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TIMELINE AIDS pathogenesis: what have two decades of HIV research taught us?
Sarah L. Rowland-Jones
22 years ago, the first cases of an acquired immunodeficiency syndrome afflicting young, homosexual American men were reported, heralding what we now know to be the beginning of the HIV epidemic. Since then, billions of US dollars have been invested in HIV research in the hope of gaining a better understanding of this infection and how to prevent and treat it. What are the landmarks in HIV research over the past two decades, and what questions still remain to be answered? What has the intense study of HIV infection taught us about other virus infections and how our immune system responds to them? reported3–5; we now know this virus as human immunodeficiency virus type 1 (HIV-1). This finding allowed the development of a reliable test for HIV infection — looking for the presence of circulating immunoglobulin-G antibodies specific for HIV — which provided the basis for screening of donated blood and for large-scale epidemiological studies. It is worth noting that, in contrast to the analysis of many other infections, HIV-specific antibodies have been widely used for two decades as a marker of persistent infection, rather than as an indicator of a past infection that has been cleared. Within a few years, it became clear that the virus was spreading rapidly beyond the ‘risk groups’, with particularly disturbing rates of infection in sub-Saharan Africa6. We now know that more than 40 million people are infected with HIV-1 throughout the world, and the epidemic shows no sign of dissipating (FIG. 2). Despite occasional dissenting views, the evidence that HIV causes AIDS is now overwhelming7. The tragic infection of a few laboratory workers with HIV in the early 1980s, who have now developed the disease8, means that HIV has fulfilled Koch’s third postulate as the cause of AIDS, something that has still not been achieved for several other important human infections. However, despite the enormous extent of the epidemic and the intensity of the research drive to understand the infection, many questions about HIV remain unanswered. Is this infection genuinely new to the human population and, if so, how and when did it first occur in humans? What are the main mechanisms responsible for the relentless decline in CD4+ T-cell function and number, In 1981, the attention of physicians in New York and San Francisco was caught by the bizarre phenomenon of young homosexual men dying from infections that a healthy immune system would normally repel with ease1,2 (FIG. 1 and TIMELINE) Within a year, the term ‘acquired immunodeficiency syndrome’ (AIDS) was coined by the United States Centers for Disease Control and Prevention (CDC) to describe this combination of opportunistic infections and tumours occurring in the setting of a markedly reduced circulating CD4+ T-cell count. Initially, the disease seemed to be confined to a few high-risk groups of people, and speculation at that time implicated a diverse range of possible behavioural and environmental mechanisms. However, the suspicion that AIDS has an infectious cause was confirmed when, in 1983–1984, the isolation of a retrovirus from the blood of patients with AIDS was 1981: first AIDS cases recognized in United States 1959: first known case of HIV-1 infection in Kinshasa, Democratic Republic of Congo 1986: first reports of high rates of HIV-1 infection in East Africa 1983: HIV-1 identified in France and the United States 1986: HIV-2 isolated from West Africa 2003: HIV-1 seroprevalence >40% in parts of southern Africa Figure 1 | The sites of key events in the development of the HIV epidemic. This world map highlights where the initial cases of infection with HIV-1 and HIV-2 in West and sub-Saharan Africa were recorded. NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | APRIL 2003 | 3 4 3 © 2003 Nature Publishing Group PERSPECTIVES Timeline | Important events in HIV immunology
First AIDS cases noted in United States CD4 identified as the main receptor for HIV-1 HIV-2 isolated in West Africa Strong HIV-specific cytotoxic T-cell responses identified in the blood and lungs of patients Cytotoxic T cells shown to select virus escape variants Lymph-node studies reveal the extent of HIV-1 infection of lymphoid tissue First studies of T-cell dynamics in HIV infection 1981 1983 1984 1985 1986 1987 1988 1989 1991 1993 1995 HIV-1 isolated in France and United States HIV-specific antibody test developed for blood screening First anti-HIV drug, AZT, enters clinical use Loss of T-helper responses to HIV antigens identified as a characteristic defect in HIV infection Virus-load tests reveal high levels of plasma viraemia, particularly during acute HIV infection CC-chemokines shown to suppress HIV-1 replication in vitro which eventually paralyses host immunity? Will everyone who is exposed to and infected with the virus ultimately develop AIDS and die? How does a virus consisting of a mere 10,000 nucleotides so successfully evade control by the human immune system? In this article, I focus on the main findings that have illuminated the central question of HIV pathogenesis — how does infection with this diminutive retrovirus lead to such devastating, and apparently inevitable, immunodeficiency?
Where did HIV come from? The earliest documented case of infection with HIV-1 was identified in a sample stored in 1959 from the city now known as Kinshasa in the Democratic Republic of Congo (DRC)9. The lack of other good-quality material from early time points in the history of HIV makes it hard to be sure about the precise timing of the human epidemic. An important feature of HIV is its inherent variability, which is a function of both the lack of a proof-reading mechanism in the viral reverse transcriptase enzyme10 and the rapid replication rate of the virus11. Together, these features allow HIV to mutate rapidly and they enable variants that are resistant to drugs or immune responses to emerge under selection pressure. Assuming that the evolutionary behaviour of the virus has been consistent over time, it is possible to use the wealth of available HIV-1 sequence data from viruses with known dates of sampling to model virus diversification and to estimate the timing of important events in the virus’ past. In this way, Korber et al.12,13 proposed that the main (M) group of HIV-1 strains that are currently infecting the human population began to diversify around 1930. This gives us some idea of the minimum length of time for which HIV has infected humans, but it does not tell us exactly how or when the first ancestral virus infected a human. It seems probable that much of the early evolution of the virus took place in central Africa, particularly in the DRC, as this is the country from which the most diverse range of virus sequences has been recovered13. The most probable source of HIV in humans is the inadvertent introduction of a simian immunodeficiency virus (SIV) from a closely related primate species. In 1986, a second retrovirus strain, known as HIV-2 and having approximately 40–60% homology with HIV-1, was isolated from patients with AIDS from West Africa14,15. Careful studies of HIV-2 genomes showed that there is a remarkably close relationship between HIV-2 and SIV strains that infect sooty mangabeys (SIVsm) in the same parts of West Africa16, and it is now thought that there have been at least three separate entries of SIVsm into the human population. For some time, the origin of HIV-1 was less clear — the most closely related viruses were those found occasionally in captive chimpanzees, but these SIVcpz strains had much less homology with HIV-1 than SIVsm did with HIV-2. The mystery was at least partly solved when SIVcpz strains with greater similarity to HIV-1 were discovered in a chimpanzee species whose habitat had marked geographical overlap with the regions of central Africa where the M group of HIV-1 is believed to have originated17. It is still not clear to what extent chimpanzees are infected with these SIV strains in the wild or exactly how humans first became infected.
HIV and immunodeficiency macaques21. Most chimpanzees artificially infected with HIV-1 remain immunologically intact over several decades. Even the transition of a virus between species is not always accompanied by severe disease: the vast majority of individuals infected with HIV-2 will die of unrelated causes, even though a small number of individuals develop a progressive immunodeficiency that is indistinguishable from AIDS caused by infection with HIV-1 (reviewed in REF. 22). So, a fundamental aspect of understanding HIV-1 pathogenesis is to explain why this retrovirus should cause such devastating immunopathology in most infected people (FIG. 3). HIV infects CD4+ T cells. Early on, clinicians determined that the main immunological feature of advanced HIV-mediated disease is a fall in the number of circulating CD4+ T cells, and this feature rapidly became the main surrogate marker for HIV-related immunodeficiency. Once the absolute CD4+ T-cell count falls below a threshold of 200 T cells per mm3 in the peripheral blood, an individual becomes vulnerable to characteristic AIDSdefining opportunistic infections and malignancies. The predilection of the virus to infect CD4+ T helper (TH) cells, as well as other CD4-expressing cells, such as macrophages and dendritic cells (DCs), was explained when, in 1984, the CD4 molecule was shown to be a high-affinity receptor for the virus23,24. The crucial role of CD4+ T cells in coordinating a range of immune functions seemed to be sufficient to account for the impact of HIV-1 on the human immune system, although there remained a discrepancy between the number of infected CD4+ T cells in the circulation and the extent of TH-cell dysfunction. This issue was resolved to some extent when investigators began to look at lymphoid tissue; it emerged that HIV-infected T cells are trapped in the follicular DC network of lymph nodes25, so that in the early stages of infection, Studies of other immunodeficiency viruses in their natural hosts indicated that, although the virus establishes a persistent infection, there is often little discernible evidence of disease or even of immune dysfunction. Sooty mangabeys and African green monkeys infected with SIVsm and SIVagm, respectively, seem to be completely healthy18–20, even though similar SIV strains can rapidly kill 344 | APRIL 2003 | VOLUME 3 www.nature.com/reviews/immunol © 2003 Nature Publishing Group PERSPECTIVES
established a clear basis for the understanding of HIV-1 tropism in vivo (following which the terms ‘NSI/SI’ and ‘macrophage-tropic/T-celltropic’ were abandoned in favour of defining the co-receptor usage — R5 or X4 — of a particular HIV isolate). Although there is an illunderstood requirement for CCR5 for the virus to establish a primary infection in most cases, during the course of infection, the tropism broadens as a result of mutations in the V3 loop of the virus envelope protein, allowing the virus to infect a wider repertoire of T cells. CCR5 is expressed mainly by memory T cells of the TH1 type39 and it is upregulated after activation (which helps to explain the early loss of antigen-specific CD4+ T cells), whereas CXCR4 is more widely expressed, particularly by naive T cells40. When the infecting virus quasispecies (that is, the population of virus variants that have evolved from the initial infecting strain) changes its predominant tropism from R5 to X4 in late disease, this is often accompanied by a sharp decline in the number of CD4+ T cells41. These discoveries have also opened up the possibility that the chemokine receptors or their ligands could provide new targets for anti-retroviral therapy. T-cell dynamics are affected by HIV-1. The development of sensitive techniques to measure HIV RNA in virions (or virus-load assays) allowed reliable quantification of replicating HIV in the circulation, and subsequently in other compartments. It was shown that there is a massive burden of HIV in acute Three-drug anti-retroviral drug regimens introduced Thymic function shown to be impaired in HIV infection Structured treatment interruption in acute HIV infection associated with enhanced immune responses and HIV control 1996 1998 1999 2000 2002 Chemokine receptors CCR5 and CXCR4 identified as the main co-receptors for HIV Closely related SIVep2 isolated from chimpanzees HIV shown to adapt to HLAassociated selection pressure at a population level 1,000-fold more infected cells are present in lymphoid tissue than can be detected in the blood26,27. However CD4+ T-cell dysfunction still seemed to be greater than could be accounted for by either the extent of T-cell depletion or the total number of infected cells, particularly during the long asymptomatic period of infection with HIV. The preference of HIV to replicate in recently activated cells28 might explain the most characteristic CD4+ T-cell abnormality — namely, a qualitative loss of T-cell help, first for the response to HIV itself and then for the response to other recall antigens29, which is evident from the earliest stages of infection30,31. The best explanation for this pattern of T-cell loss is that HIV-1 preferentially infects HIV-specific CD4+ T cells32, probably in the lymph nodes, where the activated T cells that are recruited to respond to HIV-1 antigens would be highly susceptible to infection. Subsequent recruitment and activation of other T-cell populations responding to intercurrent infections would lead to their infection and deletion also, resulting in the impairment of other antigen-specific responses. The specific loss of TH cells might underlie the ultimate failure of the immune system to control HIV replication33 and the subsequent vulnerability to opportunistic infections, most of which are past infections of the HIV+ individual that are reactivated as the CD4+ T-cell count falls. Despite the identification of CD4 as a crucial receptor for HIV, the transfection of many mammalian cell lines with human CD4 did not make them permissive for HIV infection, and almost a decade later, a second family of receptors for HIV was identified. These are members of the family of seventransmembrane spanning chemokine receptors, and although many members of this family can function as receptors for HIV, the main ones to be used are CCR5 and CXCR4. The first of these to be identified was CXCR4, which is a receptor for the strains of HIV that are characteristically found late in infection, then known as syncitium-inducing (SI) or T-cell-tropic viruses34. The fact that CXCR4 is a chemokine receptor tied in with the finding that a trio of CC-chemokines — macrophage inflammatory protein 1α (MIP1α; CCL3), MIP1β (CCL4) and RANTES (regulated on activation, normal T-cell expressed and secreted; CCL5) — were able to mediate potent suppression of replication of the other main HIV-1 phenotype, the non-syncitiuminducing (NSI) or macrophage-tropic strains that establish primary HIV-1 infection35. Shortly afterwards, several groups showed that the chemokine receptor that binds these three HIV-suppressing chemokines, CCR5, is indeed the receptor for primary NSI strains of HIV-1 (REFS 36–38). These important observations 1.2 million 980,000 570,000 6 million 550,000 440,000 1.2 million 1.5 million 29.4 million 15,000 Figure 2 | The extent of the worldwide HIV-1 epidemic. This figure shows the estimated number of people living with HIV-1 infection in the main regions throughout the world by the end of 2002, based on statistics from the Joint United Nations Programme on HIV/AIDS (UNAIDS). NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | APRIL 2003 | 3 4 5 © 2003 Nature Publishing Group PERSPECTIVES
infection42 and that the subsequent steadystate level of plasma virus load is closely related to the ultimate clinical outcome43. Moreover, a much more dynamic picture emerged of the clinically ‘latent’ period of HIV-1 infection, during which virus replication continues to be active in many compartments44, even if blood levels of the virus are low26. Studies of virus dynamics led to a debate about what happens to the pool of T cells in an HIV-infected individual. In healthy individuals, ill-understood mechanisms mediate rigorous control of lymphocyte homeostasis to maintain a constant number of T cells in the body. If T cells are lost for some reason, new or ‘naive’ T cells can differentiate from bone-marrow precursors (in which case they must undergo thymic selection) or the existing pool of ‘memory’ T cells can divide in the periphery. Even in HIV infection, T-cell homeostasis is preserved in the early stages of infection, with CD4+ T-cell loss being balanced by a corresponding increase in the number of CD8+ T cells, a situation that is maintained until shortly before the onset of AIDS45. The first studies of human T-cell dynamics in HIV-1 infection used highly effective anti-retroviral drugs to perturb the steady state of HIV-1 replication and then extrapolated rates of T-cell destruction and production from their numbers during and after therapeutic intervention. These influential studies provided a picture of a highly dynamic process of CD4+ T-cell production and destruction on a massive scale (some 70-fold greater than normal), which was likened to an open tap running into a freely draining sink46,47. The model predicted that, for a while, the level in the sink is maintained, but eventually the cistern becomes exhausted and the water level — or total number of lymphocytes — falls. These important studies focused on the number of peripheral CD4+ T cells, and it is now thought that much of the early rise in the number of CD4+ T cells in response to therapy could be explained by the redistribution of trapped T cells from lymphoid tissues48. Moreover, when the fates of CD4+ and CD8+ T cells were considered separately in studies of telomere length, surprising results were obtained. Telomeres are segments of DNA at the ends of chromosomes that become shorter with successive cell divisions, so telomere length can be used as a surrogate marker for cell division. In HIV-1 infection, the main effect on telomere length was shown to occur in the CD8+ T-cell subset, whereas the telomere length of CD4+ T cells was not markedly altered49,50. These findings were difficult to HIV infection Plasma virus load Asymptomatic period AIDS and death CD4+ T-cell count R5 virus X4 virus Memory CD4+ T cells, DCs and macrophages Virus evolution Naive CD4+ T cells CD4+ inflection point 6–12 weeks 1–15+ years 2–3+ years Figure 3 | Schematic diagram of the course of HIV-1 infection. This diagram illustrates the relationship between HIV-1 virus load (red line) and CD4+ T-cell count (bue line) over time in a typical case of untreated HIV-1 infection. DC, dendritic cell. reconcile with the previous picture of CD4+ T-cell production and destruction on a massive scale, and they indicated that, instead, much of the turnover occurs amongst CD8+ T cells, presumably antigen-specific cytotoxic T lymphocytes (CTLs) that are responding to the virus. However, these conclusions were challenged by subsequent studies of T-cell turnover. Human T-cell turnover is a difficult area to study in vivo, but using a strategy in which glucose labelled with the stable (that is, nonradioactive) 2H isotope is taken up into newly synthesized DNA and can subsequently be measured in different cell subsets using mass spectrometry, Hellerstein et al.51 showed that the lifespan of both CD4+ and CD8+ T cells is shortened (to around one third of the normal length) in HIV infection. Although CD8+ T-cell output increases modestly, there is no corresponding increase in the production of new CD4+ T cells. More recent studies using bromodeoxyuridine (BrdU) labelling indicate that increased T-cell turnover in HIV infection is manifested as a shift of both CD4+ and CD8+ T-cell subsets from a compartment that is slowly turning over to one that turns over much more rapidly; this shift closely reflects the level of plasma virus load52. These findings are best explained by a general increase in immune activation from early in infection53, which in SIV-infected macaques affects all lymphocyte sub-populations54. One important feature of HIV pathogenesis seems to be a failure in the production of naive CD4+ T cells to replace those damaged by the virus. This could reflect a failure in the generation of lymphocyte precursors from the bone marrow, thymic dysfunction or both. It used to be thought that the thymus, which steadily atrophies after adolescence, had a trivial role in adult life, but recent evidence has challenged this view. When the T-cell receptor of T cells is generated in the thymus by selecting ‘components’ from a ‘genetic library’, the unused DNA segments are neatly excised and persist as a stable DNA circle in the cell. Douek and colleagues55 showed that these thymic rearrangement excision circles (TRECs) can be used as a marker for recent thymic emigrants, and that the TRECs are gradually diluted in peripheral T cells as the cells divide. Studies in healthy adults showed that some degree of thymic selection of lymphocytes continues well into old age, although it gradually diminishes over time. In HIV infection, production of TRECs was substantially reduced from an early stage of infection, which indicated that HIV causes marked thymic impairment55. An alternative view of these findings, proposed by Miedema and colleagues56, is that the number of circulating TREC-containing cells reflects not only thymic output, but also the peripheral division of T cells, with the latter being increased in HIV infection, probably as a consequence of T-cell activation57. They hypothesize that persistent immune hyperactivation leads to increased peripheral T-cell division, even of naive T cells, for which the intrinsically low thymic activity of adults is unable to compensate. These views are not necessarily mutually exclusive58. The impact of HIV-1 infection on T-cell turnover implies that the virus affects both CD4+ and CD8+ T cells to a degree that cannot be explained on the basis of CD4+ T-cell infection alone; one component of this effect 346 | APRIL 2003 | VOLUME 3 www.nature.com/reviews/immunol © 2003 Nature Publishing Group PERSPECTIVES
is likely to be an unprecedented degree of immune activation57,59. This aspect of HIV pathogenesis remains largely unexplained. Intriguingly, levels of immune activation are significantly lower in asymptomatic patients infected with HIV-2 than in patients infected with HIV-1 (REF. 60), and studies of T-cell turnover in sooty mangabeys naturally infected with SIVsm, which remain in good health, indicate that T-cell turnover is normal despite high levels of plasma viraemia and CD4+ T-cell infection61. This indicates that indirect mechanisms of CD4+ T-cell loss, probably as a consequence of immune activation, have an important part in HIV pathogenesis. How effective is the immune response? Much of the immune system seems to be engaged in the fight against HIV infection. The CD8+ T-cell response is unusually vigorous, so that for the first time in human studies of an antiviral response, HIV-specific CTL activity could be detected directly in peripheral blood62 and other compartments, such as the lung63. The technology that was subsequently developed for the precise quantification of antigen-specific CD8+ T cells in blood using peptide–MHC tetramers64 has been used a great deal in studies of HIV-1 infection, showing that a large number of peripheral CD8+ T cells target the virus. There is a close temporal relationship between the rise in the number of virus-specific CTLs and the fall in plasma viraemia that is seen in acute HIV-1 infection65,66. However, although in stable, untreated, chronic infection, some (but not all) studies have shown an inverse correlation between the number of tetramer-staining CD8+ T cells and virus load67, the magnitude or specificity of the CTL response has shown no clear relationship to parameters such as CD4+ T-cell counts or clinical outcome68. It became increasingly clear that HIV-1 has acquired several strategies to evade the human immune response, prominent amongst which is the high mutation rate of HIV-1, which allows escape variants to emerge rapidly under selection pressure. The suggestion that virus escape mutants emerge during HIV infection that could evade the dominant CTL response69 was initially controversial, but it is now clear that CTL-mediated selection of the virus quasispecies is evident from early in infection70,71 and, moreover, that the adaptation of the virus to immune pressure can be detected at the population level through a correlation between HLA haplotype and virus sequence72. The failure of specific T-cell help, together with DC dysfunction, might further undermine the ability of the host to respond to new virus variants. Similarly, a high proportion of the body’s B cells produce HIV-specific antibodies, but HIV-specific antibodies rarely neutralize primary strains of HIV and the virus rapidly mutates to evade antibody-mediated control73.
HIV and host genes: mutual selection?
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The efficiency of acute infection of CD4+ T cells is markedly enhanced in the setting of antigen-specific immune activation. J. Exp. Med. 183, 687–692 (1996). 2. 3. 4. Another area of rapid advances in HIV research is the study of host genetic polymorphisms that can affect the probability of acquiring HIV-1 infection and the rate of disease progression (reviewed in REF. 74). The identification of CCR5 as the main co-receptor for HIV entry was closely linked to studies of cellular resistance to HIV-1 infection in vitro that identified a deletion in the CCR5 gene that prevents expression of the receptor in homozygotes (approximately 1% of Caucasians)75. Subsequently, several genetic polymorphisms have been described that affect the outcome of HIV-1 infection, notably in the HLA region and in receptors used by HIV and their ligands (reviewed in REF. 74). Although it is too early in the HIV epidemic to see how selection pressure from the infection will shape the human population, it seems highly probable that this will occur in regions where HIV is spreading most rapidly. The rapid mutation rate of HIV-1 has already provided some evidence that the virus is adapting to the populations it affects through a process of HLA-associated selection72, and further adaptation seems highly probable.
Conclusions 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. The past 20 years of HIV research have generated an unprecedented level of understanding about how a pathogen interacts with its human host to cause disease. Important immunological concepts — such as the demonstration of heterozygote advantage for HLA haplotypes76 and understanding the strength of immune selection pressure on a pathogen from both humoral and cellular immune responses — have been illuminated by HIV research, and major technological advances, such as studies of T-cell dynamics and the use of peptide–HLA tetramers to study antigen-specific T cells, have largely been developed for studies of HIV. Although many important questions remain unanswered, the study of infectious diseases in general will undoubtedly benefit from what has been learned about infection with HIV.
Sarah L. Rowland-Jones is at the MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 0DW, UK. e-mail: [email protected]
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I would like to thank Andrew McMichael for critical review of the manuscript. Online links
DATABASES The following terms in this article are linked online to: Entrez: http://www.ncbi.nlm.nih.gov/Entrez/ HIV-1 | HIV-2 | SIV LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/ CCL3 | CCL4 | CCL5 | CCR5 | CXCR4 FURTHER INFORMATION Centers for Disease Control and Prevention: http://www.cdc.gov/ Access to this interactive links box is free online. 348 | APRIL 2003 | VOLUME 3 www.nature.com/reviews/immunol © 2003 Nature Publishing Group ...
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This note was uploaded on 07/12/2011 for the course BIO 620 taught by Professor Hardy during the Spring '11 term at University of Florida.
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