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44 C H A P T E R AIDS and Lentiviruses...

44 C H A P T E R AIDS and Lentiviruses Human immunodeficiency virus (HIV) types, derived from protein, functions in “transactivation,” whereby a viral gene primate lentiviruses, are the etiologic agents of Acquired product is involved in transcriptional activation of other viral Immune Deficiency Syndrome (AIDS). The illness was first genes. Transactivation by HIV is highly efficient and may described in 1981, and HIV-1 was isolated by the end of 1983. contribute to the virulent nature of HIV infections. The Rev Since then, AIDS has become a worldwide epidemic, expand- protein is required for the expression of viral structural pro- ing in scope and magnitude as HIV infections have affected teins. Rev facilitates the export of unspliced viral transcripts different populations and geographic regions. Millions are from the nucleus; structural proteins are translated from now infected worldwide; once infected, individuals remain unspliced mRNAs during the late phase of viral replication. infected for life. Within a decade, if left untreated, the vast The Nef protein increases viral infectivity, facilitates activa- majority of HIV-infected individuals develop fatal opportu- tion of resting T cells, and downregulates expression of CD4 nistic infections as a result of HIV-induced deficiencies in the and MHC class I. The nef gene is necessary for simian immu- immune system. AIDS is one of the most important public nodeficiency virus (SIV) to be pathogenic in monkeys. The health problems worldwide at the start of the 21st century. The Vpr protein increases transport of the viral preintegration development of highly active antiretroviral therapy (HAART) complex into the nucleus and also arrests cells in the G2 phase for chronic suppression of HIV replication and prevention of of the cell cycle. The Vpu protein promotes CD4 degradation. AIDS has been a major achievement in HIV medicine. Cells contain intracellular antiviral inhibitory proteins referred to as restriction factors. One type is APOBEC3G, a cytidine deaminase that inhibits HIV replication. The Vif PROPERTIES OF LENTIVIRUSES protein promotes viral infectivity by suppressing the effects of APOBEC3G. Another inhibitory protein is TRIM5α, Important properties of lentiviruses, members of a genus in which binds to incoming retrovirus particles and recruits the Retroviridae family, are summarized in Table 44-1. them to proteasomes before much viral DNA synthesis occurs. The many different isolates of HIV are not identical but Structure and Composition appear to comprise a spectrum of related viruses (see Clas- HIV is a retrovirus, a member of the Lentivirus genus, and sification). Heterogeneous populations of viral genomes exhibits many of the physicochemical features typical of the called quasispecies are found in an infected individual. This family (see Chapter 43). The unique morphologic charac- heterogeneity reflects high rates of viral replication and teristic of HIV is a cylindrical nucleoid in the mature virion the high error rate of the viral reverse transcriptase. The (Figure 44-1). The diagnostic bar-shaped nucleoid is visible regions of greatest divergence among different isolates are in electron micrographs in those extracellular particles that localized to the env gene, which codes for the viral envelope happen to be sectioned at the appropriate angle. proteins (Figure 44-3). The SU (gp120) product of the env The RNA genome of lentiviruses is more complex than gene contains binding domains responsible for virus attach- that of transforming retroviruses (Figure 44-2). Lentiviruses ment to the CD4 molecule and coreceptors, determines contain the four genes required for a replicating retrovirus— lymphocyte and macrophage tropisms, and carries the gag, pro, pol, and env—and follow the general pattern for major antigenic determinants that elicit neutralizing anti- retrovirus replication (see Chapter 43). Up to six additional bodies. The HIV glycoprotein has five variable (V) regions genes regulate viral expression and are important in disease that diverge among isolates, with the V3 region important pathogenesis in vivo. Although these auxiliary genes show in neutralization. The TM (gp41) env product contains both little sequence homology among lentiviruses, their functions a transmembrane domain that anchors the glycoprotein in are conserved. (The feline and ungulate viruses encode fewer the viral envelope and a fusion domain that facilitates viral accessory genes.) One early-phase replication protein, the Tat penetration into target cells. The divergence in the envelope 655 Riedel_CH44_p655-p672.indd 655 04/04/19 5:12 PM  656   SECTION IV  Virology TABLE 44-1 Important Properties of Lentiviruses of HIV complicates efforts to develop an effective vaccine (Nononcogenic Retroviruses) for AIDS. Lentiviruses are completely exogenous viruses; in Virion: Spherical, 80–100 nm in diameter, cylindrical core contrast to the transforming retroviruses, the lentiviral Genome: Single-stranded RNA, linear, positive-sense, genome does not contain any conserved cellular genes (see 9–10 kb, diploid; genome more complex than that of oncogenic Chapter 43). Individuals become infected by the introduction retroviruses, contains up to six additional replication genes of virus from outside sources. Proteins: Envelope glycoprotein undergoes antigenic variation; reverse transcriptase enzyme contained inside virions; protease required for production of infectious virus Envelope: Present Classification Lentiviruses have been isolated from many species (Table 44-2), Replication: Reverse transcriptase makes DNA copy from genomic RNA; provirus DNA is template for viral RNA. Genetic variability is common. including more than two dozen different African nonhuman primate species. There are two distinct types of human AIDS Maturation: Particles bud from plasma membrane viruses: HIV-1 and HIV-2. The two types are distinguished on Outstanding characteristics: the basis of genome organization and phylogenetic (evolution- Members are nononcogenic and may be cytocidal ary) relationships with other primate lentiviruses. Sequence divergence between HIV-1 and HIV-2 exceeds 50%. Infect cells of the immune system Based on env gene sequences, HIV-1 comprises three dis- Proviruses remain permanently associated with cells tinct virus groups (M, N, and O); the predominant M group Viral expression is restricted in some cells in vivo contains at least 11 subtypes or “clades” (A–K). Recombi- Cause slowly progressive, chronic diseases nant forms of virus are also found in circulation in humans Replication is usually species specific in different geographic regions. Similarly, eight subtypes of HIV-2 (A–H) have been identified. Within each subtype Group includes the causative agents of AIDS there is extensive variability. The genetic clades do not seem FIGURE 44-1 Electron micrographs of HIV-infected lymphocytes, showing a large accumulation of freshly produced virus at the cell surface (top, 46,450×, bar = 100 nm); newly formed virus budding from cytoplasmic membrane (lower left, 49,000×, bar = 100 nm); and two virions about to be cast off from cell surface (lower right, 75,140×, bar = 100 nm). Riedel_CH44_p655-p672.indd 656 04/04/19 5:12 PM  CHAPTER 44 AIDS and Lentiviruses   657 1 gp120 551 gp41 862 5′ LTR 3′ LTR surface (SU) transmembrane (TM) gag vif rev pro pol tat nef Signal Variable regions 1–5 Fusion Transmembrane peptide CD4 binding anchor env vpr vpu III V3 MA CA NC PR RT IN SU TM p17 p24 p9 p11 p66 p32 gp120 gp41 V2 IV p51 V4 II V1 V I NH2 V5 NH2 COOH tRNA Viral TM primer genomic HIV-1 COOH RNA FIGURE 44-3 HIV-1 envelope proteins. The gp160 precursor polypeptide is shown at the top. The gp120 subunit is on the outside of the cell, and gp41 is a transmembrane protein. Hypervariable domains in gp120 are designated V1 through V5; the positions of disulfide bonds are shown as connecting lines in the loops. Important regions in the gp41 subunit are the fusion domain at the amino terminal and the transmembrane domain (TM). Amino (NH2) and carboxyl (COOH) terminals are labeled for both subunits. (Reproduced from Peterlin BM: Molecular biology of HIV. In Levy JA [editor]. The Viruses. Vol 4: The Retroviridae. Plenum, 1995. Modified there from Myers G, et al: Human Retroviruses and AIDS 1993: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. FIGURE 44-2 HIV genome and virion structure. The HIV-1 Theoretical Biology and Biophysics Group T-10, Los Alamos National genome is shown at the top. Viral proteins are synthesized as Library, Los Alamos, New Mexico.) precursor polyproteins (Gag-Pol [Pr160], Gag [Pr55], and Env [gp160]), which are enzymatically processed to yield mature virion proteins. Gag-Pol and Gag are cleaved by the viral protease PR to produce the have neither vpu nor vpx genes. The sequences of the gag and indicated smaller proteins. Env is cleaved by a cellular PR, producing pol genes are highly conserved. There is significant diver- SU gp120 and TM gp41. The placements of virion proteins in the gence among the envelope glycoprotein genes; the sequences virus particle are indicated by symbols (bottom of figure). HIV-2 of the transmembrane protein portion are more conserved and SIV lack the vpu gene but contain a vpx gene. (Reproduced than the external glycoprotein sequences (the protein com- from Peterlin BM: Molecular biology of HIV. In Levy JA [editor]. The ponent exposed on the exterior of the virus particle). Viruses. Vol 4: The Retroviridae. Plenum, 1995. Modified there from The SIVs appear to be nonpathogenic in their host species Luciw PA, Shacklett BL: HIV: Molecular Organization, Pathogenicity and of origin (eg, African green monkey or sooty mangabey), spe- Treatment. Morrow WJW, Haigwood NL [editors]. Elsevier, 1993.) cies known to be infected in their natural habitats. However, SIVcpz, the precursor of HIV-1, is pathogenic in chimpanzees in the wild, causing AIDS-like pathology and premature to correspond to neutralization serotype groups, and there death. In contrast, rhesus monkeys are not infected naturally is currently no evidence that subtypes differ in biology or in the wild in Asia but are susceptible to induction of sim- pathogenesis. ian AIDS by various SIV isolates. The virus first recovered Numerous lentivirus isolates have been obtained from from captive rhesus monkeys (SIVmac) is the sooty mangabey/ nonhuman primate species. The primate lentiviruses fall HIV-2 strain. into six major phylogenetic lineages (Table 44-2). SIV from The nonprimate lentiviruses establish persistent infec- sooty mangabeys (a type of monkey in West Africa) and tions affecting various animal species. These viruses cause HIV-2 are considered to be variants of the same virus, as are chronic debilitating diseases and sometimes immunodefi- chimpanzee isolates and HIV-1. The SIVs from African green ciency. The prototype agent, visna virus (also called maedi monkeys, Sykes monkeys, mandrills, and colobus monkeys virus), causes neurologic symptoms or pneumonia in sheep represent additional discrete lineages. in Iceland. Other viruses cause infectious anemia in horses The organization of the genomes of primate lentiviruses and arthritis and encephalitis in goats. Feline and bovine (human and simian) is very similar. One difference is that lentiviruses may cause an immunodeficiency. Nonprimate HIV-1 and the chimpanzee virus carry a vpu gene, whereas lentiviruses are not known to infect any primates, including HIV-2 and the SIVsm group have a vpx gene. Other SIV isolates humans. Riedel_CH44_p655-p672.indd 657 04/04/19 5:12 PM  658   SECTION IV  Virology TABLE 44-2 Representative Members of the Lentivirus Genus Origin of Isolates Virus Diseases Humans HIV-1 a Acquired Immune Deficiency Syndrome (AIDS) HIV-2 Nonhuman primatesb Simian AIDS Chimpanzee SIVcpz Sooty mangabey SIVsm   Macaques c SIVmac African green monkey SIVagm Sykes monkey SIVsyk Mandrill SIVmnd   L’Hoest monkeyc SIVlhoest Colobus monkey SIVcol Nonprimates d Cat Feline immunodeficiency virus Feline AIDS Cow Bovine immunodeficiency virus Bovine AIDS Sheep Visna/maedi virus Lung, central nervous system disease Horse Equine infectious anemia virus Anemia Goat Caprine arthritis encephalitis virus Arthritis, encephalitis The origins of HIV-1 and HIV-2 were cross-species transmissions of SIVcpz and SIVsm, respectively. a b Disease not caused in host of origin by SIVs but requires transmission to a different species of monkey (rhesus are the most susceptible to disease). The Asian macaques (rhesus) show no evidence of SIV infection in the wild; SIVsm was probably accidentally introduced to macaques in captivity. c Indention indicates that the virus is in the same phylogenetic lineage as the one above it. d Nonprimate lentiviruses cause disease in species of origin. Origin of AIDS exposure to undiluted bleach for at least 30 seconds is neces- sary for inactivation. HIV in humans originated from cross-species infections by The virus is not inactivated by 2.5% Tween 20. Although simian viruses in rural Africa, probably due to direct human paraformaldehyde inactivates virus free in solution, it is not contact with infected primate blood. Current evidence is that known if it penetrates tissues sufficiently to inactivate all virus the primate counterparts of HIV-1 and HIV-2 were transmit- that might be present in cultured cells or tissue specimens. ted to humans on multiple (at least seven) different occasions. HIV is readily inactivated in liquids or 10% serum by Sequence evolution analyses place the introduction of SIVcpz heating at 56°C for 10 minutes, but dried proteinaceous mate- into humans that gave rise to HIV-1 group M at about 1930, rial affords marked protection. Lyophilized blood products although some estimates push the date back to about 1908. would need to be heated at 68°C for 72 hours to ensure inac- Presumably, such transmissions occurred repeatedly over the tivation of contaminating virus. ages, but particular social, economic, and behavioral changes that occurred in the mid-20th century provided circum- stances that allowed these virus infections to expand, become well established in humans, and reach epidemic proportions. Animal Lentivirus Systems Insights into the biologic characteristics of lentivirus infections have been gained from experimental infections, including sheep Disinfection and Inactivation with visna virus (Table 44-2). Natural disease patterns vary HIV is completely inactivated (≥105 units of infectivity) by among species, but certain common features are recognized. treatment for 10 minutes at room temperature with any of the following: 10% household bleach, 50% ethanol, 35% iso- 1. Viruses are transmitted by exchange of body fluids. propanol, 1% nonionic detergent P-40, 0.5% Lysol, 0.5% para- 2. Virus persists indefinitely in infected hosts, although it formaldehyde, or 0.3% hydrogen peroxide. The virus is also may be present at very low levels. inactivated by extremes of pH (pH 1.0, pH 13.0). When HIV 3. Viruses have high mutation rates, and different mutants will is present in clotted or unclotted blood in a needle or syringe, be selected under different conditions (host factors, immune Riedel_CH44_p655-p672.indd 658 04/04/19 5:12 PM  CHAPTER 44 AIDS and Lentiviruses   659 responses, tissue types). Infected hosts contain “swarms” of SDF-1, is the coreceptor for lymphocyte-tropic strains of closely related viral genomes, known as quasispecies. HIV-1. The chemokine receptors used by HIV for cell entry 4. Virus infection progresses slowly through specific stages. are found on lymphocytes, macrophages, and thymocytes as Cells in the macrophage lineage play central roles in the well as on neurons and cells in the colon and cervix. Individu- infection. Lentiviruses differ from other retroviruses in that als who possess homozygous deletions in CCR5 or produce they can infect nondividing, terminally differentiated cells. mutant forms of the protein may be protected from infection However, those cells must be activated before viral replica- by HIV-1; mutations in the CCR5 gene promoter appear to tion ensues and progeny virus is produced. Virus is cell- delay disease progression. The requirement for a corecep- associated in monocytes and macrophages, but only about tor for HIV fusion with cells provided new targets for anti- one cell per million is infected. Monocytes carry the virus viral therapeutic strategies, with the first HIV entry inhibitor around the body in a form that the immune system cannot licensed in the United States in 2003. recognize, seeding other tissues. Lymphocyte-tropic strains Another molecule, integrin α-4 β-7, appears to function of virus tend to cause highly productive infections, whereas as a receptor for HIV in the gut. A dendritic cell-specific lec- replication of macrophage-tropic virus is restricted. tin, DC-SIGN, appears to bind HIV-1 but not to mediate cell 5. It may take years for disease to develop. Infected hosts usu- entry. Rather, it may facilitate transport of HIV by dendritic ally make antibodies, but they do not clear the infection, cells to lymphoid organs and enhance infection of T cells. so virus persists lifelong. New antigenic variants periodi- cally arise in infected hosts, with most mutations occur- ring in envelope glycoproteins. Clinical symptoms may develop at any time, but chronic disease typically manifests HIV INFECTIONS IN HUMANS after months to years of infection. The exceptions to long incubation periods for lentivirus disease include AIDS in Pathogenesis and Pathology children, infectious anemia in horses, and encephalitis in A. Overview of Course of HIV Infection young goats. The typical course of untreated HIV infection spans about a decade (Figure 44-4). Stages include the primary infection, Host factors important in pathogenesis of disease include dissemination of virus to lymphoid organs, clinical latency, age (the young are at greater risk), stress (may trigger disease), elevated HIV expression, clinical disease, and death. The dura- genetics (certain breeds of animals are more susceptible), and tion between primary infection and progression to clinical concurrent infections (may exacerbate disease or facilitate disease averages about 10 years. In untreated cases, death usu- virus transmission). ally occurs within 2 years after the onset of clinical symptoms. The diseases in horses, sheep, and goats are not compli- Following primary infection, there is a 4- to 11-day cated by opportunistic secondary infections. Equine infectious period between mucosal infection and initial viremia; the anemia virus can be spread among horses by bloodsucking viremia is detectable for about 8–12 weeks. Virus is widely horseflies, the only lentivirus known to be transmitted by an disseminated throughout the body during this time, and the insect vector. lymphoid organs become seeded. An acute mononucleosis- Simian lentiviruses share molecular and biologic charac- like syndrome develops in many patients (50–75%) 3–6 weeks teristics with HIV and cause an AIDS-like disease in rhesus after primary infection. There is a significant drop in num- macaques. The SIV model is important for understanding bers of circulating CD4 T cells at this early time. An immune disease pathogenesis and developing vaccine and treatment response to HIV occurs 1 week to 3 months after infection, strategies. plasma viremia drops, and levels of CD4 cells rebound. How- ever, the immune response is unable to clear the infection completely, and HIV-infected cells persist in the lymph nodes. Virus Receptors This period of clinical latency may last for 10 years or All primate lentiviruses use as a receptor the CD4 molecule, more. During this time, there is a high level of ongoing viral which is expressed on macrophages and T lymphocytes. A sec- replication. It is estimated that 10 billion HIV particles are ond coreceptor in addition to CD4 is necessary for HIV-1 to produced and destroyed each day. The half-life of the virus in gain entry to cells. The second receptor is required for fusion plasma is about 6 hours, and the virus life cycle (from the time of the virus with the cell membrane. The virus first binds to of infection of a cell to the production of new progeny that CD4 and then to the coreceptor. These interactions cause con- infect the next cell) averages 2.6 days. CD4 T lymphocytes, formational changes in the viral envelope, activating the gp41 major targets responsible for virus production, appear to have fusion peptide and triggering membrane fusion. Chemokine similar high turnover rates. Once productively infected, the receptors serve as HIV-1 second receptors. (Chemokines are half-life of a CD4 lymphocyte is about 1.6 days. soluble factors with chemoattractant and cytokine properties.) Viral diversity studies have shown that in most cases of CCR5, the receptor for chemokines RANTES, MIP-1α, and sexual transmission a single HIV variant establishes a new MIP-1β, is the predominant coreceptor for macrophage-tropic infection. Early in infection, viral sequences are quite homo- strains of HIV-1, whereas CXCR4, the receptor for chemokine geneous, but because of rapid viral proliferation and the Riedel_CH44_p655-p672.indd 659 04/04/19 5:12 PM  660   SECTION IV  Virology ±Acute HIV syndrome Death Wide dissemination of virus Seeding of lymphoid organs Opportunistic diseases Primary Constitutional infection 1200 symptoms 108 HIV RNA Copies per mL Plasma 1100 1000 107 CD4+ T Lymphocyte count (cells/µL) 900 Clinical Latency 800 106 700 600 105 500 400 104 300 200 103 100 0 102 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 Weeks Years FIGURE 44-4 Typical course of untreated HIV infection. During the early period after primary infection, there is widespread dissemination of virus and a sharp decrease in the number of CD4 T cells in peripheral blood. An immune response to HIV ensues, with a decrease in detectable viremia followed by a prolonged period of clinical latency. Sensitive assays for viral RNA show that virus is present in the plasma at all times. The CD4 T-cell count continues to decrease during the following years until it reaches a critical level below which there is a substantial risk of opportunistic diseases. (Reproduced with permission from Fauci AS, Lane HC: Human immunodeficiency virus disease: AIDS and related disorders. In Longo DL, Fauci AS, Kasper DL, et al (editors). Harrison’s Principles of Internal Medicine, 18th ed. McGraw-Hill, 2012. © McGraw-Hill Education.) inherent error rate of the HIV reverse transcriptase, quasispe- replaced by T-tropic viruses. Laboratory adaptation of these cies of virus accumulate. It is estimated that every nucleotide primary isolates in immortalized T-cell lines results in loss of of the HIV genome probably mutates on a daily basis. ability to infect monocytes and macrophages. Eventually, the patient develops constitutional symptoms The consequences of CD4 T-cell dysfunction caused by and clinically apparent disease, such as opportunistic infec- HIV infection are devastating because the CD4 T lymphocyte tions or neoplasms. Higher levels of virus are readily detect- plays a critical role in the human immune response. It is respon- able in the plasma during the advanced stages of infection. sible directly or indirectly for induction of a wide array of lym- HIV found in patients with late-stage disease is usually much phoid and nonlymphoid cell functions. These effects include more virulent and cytopathic than the strains of virus found activation of macrophages; induction of functions of cytotoxic early in infection. Often, a shift from monocyte-tropic or mac- T cells, natural killer (NK) cells, and B cells; and secretion of a rophage-tropic (M-tropic) strains of HIV-1 to lymphocyte- variety of soluble factors that induce growth and differentiation tropic (T-tropic) variants accompanies progression to AIDS. of lymphoid cells and affect hematopoietic cells. At any given time, only a small fraction of CD4 T cells are B. CD4 T Lymphocytes, Memory Cells, and Latency productively infected. Many infected T cells are killed, but a The cardinal feature of HIV infection is the depletion of T fraction survives and reverts to a resting memory state. There helper-inducer lymphocytes—the result of HIV replication is little or no virus gene expression in the memory cells, but in this population of lymphocytes as well as of the death they provide a long-term, stable latent reservoir for the virus. of uninfected T cells by indirect mechanisms. The T cells Less than 1 cell per million resting CD4 T cells harbors latent express the CD4 phenotypic marker on their surface. The HIV-1 provirus in patients on successful antiretroviral ther- CD4 molecule is the major receptor for HIV; it has a high apy. Even after 10 years of treatment, patients show very little affinity for the viral envelope. The HIV coreceptor on lym- change in the size of the latent HIV reservoir because the phocytes is the CXCR4 chemokine receptor. latent reservoir of infected memory cells decays very slowly. Early in infection, primary HIV isolates are M-tropic. When exposed to antigen or when drug therapy is discontin- However, all strains of HIV infect primary CD4 T lympho- ued, the memory cells become activated and release infectious cytes (but not immortalized T-cell lines in vitro). As the virus. It is possible that other drug-insensitive reservoirs exist infection progresses, the dominant M-tropic viruses are among macrophages, hematopoietic stem cells, or brain cells. Riedel_CH44_p655-p672.indd 660 04/04/19 5:12 PM  CHAPTER 44 AIDS and Lentiviruses   661 It is unlikely that an HIV infection can be cured with stan- activators. For example, active infection by Mycobacterium dard therapy; if there were a million infected memory cells in tuberculosis substantially increases plasma viremia. The the body, it would take about 70 years for them to decay. There damaging effects of HIV on the immune system leave patients has been a recent report of an apparent cure. An HIV-infected vulnerable to many types of infection. The World Health man in Germany developed acute myeloid leukemia that Organization reports that infection with HIV increases necessitated a bone marrow transplant in 2007. After ablation the risk of getting tuberculosis as much as 20-fold. Of the of the patient’s immune system, he was transplanted with cells 9 million new tuberculosis cases worldwide in 2007, it is esti- from a donor homozygous for a CCR5 mutation that protects mated that 15% occurred in persons infected with HIV. against HIV infection. The patient stopped taking antiretro- Other concomitant viral infections—with Epstein-Barr viral drugs and remained free of detectable HIV. This success virus, cytomegalovirus, herpes simplex virus, or hepatitis B has prompted research to develop ways to purge the latently virus—may serve as cofactors of AIDS. Hepatitis C virus coin- infected reservoirs in HIV-infected individuals. fection, which occurs in 15–30% of HIV cases in the United States and often results in liver disease, is a leading cause of C. Monocytes and Macrophages morbidity and mortality in HIV-infected persons. There is Monocytes and macrophages play a major role in the dissem- also a high prevalence of cytomegalovirus infection in HIV- ination and pathogenesis of HIV infection. Certain subsets positive individuals. of monocytes express the CD4 surface antigen and therefore Coinfections with two different strains of HIV can bind to the envelope of HIV. The HIV coreceptor on mono- occur. There are documented cases of superinfection with a cytes and macrophages is the CCR5 chemokine receptor. In second strain in an HIV-infected individual, even in the pres- the brain, the major cell types infected with HIV appear to be ence of a strong CD8 T-cell response to the first strain. HIV the monocytes and macrophages, and this may have impor- superinfection is considered to be a rare event. tant consequences for the development of neuropsychiatric manifestations associated with HIV infection. Clinical Findings Macrophage-tropic strains of HIV predominate early Symptoms of acute HIV infection are nonspecific and include after infection, and these strains are responsible for initial fatigue, rash, headache, nausea, and night sweats. AIDS is infections even when the transmitting source contains both characterized by pronounced suppression of the immune M-tropic and T-tropic viruses. system and development of a wide variety of severe oppor- It is believed that monocytes and macrophages serve tunistic infections or unusual neoplasms (especially Kaposi as major reservoirs for HIV in the body. Unlike the CD4 T sarcoma). The more serious symptoms in adults are often lymphocyte, the monocyte is relatively refractory to the cyto- preceded by a prodrome (“diarrhea and dwindling”) that pathic effects of HIV so that the virus not only can survive can include fatigue, malaise, weight loss, fever, shortness of in this cell but can also be transported to various organs in breath, chronic diarrhea, white patches on the tongue (hairy the body (such as the lungs and brain). Infected macrophages leukoplakia, oral candidiasis), and lymphadenopathy. Disease may continue to produce virus for a long period of time. symptoms in the gastrointestinal tract from the esophagus to the colon are a major cause of debility. With no treatment, the D. Lymphoid Organs interval between primary infection with HIV and the first Lymphoid organs play a central role in HIV infection. Lym- appearance of clinical disease is usually long in adults, aver- phocytes in the peripheral blood represent only about 2% of aging about 8–10 years. Death occurs about 2 years later. the total lymphocyte pool, the remainder being located chiefly in lymphoid organs. It is in the lymphoid organs that specific A. Plasma Viral Load immune responses are generated. The network of follicular The amount of HIV in the blood (viral load) is of significant dendritic cells in the germinal centers of lymph nodes traps prognostic value. There are continual rounds of viral repli- antigens and stimulates an immune response. Throughout the cation and cell killing in each patient, and the steady-state course of untreated infection—even during the stage of clinical level of virus in the blood (viral set point) varies from indi- latency—HIV is actively replicating in lymphoid tissues. The vidual to individual during the asymptomatic period. This microenvironment of the lymph node is ideal for the establish- level reflects the total number of productively infected cells ment and spread of HIV infection. Cytokines are released, acti- and their average burst size. A single measurement of plasma vating a large pool of CD4 T cells that are highly susceptible to viral load about 6 months after infection is able to predict HIV infection. As the late stages of HIV disease progress, the the subsequent risk of development of AIDS in men several architecture of the lymph nodes becomes disrupted. years later in the absence of treatment (Figure 44-5). High set points tend to correlate with rapid disease progression and E. Viral Coinfections poorer responses to treatment. However, more recent data Activation signals are required for the establishment of a pro- suggest a gender difference in this parameter—in women, ductive HIV infection. In the HIV-infected individual, a wide the viral load may be less predictive of progression to AIDS. range of in vivo antigenic stimuli seem to serve as cellular Plasma HIV RNA levels can be determined using a variety of Riedel_CH44_p655-p672.indd 661 04/04/19 5:12 PM  662   SECTION IV  Virology Patients with AIDS has difficulty containing the infection. A small percentage of 106 5 years after infection infants (≤5%) display transient HIV infections, suggesting that some infants can clear the virus. 62% C. Neurologic Disease HIV-1 RNA in plasma (copies/mL) 105 Neurologic dysfunction occurs frequently in HIV-infected persons. Around 40–90% of patients have neurologic symp- 49% toms, and many are found during autopsy to have neuro- pathologic abnormalities. 104 26% Several distinct neurologic syndromes that occur fre- quently include subacute encephalitis, vacuolar myelopathy, aseptic meningitis, and peripheral neuropathy. AIDS demen- 8% tia complex, the most common neurologic syndrome, occurs 103 as a late manifestation in 25–65% of AIDS patients and is characterized by poor memory, inability to concentrate, apa- Detection threshold thy, psychomotor retardation, and behavioral changes. Other neurologic diseases associated with HIV infection include 0 0.5 1.0 1.5 2.0 toxoplasmosis, cryptococcosis, primary lymphoma of the Years after infection central nervous system, and JC virus-induced progressive multifocal leukoencephalopathy. Mean survival time from FIGURE 44-5 Prognostic value of HIV-1 RNA levels in the onset of severe dementia is usually less than 6 months. plasma (viral load). The virologic set point predicts the long-term Pediatric AIDS patients also display neurologic abnor- clinical outcome. (Reproduced with permission from Ho DD: Viral counts count in HIV infection. Science 1996;272:1124. Reprinted with malities. These include seizure disorders, progressive loss permission from AAAS.) of behavioral developmental milestones, encephalopathy, attention deficit disorders, and developmental delays. HIV encephalopathy may occur in as many as 12% of children, usu- commercially available assays. The plasma viral load appears ally accompanied by profound immune deficiency. Bacterial to be the best predictor of long-term clinical outcome, whereas pathogens predominate in pediatric AIDS as the most com- CD4 lymphocyte counts are the best predictor of short-term mon cause of meningitis. risk of developing an opportunistic disease. Plasma viral load As children born with HIV infection are living to ado- measurements are a critical element in assessing the effec- lescence and adulthood due to antiretroviral therapy, many tiveness of antiretroviral drug therapy. appear to be at high risk for psychiatric disorders. The most common problems are anxiety disorders. B. Pediatric AIDS The responses of infected neonates are different from those D. Opportunistic Infections observed in HIV-infected adults. Pediatric AIDS—acquired The predominant causes of morbidity and mortality among from infected mothers—usually presents with clinical symp- patients with late-stage HIV infection are opportunistic infec- toms by 2 years of age; death follows in another 2 years. The tions, that is, severe infections induced by agents that rarely neonate is particularly susceptible to the devastating effects cause serious disease in immune-competent individuals. of HIV because the immune system has not developed at Opportunistic infections usually do not occur in HIV-infected the time of primary infection. Clinical findings may include patients until CD4 T-cell counts have dropped from the nor- lymphoid interstitial pneumonitis, pneumonia, severe oral mal level of about 1000 cells/µL to less than 200 cells/µL. As candidiasis, encephalopathy, wasting, generalized lymphade- treatments are developed for some common opportunistic nopathy, bacterial sepsis, hepatosplenomegaly, diarrhea, and pathogens and management of AIDS patients permits longer growth retardation. survivals, the spectrum of opportunistic infections changes. Children with perinatally acquired HIV-1 infection— The most common opportunistic infections in untreated if untreated—have a very poor prognosis. A high rate of dis- AIDS patients include the following: ease progression occurs in the first few years of life. High levels of plasma HIV-1 load appear to predict infants at risk 1. Protozoa: Toxoplasma gondii, Isospora belli, Cryptospo- of rapid progression of disease. The pattern of viral replica- ridium species. tion in infants differs from that in adults. Viral RNA load lev- 2. Fungi: Candida albicans, Cryptococcus neoformans, Coccidi- els are generally low at birth, suggesting infection acquired oides immitis, Histoplasma capsulatum, Pneumocystis jiroveci. close to that time; RNA levels then rise rapidly within the first 3. Bacteria: Mycobacterium avium-intracellulare, M. tuberculosis, 2 months of life and are followed by a slow decline until the age Listeria monocytogenes, Nocardia asteroides, Salmonella spe- of 24 months, suggesting that the immature immune system cies, Streptococcus species. Riedel_CH44_p655-p672.indd 662 04/04/19 5:12 PM  CHAPTER 44 AIDS and Lentiviruses   663 4. Viruses: Cytomegalovirus, herpes simplex virus, varicella- TABLE 44-3 Major Gene Products of HIV That Are zoster virus, adenovirus, JC polyomavirus, hepatitis B Useful in Diagnosis of Infection virus, hepatitis C virus. Gene Producta Description Herpesvirus infections are common in AIDS patients, gp160b Precursor of envelope glycoproteins and multiple herpesviruses are frequently detected being gp120 b Outer envelope glycoprotein of virion, SUc shed in saliva. Cytomegalovirus retinitis is the most common p66 Reverse transcriptase and RNase H from severe ocular complication of AIDS. polymerase gene product E. Cancer p55 Precursor of core proteins, polyprotein from gag gene AIDS patients exhibit a marked predisposition to the develop- ment of cancer, another consequence of immune suppression. p51 Reverse transcriptase, RT AIDS-associated cancers tend to be those with a viral cofac- gp41b Transmembrane envelope glycoprotein, TM tor and include non-Hodgkin lymphoma (both systemic and p32 Integrase, IN central nervous system types), Kaposi sarcoma, cervical can- cer, and anogenital cancers. Epstein-Barr viral DNA is found p24b Nucleocapsid core protein of virion, CA in the majority of B-cell malignancies classified as Burkitt p17 Matrix core protein of virion, MA lymphoma and those of the central nervous system (but is a Number refers to the approximate molecular mass of the protein in kilodaltons. not found in most of the systemic lymphomas). Burkitt lym- b Antibodies to these viral proteins are the most commonly detected. phoma occurs 1000 times more commonly in AIDS patients Two-letter abbreviation for viral protein. c than in the general population. Kaposi sarcoma is a vascular tumor thought to be of endothelial origin that appears in skin, mucous membranes, lymph nodes, and visceral organs. Before this type of malig- glycoprotein shows great sequence variability. This natural nancy was observed in AIDS patients, it was considered to variation may allow the evolution of successive populations be a very rare cancer. Kaposi sarcoma is 20,000 times more of resistant virus that escape recognition by existing neutral- common in untreated AIDS patients than in the general pop- izing antibodies. ulation. Kaposi sarcoma-associated herpesvirus, or HHV8, The neutralizing antibodies can be measured in vitro by appears to be causally related to the cancer (see Chapter 33). inhibiting HIV infection of susceptible lymphocyte cell lines. Cervical cancer is caused by high-risk papillomaviruses; the Viral infection is quantified by (1) reverse transcriptase assay, anogenital cancers also arise as a result of coinfections with which measures the enzyme activity of released HIV parti- human papillomaviruses (see Chapter 43). cles; (2) indirect immunofluorescence assay, which measures Effective antiretroviral drug therapy has resulted in a the percentage of infected cells; and (3) reverse transcriptase- marked reduction in the occurrence of Kaposi sarcomas but polymerase chain reaction (RT-PCR) or branched-chain has had less of an effect on the incidence of non-Hodgkin DNA (bDNA) amplification assays that measure HIV nucleic lymphomas in HIV-infected individuals. acids. As HIV-infected persons live longer lives due to effective Cellular responses develop that are directed against HIV antiretroviral therapy, they are developing a broad spectrum proteins. Cytotoxic T lymphocytes (CTLs) recognize env, of cancers at higher frequencies than the noninfected popu- pol, gag, and nef gene products; this reactivity is mediated lation. These HIV-associated malignancies include head and by major histocompatibility complex–restricted CD3–CD8 neck cancer, lung cancer, Hodgkin lymphoma, liver cancer, lymphocytes. The env-specific reactivity occurs in nearly all melanoma, and oral cancer. There does not appear to be an infected people and decreases with progression of disease. increased risk of breast, colon, or prostate cancer. NK cell activity has also been detected against HIV-1 gp120. It is not clear which host responses are important in pro- viding protection against HIV infection or development of Immunity disease. A problem confronting AIDS vaccine research is that HIV-infected persons develop both humoral and cell- the correlates of protective immunity are not known, includ- mediated responses against HIV-related antigens. Antibod- ing the relative importance of humoral and cell-mediated ies to a number of viral antigens develop soon after infection immune responses. (Table 44-3). Most infected individuals make neutralizing antibod- ies against HIV, directed against the envelope glycoprotein. Laboratory Diagnosis However, the levels of neutralizing activity are low; many Evidence of infection by HIV can be detected in three ways: anti-envelope antibodies are nonneutralizing. It is believed (1) virus isolation, (2) serologic determination of antivi- that the dense glycosylation may inhibit binding of neu- ral antibodies, and (3) measurement of viral nucleic acid or tralizing antibody to the envelope protein. The envelope antigens. Riedel_CH44_p655-p672.indd 663 04/04/19 5:12 PM  664   SECTION IV  Virology Seroconversion Death results. The most widely used confirmation assay is the West- Infection ern blot technique, in which antibodies to HIV proteins of Minor or no symptoms AIDS specific molecular weights can be detected. A positive result 1000 is defined as the presence of any two bands corresponding to Cells/µL p24, gp41, and gp120/160. The Western blot can be indeter- 500 CD4 T cells minate or negative early in HIV infection, and detection of 0 HIV RNA is an alternate means for confirmation of the diag- Antibodies to HIV Env nosis. Infection with HIV-2 can yield indeterminate Western blot results for HIV-1 and requires a separate HIV-2 Western HIV-specific CTL blot for confirmation. The response pattern against specific viral antigens Antibodies to HIV p24 changes over time as patients progress to AIDS. Antibodies Viremia to the envelope glycoproteins (gp41, gp120, gp160) are main- tained, but those directed against the Gag proteins (p17, p24, p55) decline. The decline of anti-p24 may herald the begin- 4–8 weeks Up to 10 years 2–3 years ning of clinical signs and other immunologic markers of pro- gression (Figure 44-6). FIGURE 44-6 Pattern of HIV antibody responses related to the Simple, rapid tests for detecting HIV antibodies are course of HIV infection. (CTL, cytotoxic T lymphocytes.) (Reproduced available for use in laboratories ill-equipped to perform EIA with permission from Weiss RA: How does HIV cause AIDS? Science 1993;260:1273. Reprinted with permission from AAAS.) tests and in settings where test results are desired with little delay. The simple tests can be performed on blood or oral fluid and are based on principles such as particle agglutina- tion or immunodot reactions. There are rapid tests that can A. Virus Isolation detect HIV antibodies in whole-blood specimens that require HIV can be cultured from lymphocytes in peripheral blood no processing. These tests can be performed outside the tra- (and occasionally from specimens from other sites). The ditional laboratory setting. The mean time to seroconver- numbers of circulating infected cells vary with the stage of sion after HIV infection is 3–4 weeks. Most individuals will disease (Figure 44-4). Higher titers of virus are found in the have detectable antibodies within 6–12 weeks after infection, plasma and in peripheral blood cells of patients with AIDS whereas virtually all will be positive within 6 months. HIV as compared with asymptomatic individuals. The magni- infection for longer than 6 months without a detectable anti- tude of plasma viremia appears to be a better correlate of body response is very uncommon. the clinical stage of HIV infection than the presence of any antibodies (Figure 44-6). The most sensitive virus isola- C. Detection of Viral Nucleic Acid or Antigens tion technique is to cocultivate the test sample with unin- HIV nucleic acid testing (NAT) assays, such as the RT-PCR, fected, mitogen-stimulated peripheral blood mononuclear DNA PCR, and branched DNA (bDNA) tests, are commonly cells. Primary isolates of HIV grow very slowly compared used to detect viral nucleic acid in clinical specimens. The with laboratory-adapted strains. Viral growth is detected RT-PCR assay uses an enzymatic method to amplify HIV by testing culture supernatant fluids after about 7–14 days RNA; the bDNA assay amplifies viral RNA by sequential for viral reverse transcriptase activity or for virus-specific oligonucleotide hybridization steps. These molecular-based antigens (p24). tests are very sensitive and form the basis for plasma viral The vast majority of HIV-1 antibody-positive persons load determinations. The HIV RNA levels are important will have virus that can be cultured from their blood cells. predictive markers of disease progression and valuable However, virus isolation techniques are time consuming and tools with which to monitor the effectiveness of antiviral laborious and are limited to research studies. PCR amplifica- therapies. Dried blood spot specimens are an alternative to tion techniques are commonly used for detection of virus in plasma specimens for viral monitoring in resource-limited clinical specimens. settings. Early diagnosis of HIV infection in infants born to B. Serology infected mothers can be accomplished using plasma HIV-1 Test kits are commercially available for measuring antibod- RNA or whole-blood DNA PCR to detect chromosomally ies by enzyme-linked immunoassay (EIA). If properly per- integrated (proviral) DNA. The presence of maternal anti- formed, these tests have a sensitivity and specificity exceeding bodies makes serologic tests uninformative. 98%. When EIA-based antibody tests are used for screening Low levels of circulating HIV-1 p24 antigen can populations with a low prevalence of HIV infections (eg, be detected in the plasma by EIA soon after infection. blood donors), a positive test in a serum sample must be con- The antigen often becomes undetectable after antibod- firmed by a repeat test. If the repeat EIA test is reactive, a ies develop (because the p24 protein is complexed with confirmation test is performed to rule out false-positive EIA p24 antibodies) but may reappear late in the course of Riedel_CH44_p655-p672.indd 664 04/04/19 5:12 PM  CHAPTER 44 AIDS and Lentiviruses   665 infection, indicating a poor prognosis. Fourth-generation Phenotypic resistance tests involve growth of recombi- HIV diagnostic assays that include HIV antibody and p24 nant virus in the presence of antiviral drugs. The relevant antigen detection can decrease the window period when genes (reverse transcriptase, protease, or integrase) are earlier serologic tests would not detect infection. Newer cloned from the patient’s virus into a laboratory HIV strain fifth-generation tests simultaneously detect and differ- and the concentration of drug that inhibits 50% of viral rep- entiate HIV-1 antibody, HIV-2 antibody, and p24 anti- lication (IC50) is determined. The ratio of patient virus IC50 gen. Detection of p24 antigen in HIV antibody-negative to the reference IC50 value indicates the fold resistance to the individuals is important because individuals in this stage tested drug. are highly viremic and can readily transmit infection. HIV resistance testing is recommended at the time of HIV NAT further reduces the infectious window period initial diagnosis and when managing treatment failures or and is commonly performed on patients with suspected suboptimal viral load reduction. Genotypic resistance testing acute HIV infection, health care workers exposed through is the standard method, but phenotypic testing can be useful needlestick injuries, and blood donors. in patients with complex resistance mutation patterns. D. HIV Resistance Testing HIV genotyping is the most common method to determine Epidemiology viral resistance. It is performed by sequencing portions of the A. Worldwide Spread of AIDS reverse transcriptase and protease genes to identify mutations AIDS was first described in the United States in 1981 as a known to confer resistance to inhibitors of these gene prod- new disease entity in homosexual men. Twenty years later, ucts. Mutations are identified as promoting resistance if they AIDS was recognized as a worldwide epidemic that continues allow virus to be grown in the presence of drug, or are associ- to expand. It is estimated that more than 35 million people ated with clinical treatment failures. Databases maintained worldwide are living with HIV/AIDS, the majority having by the International AIDS Society and Stanford University been infected by heterosexual contact (Figure 44-7). In 2009, are updated with newly identified resistance mutations. it was estimated that 1.8 million people died of AIDS and Development of an optimal treatment regimen is compli- that 2.6 million new infections with HIV occurred, including cated, requiring knowledge of viral resistance patterns, drug 370,000 children, many of whom were babies infected peri- activities, side effects, and interactions and typically requires natally. The World Health Organization estimates that more a specialist in HIV treatment. than 36 million people worldwide have died of AIDS and that Assays are also available to assess HIV integrase and over 16.6 million children had been orphaned, 14 million of fusion inhibitor resistance. Coreceptor tropism is a pheno- whom were living in sub-Saharan Africa. typic assay to determine whether virus is likely to respond to The epidemic varies by geographic region. Based on 2009 CCR5 antagonist drugs. data, sub-Saharan Africa had the highest number of HIV Western & Eastern Europe Central Europe & Central Asia 820,000 1.4 million North America [720,000–910,000] [1.3–1.6 million] 1.5 million East Asia [1.2–2.0 million] 770,000 [560,000–1.0 million] Middle East & North Africa Caribbean 460,000 South & South-East Asia 240,000 [400,000–530,000] [220,000–270,000] 4.1 million [3.7–4.6 million] Sub-Saharan Africa Central & South America 22.5 million [20.9–24.2 million] Oceania 1.4 million [1.2–1.6 million] 57,000 [50,000–64,000] FIGURE 44-7 Adults and children estimated to be living with HIV/AIDS, by continent or region, as of December 2009, totaling 33.3 million. It is estimated that about 1.8 million people worldwide died of HIV/AIDS in 2009. (Data from the Joint United Nations Program on HIV/AIDS.) Riedel_CH44_p655-p672.indd 665 04/04/19 5:12 PM  666   SECTION IV  Virology infections (Figure 44-7). In certain high-prevalence cities minority communities were disproportionately affected, in Africa, as many as one of every three adults was infected accounting for about two-thirds of reported HIV/AIDS cases. with the virus. The epidemic here appears to have stabilized, Heterosexual transmission was increasingly more common, although often at high levels. Major efforts are being made to and about one-quarter of new diagnoses were in women. distribute antiretroviral therapies in the most highly impacted Most heterosexually acquired AIDS cases were attributed to countries. Infections were spreading also in southern and sexual contact with an injecting drug user or a partner with southeastern Asia (especially in India, China, and Russia). HIV infection. Despite recommendations issued by the Cen- Because AIDS tends to strike young adults and workers in ters for Disease Control and Prevention in 2006 to have HIV their prime, the AIDS epidemic is having devastating effects screening be part of routine medical care for persons aged on social and economic structures in some countries. 13–64 years, it is estimated that, in 2011, 20% of those living Group M viruses are responsible for most HIV-1 infec- with HIV were unaware of their infection. tions worldwide, but subtype distributions vary. Subtype C By the end of 2007, over 1.5 million HIV/AIDS cases predominates in southern Africa, subtype A in West Africa, were estimated to have occurred (of which over 500,000 had and subtype B in the United States, Europe, and Australia. resulted in death). Over 1 million persons are living with HIV-2 has remained localized primarily to West Africa. HIV/AIDS in the United States, and an estimated 50,000 new The World Health Organization estimates that of all the cases occur each year. The death rate decreased for the first new HIV infections each year, 90% are occurring in develop- time in 1996, reflecting the use of antiretroviral combination ing countries. In those countries, AIDS is overwhelmingly a therapy and prevention of secondary opportunistic infec- heterosexually transmitted disease, and there are about equal tions (Figure 44-8). numbers of male and female cases. Pediatric AIDS increased as the number of HIV-infected It is thought that the rapid dissemination of HIV globally women increased. It was estimated that 1650 newborns in the latter part of the 20th century was fostered by massive acquired the virus in 1991 in the United States. The num- migration of rural inhabitants to urban centers, coupled with bers of new infections have been reduced dramatically by the international movement of infected individuals as a conse- development in 1994 of zidovudine antenatal, intrapartum, quence of civil disturbances, tourism, and business travels. and neonatal therapy (see below). From transmission rates of 25–30% with no interventions, drug treatments have reduced B. United States transmission rates to less than 2%. Mother-to-child trans- The face of the AIDS epidemic has changed in the United mission continues to occur because of undiagnosed HIV States since 1981. At first, most of the cases occurred in infection in the mother and lack of medical treatment. homosexual men. Then the disease was identified in hemo- The success in reducing perinatal HIV transmission in philiacs and injecting drug users. By 2005, racial and ethnic the United States prompted efforts to reduce this route of AIDS surveillance case definition expanded No. of living with AIDS diagnosis/HIV infection 80 1,200 No. of AIDS diagnoses/deaths (in thousands) Introduction of highly active antiretroviral therapy AIDS diagnoses 1,100 70 AIDS deaths 1,000 60 Living with HIV infection 900 (in thousands) Living with AIDS diagnosis 800 50 700 40 600 500 30 400 20 300 200 10 100 0 0 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 Year FIGURE 44-8 Estimated numbers of persons living with HIV/AIDS and of AIDS deaths in the United States from 1981 to 2008. (Reproduced with permission from Centers for Disease Control and Prevention in HIV surveillance—United States, 1981–2008. MMWR Morb Mortal Wkly Rep 2011;60:689.) Riedel_CH44_p655-p672.indd 666 04/04/19 5:12 PM  CHAPTER 44 AIDS and Lentiviruses   667 infection in other countries. Programs such as the President’s The routes of transmission (blood, sex, and birth) Emergency Plan For AIDS Relief (PEPFAR) have improved described above account for almost all HIV infections. There drug access and reduced maternal–fetal transmission in sev- has been considerable concern that in rare circumstances eral countries, though more remains to be done. In 2013, more other types of transmission may occur, such as through than 11 million people in low- and middle-income countries “casual” contact with HIV-infected persons or insect vectors, with HIV had access to antiretroviral therapy. but there is no strong evidence of virus transmission under these casual conditions. C. Routes of Transmission High titers of HIV are found in two body fluids—blood and semen. HIV is transmitted during sexual contact (including Prevention, Treatment, and Control genital–oral sex), through parenteral exposure to contami- A. Antiviral Drugs nated blood or blood products, and from mother to child A growing number of antiviral drugs are approved for treat- during the perinatal period. The presence of other sexually ment of HIV infections (see Table 44-4 and Chapter 30). transmitted diseases, such as syphilis, gonorrhea, or herpes Classes of drugs include both nucleoside and nonnucleo- simplex type 2, increases the risk of sexual HIV transmis- side inhibitors of the viral enzyme reverse transcriptase and sion as much as a 100-fold because the inflammation and inhibitors of the viral protease enzyme. The protease inhibi- sores facilitate the transfer of HIV across mucosal barri- tors are potent antiviral drugs because the protease activity ers. Asymptomatic virus-positive individuals can transmit is absolutely essential for production of infectious virus, and the virus. Since the first description of AIDS, promiscuous the viral enzyme is distinct from human cell proteases. Newer homosexual activity has been recognized as a major risk classes of drugs include fusion inhibitors that block virus factor for acquisition of the disease. The risk increases in entry into cells, entry inhibitors that block coreceptor CCR5 proportion to the number of sexual encounters with differ- binding by HIV, and integrase inhibitors that interfere with ent partners. the chromosomal integration required for HIV replication. Transfusion of infectious blood or blood products is an Therapy with combinations of antiretroviral drugs, effective route for viral transmission. For example, over 90% referred to as HAART, became available in 1996. It often of hemophiliac recipients of contaminated clotting factor can suppress viral replication to below limits of detection in concentrates in the United States (before HIV was detected) plasma, decrease viral loads in lymphoid tissues, allow the developed antibodies to HIV. Injection users of illicit drugs recovery of immune responses to opportunistic pathogens,