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Where Does HIV Live?
Justin Stebbing, M.D., Ph.D., Brian Gazzard, M.D., and Daniel C. Douek, M.D., Ph.D.
New England Journal of Medicine
April 29, 2004, Number 18
The Simian Origins of HIV
Cellular Receptors for HIV
The Cellular Home of HIV

CD4+ T Cells
Dendritic Cells
CD8+ T Cells
Natural Killer T Cells
Natural Killer Cells
The Anatomical Home of HIV
Lymphoid Organs
The Central Nervous System
The Genitourinary Tract
Conclusions and Future Perspectives
The worldwide dissemination of human immunodeficiency virus (HIV) over the past four decades is one of the most catastrophic examples of the emergence, transmission, and propagation of a microbial genome.1 We now know that thecellular and anatomical sites of HIV replication influence the course of the infection, the ability of antiretroviral therapy to reduce viremia, and the establishment of the viral reservoir. This highly mutable virus inserts its genome into the genomes of crucially important cells of the host and, despite therapy, maintains a reservoir of latent HIV within the body.2 The virus has apredilection for activated HIV-specific CD4+ T cells, although other cells are also susceptible to the virus. This tropism for particular cells is determined mainly by cellular receptors to which HIV attaches in order to enter cells. In this review, we will discuss the origins of HIV and its cellular and anatomical localization.
The Simian Origins of HIV
The earliest documented case of HIV infection in humans was identified in a sample of serum from Kinshasa (Democratic Republic of Congo) that was stored in 1959.3 On the basis of the HIV type 1 (HIV-1) sequences obtained from this andnumerous other, more recent isolates, it has been estimated that the main (M) group of HIV-1 strains diversified in humans in about 1931 (95 percent confidence interval, 1911 to 1941).4 Similarly, the most recent common ancestors of HIV type 2 (HIV-2) subtypes have been dated to the 1940s.5
There is persuasive evidence that HIV-1 came to humans from the chimpanzee (Pan troglodytes), which harbors the related simian immunodeficiency virus (SIVcpz) and lives in central Africa.6,7 HIV-2, whose DNA has 40 to 60 percent homology with HIV-1 DNA, originated from the SIVsm of the sooty mangabey (Cercocebus atys) monkeys of coastal West Africa, from Senegal to the Ivory Coast, the endemic epicenter of HIV-28 (Figure 1). In these areas, nonhuman primates are kept as pets and butchered for food, suggesting routes of transmission — monkey and ape to human — that are in accord with phylogenetic data implying cross-species infection.9 Estimates of when HIV was introduced into the human population, on the basis of a molecular clock and the distribution of SIV genomic sequences among the chimpanzees of central Africa, render it highly improbable that contaminated poliovirus vaccines were the source of HIV.
HIV-1 originates from a single subspecies of the chimpanzee, Pan troglodytes troglodytes. HIV-2 originates from the sooty mangabey, Cercocebus atys. Panels A and B kindly provided by Katrina Boardman, Marc Hauser, and Irwin Bernstein. In Panel C, the radial phenogram demonstrates the close relationship between HIV and SIV sequences (distances indicate the relative degree of evolutionary relatedness). Env sequences (gp120) were obtained from the National Center forBiotechnology Information (accession numbers HIV-1 AY093606[GenBank] , SIVcpz AF135498[GenBank] , HIV-2 U67352[GenBank] , and SIVsm U48824[GenBank] , available at http://www.ncbi.nlm.nih.gov/). The evidence used to substantiate cross-species contamination includes similarities in genomic organization, phylogenetic relatedness, prevalence in the natural host, geographic coincidence, and plausible routes of transmission. At least three chimpanzee-to-human events created the HIV-1 M, N, and O groups, and at least seven sooty mangabey-to-human events created HIV-2 groups (formerly known as subtypes) A through G.
Strikingly, in all known instances of infection of the natural primate host of SIV, neither a disease resembling the acquired immunodeficiency syndrome (AIDS) nor a profound depletion of CD4+ T cells develops, despite the presence of very high viral loads.8,10 In contrast, transmission of SIV to unnatural hosts, such as the rhesus macaque (Macaca mulatta) or humans, causes a progressive loss of CD4+ T cells and a high degree of susceptibility to opportunistic infections. The importance of this point cannot be overstated and must surely lie at the core of the pathogenic mechanisms of HIV, which is in effect a zoonotic infection. It is unclear why SIV infection of its natural hosts fails to cause disease, but recent studies have shown that SIV does not elicit the prominent T-cell activation that is seen in chronic HIV infection. Other studies that analyzed polymorphisms in major-histocompatibility-complex genes suggest that present-day animals, which have SIV infection but no disease, may in fact represent the survivors of an ancient retroviral pandemic.11
Cellular Receptors for HIV
One year after the identification of the human T-cell lymphotropic virus that became known as HIV-1,12,13 the particular susceptibility of CD4+ helper T cells to infection by the virus was explained by the discovery that CD4 is a receptor with high affinity for gp120, the viral-envelope glycoprotein.14,15 Indeed, the crucial role of CD4+ T cells in a range of immune functions appeared sufficient to account for the clinical effects of HIV-1 infection, despite the discrepancy between the number of infected CD4+ T cells in the blood and the extent of immune dysfunction.
Another inconsistency was that the transfection of mammalian cell lines with the gene for human CD4 did not make them susceptible to HIV infection, implying that CD4 is not the sole receptor for HIV. Almost a decade later, a second group of receptors was identified. This group consists of the cell-surface receptors that bind chemokines, a family of cytokines that mediate chemotaxis. Two of these receptors are relevant to HIV infection; the first to be recognized was originally named fusin.16 It is now designated CXCR4 and serves as a receptor for HIV strains that characteristically appear late in infection and were previously known as syncytium-inducing or T-cell--tropic viruses. The second chemokine receptor, CCR5, is the receptor for primary HIV and SIV strains previously referred to as nonsyncytium-inducing or macrophage-tropic viruses.17,18 Studies of disease progression in humans19,20 and in nonhuman primates21 have established that the tropism of viral isolates for CXCR4 or CCR5 clearly defines the cellular targets for HIV in vivo.
The Cellular Home of HIV
There is evidence that HIV is present in cells from both the innate and the adaptive arms of the immune system. Soon after the promulgation of the "hit hard and early" hypothesis, which advocates treatment with multiple antiretroviral drugs as early as possible after infection,22 it was recognized that viral rebound occurred after even long periods in which HIV was undetectable in plasma. The use of advanced techniques of cell purification has made it possible to show that replication-competent HIV remains in CD4+ T cells and that these cells constitute a long-term reservoir of potentially infectious virus.
CD4+ T Cells
A distinctive feature of HIV-1 infection is a profound loss of CD4+ T cells, the main home of HIV. The dramatic loss of CD4+ T cells accounts for many of the manifestations of HIV disease23; however, although HIV is clearly a cytopathic virus24 and renders infected cells targets for HIV-specific CD8+ T cells, the mechanisms that underlie the depletion and dysfunction of CD4+ T cells are not well understood. Substantial depletion of mucosal CD4+ T cells probably occurs in the early stages of acute infection, possibly owing to viral cytopathogenicity and the action of HIV-specific CD8+ T cells. A number of events follow that conspire to deplete CD4+ T cells over the protracted, chronic phase of the infection. These factors, which together impose a homeostatic strain on the maintenance of the population of CD4+ T cells, are thought to include chronic activation of T cells, inhibition of thymic output, suppression of the bone marrow, destruction of lymph-node architecture, and low-level ongoing infection of memory CD4+ T cells. Although it is the sustained immune activation induced by HIV infection that underlies the high rates of proliferation and death of both CD4+ and CD8+ T cells, the pool of CD4+ T cells, which is already depleted in acute infection, is more vulnerable to the effects of this disrupted homeostasis.25
Recently, the use of polychromatic flow cytometry to sort multiple subtypes of T cells to more than 99 percent purity, followed by quantification of HIV DNA in thesorted cells, has confirmed that the predominant infected population consists of memory CD4+ T cells; naive CD4+ T cells are infected at a lower frequency.26Interestingly, the memory CD4+ T cells that have a longer history of in vivo proliferation actually contain little HIV, thus providing indirect evidence that infection of a T cell by HIV shortens its in vivo life span. The high numbers of proliferating CD4+ T cells that are characteristic of the chronic immune activation produced by HIV infection also act as a constant supply of cellular targets. By inducing the activation of T cells, HIV generates its own substrate, thus perpetuating viral replication.27
Since HIV replicates most efficiently in activated CD4+ T cells, it might be expected that the HIV-specific population of CD4+ T cells would become infected more frequently than the general population of CD4+ T cells. By this means, the number of HIV-specific helper T cells would decrease, resulting in the loss of immune control of viral replication. In support of this view, recent experiments have shown that HIV-specific memory CD4+ T cells contain more HIV DNA than memory CD4+ T cells of other specificities at all stages of the infection.25 Thus, by inducing a response in HIV-specific CD4+ T cells, HIV can infect the very cells elicited against it.
Another crucial aspect of CD4+ T-cell infection is that a small proportion of the infected cells stop proliferating and enter a pool of infected quiescent T cells, theso-called latent reservoir, which, even though there may be other cellular reservoirs, appears sufficient to ensure lifelong persistence of the virus even with the use of current regimens of highly active antiretroviral therapy (HAART).28 In late 1997, three groups independently demonstrated that a pool of CD4+ T cells from which virus could be isolated persists in the majority of infected people despite suppression of viremia by HAART.29,30,31 This reservoir is long-lived, with a half-life of 44 months, even after as many as 7 years of suppression of viral replication.2 It is likely that the latent reservoir is continually being maintained by undetectable levels of viral replication, even during effective HAART, but it is also clear that many viral species that evolve in the patient, including drug-resistant mutants, are also archived from the early stages of infection.32 The clinical implications of this process are critical, since drug-resistant virus, once it has evolved and been selected for, may reemerge at any time.
Dendritic Cells
Dendritic cells capture antigens in peripheral tissues, transport them to lymphoid organs, digest them, and display the resulting peptides to T cells. These cells are only moderately susceptible to HIV infection in vitro,33,34 probably because they express low levels of CD4, CXCR4, and CCR5.35 Indeed, infection of Langerhans cells, which belong to the family of dendritic cells, depends on the levels of CCR5 they express.36 During experimental transmission of SIV across the vaginal epithelium of the rhesus macaque, intraepithelial Langerhans cells become productively infected at a low level within 18 hours after inoculation of the virus. When these cells migrate to local lymph nodes, they can infect resident CD4+ T cells with the virus.37,38 In humans, the first cells to become infected by HIV may, however, be CD4+ T cells and not dendritic cells,39,40 especially within the thin rectal and cervical epithelia. Nevertheless, dendritic cells may play a role in the initial phases of HIV infection because they display a specific cell-surface lectin, dendritic-cell--specific intercellular adhesion molecule 3--grabbing nonintegrin (DC-SIGN), which captures carbohydrate moieties on the gp120 of HIV and mediates clustering of dendritic cells with T cells.41,42 DC-SIGN, which is not expressed by Langerhans cells, appears to act by concentrating virus in dendritic cells or by transmitting bound HIV to CD4+ T cells that express either CXCR4 or CCR5 surface receptors.43
Thus, DC-SIGN on the surface of dendritic cells captures HIV, thereby allowing efficient cross-infection of CD4+ T cells in the vicinity. This mechanism can account for the discrepancy between the ability of dendritic cells to capture virus and their susceptibility to productive infection. DC-SIGN neither triggers fusion of HIV with T cells nor circumvents the requirement for HIV receptors on the target cells, but allows efficient infection by aggregating virus on the surface of dendritic cells. Microscopy of conjugates formed between live dendritic cells and CD4+ T cells suggests that CD4, CXCR4, and CCR5 on the T cell are recruited to points of contact between the two types of cells, while dendritic cells concentrate HIV in these same regions (Figure 2).44
The recruitment of virus (green-fluorescent-protein--labeled HIVLAI, depicted as green dots) to sites of cell--cell interaction suggests a mechanism by which dendritic cells enhance viral infectivity as virus particles cluster along the surface between the dendritic cell and the CD4+ T cell (blue areas denote DNA, and red areas actin). Concomitantly, HIV receptors travel to this site, enabling HIV particles to travel between cells. The large surface area of the dendritic cells may enable as many particles as possible to gather at the interface. Image kindly provided by Thomas Hope.
Cells of the macrophage lineage are an important target of HIV, and productively infected macrophages have been found in both untreated patients and those receiving HAART.45,46 Macrophages and their precursors express only low levels of CD4 but abundant levels of heparan sulfate proteoglycans, especially syndecan. When expressed in nonpermissive cells, syndecan allows the adsorption of HIV by binding to gp120. The adsorbed HIV retains its infectivity and can be transmitted to T cells in culture.47 Like DC-SIGN, syndecan binds to HIV efficiently and is an important factor in viral dissemination and tropism. Another receptor expressed bymacrophages, CD91, binds to heat-shock proteins, including those on the HIV virion membrane.48 Although macrophages may be a primary target for infection andsource of virus production, particularly during opportunistic infections,49 the longevity of macrophages in vivo and their role as a persistently infected long-term reservoir is unclear.
CD8+ T Cells
There have been reports of HIV infection of CD8+ T cells, particularly in patients with late-stage disease.50 The expression of CD4 by activated CD8+ T cells mayexplain these findings.51 Recent studies using high-purity flow-cytometric sorting have shown that the frequency of infected CD8+ memory T cells is very low inpatients with HIV infection, but that the cells within this population that express CD4 are preferentially infected.26 However, naive CD8+ T cells, unlike naive CD4+T cells, are rarely, if ever, infected. This finding suggests that if thymocytes, the majority of which express both CD4 and CD8, become infected with HIV, they areunlikely to survive and enter the peripheral T-cell pools; otherwise one would expect the frequency of infected naive CD8+ T cells to be higher. Whether the infection of activated CD8+ T cells affects the development or course of AIDS or the viral reservoir remains to be determined.
Natural Killer T Cells
A distinct subgroup of CD4+ T cells termed natural killer T cells also appears to be susceptible to infection by HIV.52 Unlike the highly variable antigen receptor ofCD4+ T cells, the receptor on natural killer T cells is invariant and specific for hydrophobic glycolipid antigens presented by CD1 molecules on dendritic cells. CD4+ natural killer T cells express CCR5 and are highly susceptible to infection with CCR5-tropic strains of HIV, which may explain the depletion of these cells during HIV infection.52 The clinical significance, if any, of such depletion remains unclear.
Natural Killer Cells
Natural killer cells, which do not require prior sensitization to recognize and kill targets, express CD4 and can be productively infected by both CXCR4- andCCR5-tropic strains in vitro. Viral DNA persists in natural killer cells even after one or two years of effective HAART.53 This finding suggests that natural killer cellsact as a viral reservoir.
The Anatomical Home of HIV
Lymphoid Organs
The tissue distribution of target cells defines the anatomical reservoirs of HIV. In acute infection, the mucosa are the dominant site of infection. The gastrointestinal tract and other mucosal tissues contain at steady state at least half of the body's T cells.54 These T cells are predominantly CCR5+, and many of them are in an activated state. During acute HIV infection, the virus rapidly multiplies and propagates in the lymphoid component of mucosal tissues, thereby profoundly affecting the immune system soon after infection. In macaques infected with SIV, intestinal CD4+ T cells are almost entirely depleted within three weeks after infection.39 Despite few studies of the most acute stages of HIV-1 infection in humans, it is likely that there is a similar profound and rapid loss of intestinal CD4+ T cells early in infection. Moreover, this loss of CD4+ T cells persists through the later stages of the infection.55,56,57,58 The large loss of mucosal CD4+ T cells so early in the infection suggests that counts of peripheral-blood CD4+ T cells underestimate the degree of T-cell destruction. The effects on mucosal T cells are likely to set the stage for the marked perturbations of T-cell homeostasis that define the chronic phase of the infection.23
During the acute phase and into the chronic phase of infection, the sites of HIV replication begin to include other peripheral lymphoid organs. High levels of HIVaccumulate in lymph-node follicular dendritic cells, which are of epithelial origin and therefore distinct from the dendritic cells of hematopoietic origin discussedabove.59 These cells may become a major reservoir of infectious HIV in the later stages of infection.60,61,62,63,64 There are many more infected cells in lymph nodes than in the blood (which in any case contains fewer than 2 percent of total body lymphocytes). Indeed, ongoing high-level viral replication and the ensuing activation of T cells within the lymph nodes may be responsible for the destruction of lymph-node architecture that is typical of the infection.65
The primary sites of lymphopoiesis — the thymus and bone marrow — may also be sites of HIV replication. In both children and adults, HIV infection causesinvolution of the thymus and depletion of thymocytes.66,67,68 SIV infection in rhesus macaques causes similar changes.69 Indeed, studies of cultured thymus tissue and of human thymus grafts in mice with severe combined immunodeficiency have shown that thymocytes at almost all stages of maturation are targets of HIV infection.70,71,72,73,74 Although hematopoietic progenitors in the bone marrow are not infected with the virus, the stromal auxiliary cells are persistently infected and dysfunctional.75 Although these events are likely to result in diminished production of T cells, it remains unclear whether the thymus and bone marrow act as anatomical reservoirs for the virus.
The Central Nervous System
The capacity of HIV to cause disease in the central nervous system suggests that the virus may persist and replicate there.45,76,77 Viral particles have been identified in brain-derived macrophages and microglia78,79 and isolated from the cerebrospinal fluid.80 In patients with neurologic symptoms associated with AIDS,HIV-specific antibodies have been detected in the cerebrospinal fluid.81,82 HIV isolated from cerebrospinal fluid tends to be more macrophage-tropic than does virus circulating in plasma, and thus HIV replication may be compartmentalized in the central nervous system.83,84 HIV-specific T-cell responses have also been observed, and CD8+ T cells in the brain tissue of the SIV macaque model exhibit a restricted repertoire of T-cell clones.85 Apart from direct damage to microglia, the mechanisms underlying the neurologic complications of HIV infection are unclear. The HIV transactivating factor Tat, which is taken up into neurons by means of CD91,86 is thought to exert neurotoxic effects by increasing the production of nitric oxide and interfering with the integrity of the blood--brain barrier.87 The penetration of antiretroviral drugs into the central nervous system and the maintenance of high therapeutic levels of these drugs are matters of concern, since the levels of all classes of antiretroviral agents are lower in the cerebrospinal fluid than in the plasma.88 Indeed, different patterns of drug-resistance mutations have been observed in viral isolates from paired samples of plasma and cerebrospinal fluid from patients who are following nonsuppressive antiretroviral regimens.89 Thus, the central nervous system may act as a reservoir for replication of HIV even during maximal treatment with antiretroviral agents.
The Genitourinary Tract
The blood--testis barrier does not prevent virus from reaching semen.90,91 HIV replication has been detected in T cells and macrophages present in semen92 andwithin the renal epithelium.93,94 In situ hybridization of renal-biopsy tissue from patients with HIV nephropathy suggests the presence of a reservoir of HIV, even inpatients with undetectable levels of viral RNA in plasma. Similarly, HIV has been detected in macrophages and lymphocytes within the cervix.95 As with the virusthat is found in cerebrospinal fluid, the genotypic and phenotypic compartmentalization of HIV from genital secretions suggests that antiretroviral drugs have difficulty penetrating into this site.96,97 Although levels of antiretroviral drugs in seminal fluid are similar to levels in plasma,90,91 drug levels in cervical fluid are very low. Furthermore, it is unclear whether HIV can become truly latent in the genitourinary tract or whether it merely continues to replicate slowly, impervious to the effects of HAART. These factors clearly affect not only the course of the infection within individual patients, but also the transmission of the virus to sexual partners.
Conclusions and Future Perspectives
HIV infection appears to be a zoonosis, with AIDS resulting from the failure of HIV to adapt to a relatively new host, or perhaps a failure of humans to adapt to HIVinfection. Either mechanism suggests that HIV and humans will eventually adapt and coexist, akin to the situation observed in natural SIV infection of chimpanzeesand certain Old World monkeys. Clearly, the epidemic has already caused dramatic shifts in mortality within human populations worldwide. Evidence is alsoemerging that immunologic pressure against HIV in human hosts is causing population-dependent genetic changes in the virus itself. For example, theimmunogenicity of regions of the virus that are potential targets for CD8+ T cells restricted through the more common HLA class I alleles has been widely eliminated from the pool of viruses circulating in the human population.98 This suggests that the viruses currently infecting people already reflect the changes of an evolving host--pathogen relationship.
Although the eradication of HIV is a daunting task, the goal of long-term containment of viral replication and prevention of immune dysfunction is eminently achievable. It is unlikely that current or more potent drug regimens, even if initiated early, will be able to eradicate virus within an infected person, since the T-cell reservoir of virus diminishes too slowly.2 Furthermore, treatment options may be stymied by the archiving of drug-resistant variants in this reservoir. Attempts to interrupt therapy in a structured fashion, aimed variously at reducing the toxic effects of the drugs or boosting HIV-specific immunity, have unfortunately failed to prove feasible, because the virus inevitably and rapidly reemerges.99,100 However, the reactivation of latent reservoirs in order to "flush out" and then tackle the virus is currently a subject of intense and promising investigation.101 Such alternative strategies are critical, since drug-related toxic effects are becoming one of the major obstacles to long-term therapy.102
The challenges that we face include the design of vaccines that will prevent the early, rapid depletion of mucosal CD4+ T cells during which the infection establishes itself. We must also continue to develop therapeutic agents that will suppress viral replication while they deplete the reservoir of archived viruses in HIV-infected cells in all the organs where these cells may reside. A detailed understanding of the localized cellular and anatomical sites of HIV replication is crucial to such an endeavor.
Source Information
From the Department of Immunology, Division of Investigative Science, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Chelsea and Westminster Hospital, London (J.S., B.G.); and the Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. (D.C.D).
Address reprint requests to Dr. Douek at the Vaccine Research Center, National Institutes of Health, 40 Convent Dr., Bethesda, MD 20892, or at ddouek@nih.gov.
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