tremor, and difficulty with rapid alternating movements. Increased tone and deep tendon reflexes may be found in patients with spinal cord involvement. Late stages may be complicated by bowel and/or bladder incontinence. Behavioral problems include apathy, irritability, and lack of initiative, with progression to a vegetative state in some instances. Some patients develop a state of agitation or mild mania. These changes usually occur without significant changes in level of alertness. This is in contrast to the finding of somnolence in patients with dementia due to toxic/metabolic encephalopathies.
HIV-associated dementia is the initial AIDS-defining illness in ~3% of patients with HIV infection and thus only rarely precedes clinical evidence of immunodeficiency. Clinically significant encephalopathy eventually develops in ~25% of untreated patients with AIDS. As immunologic function declines, the risk and severity of HIV-associated dementia increases. Autopsy series suggest that 80–90% of patients with HIV infection have histologic evidence of CNS involvement. Several classification schemes have been developed for grading HIV encephalopathy; a commonly used clinical staging system is outlined in Table 197-15.
TABLE 197-15Clinical Staging of HAND According to Frascati Criteria ||Download (.pdf) TABLE 197-15 Clinical Staging of HAND According to Frascati Criteria
|Stage ||Neurocognitive Statusa ||Functional Statusb |
|Asymptomatic ||1 SD below mean in 2 cognitive domains ||No impairments in activities of daily living |
|Mild neurocognitive disorder ||1 SD below mean in 2 cognitive domains ||Impairments in activities of daily living |
|HIV-associated dementia ||2 SD below mean in 2 cognitive domains ||Notable impairments in activities of daily living |
The precise cause of HIV-associated dementia remains unclear, although the condition is thought to be a result of a combination of direct effects of HIV on the CNS and associated immune activation. HIV has been found in the brains of patients with HIV encephalopathy by Southern blot, in situ hybridization, PCR, and electron microscopy. Multinucleated giant cells, macrophages, and microglial cells appear to be the main cell types harboring virus in the CNS. Histologically, the major changes are seen in the subcortical areas of the brain and include pallor and gl