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J Med Primatol doi:10.1111/j.1600-0684.2008.00328.x ORIGINAL ARTICLE AIDS pathogenesis: a tale of two monkeys Guido Silvestri Departments of Pathology and Laboratory Medicine, and Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, and Yerkes National Primate Research Center of Emory University, Atlanta, GA, USA Keywords AIDS – macaques – mangabeys – SIV Correspondence Guido Silvestri, University of Pennsylvania School of Medicine, 705 Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19143, USA. Tel.: +1 215 5735363; fax: +1 215 5735369; e-mail: [email protected] Despite many years of intense scientific effort, the pathogenic mechanisms underlying the immunodeficiency that follows human immunodeficiency virus (HIV) infection are still poorly understood. This lack of understanding is likely the main reason why at present there is neither a cure nor a vaccine for AIDS. Important clues on the immunopathogenesis of primate lentiviral infections have been provided by comparative studies of two simian models of SIV infection: the non-pathogenic SIV infection of sooty mangabey, an African natural host species, and the pathogenic SIV-infection of non-natural host rhesus macaques, that develop a disease that closely resembles AIDS in humans. While the final mechanisms underlying the difference in infection outcome between these two species are still incompletely understood, a series of recent studies has allowed the identification of key similarities and differences between the two models of infection. In this article we summarize these findings and review the main implications in terms of HIV pathogenesis, therapy, and vaccines. AIDS pathogenesis: a tale of two monkeys With several million deaths per year, the AIDS pandemic represents without any question one of the worst medical tragedies of modern times. As such, the etiologic agent of this disease, the human immunodeficiency virus (HIV), is correctly considered a highly pathogenic microbe. Since 1983, the year when the virus was discovered, a great deal of progress has been made in terms of understanding the genetic and molecular structure of the virus, elucidating its life cycle, and designing compounds able to inhibit HIV replication. The practical result of these conceptual advances is the availability of highly effective antiretroviral regimens whose widespread usage had a dramatic effect on reducing mortality, morbidity, and transmission of the infection, particularly in developed countries. Unfortunately, the mechanisms linking the replication of HIV with the development of a progressive and eventually life-threatening immunodeficiency have not yet been fully elucidated. In my opinion, this lack of 6 understanding of the interaction between the virus and the host immune system is the reason why we are unable to eradicate the infection and do not have an effective AIDS vaccine. Historically, the field of HIV immunology has by and large adapted a basic working model – in part derived from real or perceived analogies with murine models of viral infections – which postulates that antiHIV adaptive immune responses, both humoral or cellular, are inherently ‘good’ as they have the potential of suppressing virus replication, either via antibodymediated neutralization or cytotoxic T-lymphocyte (CTL)-based lysis of infected cells. While plenty of evidence indicates that the adaptive immune system may control HIV/SIV replication under certain circumstances [24], the reality of the interaction between HIV and the host immune system is much more complex. The well-known observation that HIV preferentially infects and kills activated CD4+ T cells indicates that every adaptive immune response to this virus – which will involve the activation of CD4+ T helper J Med Primatol 37 (Suppl 2) (2008) 6–12 ª 2008 The Author Journal compilation ª 2008 Blackwell Munksgaard Silvestri cells – inevitably result in the generation of new fuel for HIV replication. As such, any attempt to artificially strengthen the in vivo immune responses to HIV with the intent of inhibiting virus replication is complicated by the potential, paradoxical risk of inducing more target cells for the virus. Furthermore, the tremendous ability of HIV to mutate and escape the host adaptive immune responses often delineates a scenario wherein vigorous but largely ineffective antiviral responses result in more damage than help to the overall function of the host immune system. This latter point is most eloquently revealed by the fact that during HIV infection the level of CD8+ T cell activation appears to predict disease progression even better than the level of virus replication itself [10, 11]. In keeping with this observation, several authors proposed that the state of chronic, generalized immune activation that is associated with HIV infection is a key determinant of AIDS pathogenesis [15, 17, 27, 43, 47]. The possibility that the replication of a cytopathic primate lentivirus which targets mainly activated CD4+ T cells does not necessarily leads to AIDS is illustrated by the well known observation that SIV infection of natural hosts African non-human primate species (including chimpanzees, sooty mangabeys, African green monkeys, mandrills, and several others) is typically non-pathogenic despite levels of viremia similar to those observed in HIV infection [7, 18, 36, 39, 46, 49]. While the exact mechanisms by which natural SIV hosts remain healthy are still relatively poorly understood, a number of key observations have been made over the past few years that have clarified several important immunological and virological aspects of these infections (reviewed in 14). In this article I will summarize these advances by reviewing what aspects of natural, non-pathogenic SIV infection of sooty mangabeys (SMs, a paradigmatic model of natural SIV infection) are either similar or different from what has been observed in the non-natural, pathogenic model of SIVmac infection of Indian rhesus macaques (RMs). I wish to emphasize that natural SIV infection of SMs is particularly relevant because SIVsmm, the virus infecting SMs, is the origin of HIV-2 epidemics in humans and the progenitor of the various RMadapted SIVmac viruses (i.e., SIVmac239, SIVmac251) that are commonly used for studies of AIDS pathogenesis and vaccines [16, 19]. The main postulate of this ‘tale of two monkeys’ is that any feature of the infection that is similar in SMs and RMs is unlikely to be a key determinant of the striking different outcomes observed in these two species. On the contrary, the identification of species-specific differences between SIV-infected SMs and RMs may provide useful J Med Primatol 37 (Suppl 2) (2008) 6–12 ª 2008 The Author Journal compilation ª 2008 Blackwell Munksgaard AIDS pathogenesis: a tale of two monkeys information with respect to the molecular and cellular mechanisms ultimately responsible for progression to AIDS. Common features of non-pathogenic SIV-infection of SMs and pathogenic SIV infection of RMs Perhaps surprisingly, in the backdrop of the clear difference of outcomes (i.e., pathogenic in RMs and nonpathogenic in SMs) there are actually numerous similarities in the immunological and virological features of SIV infection in these two monkey species. In both RMs and SMs, the acute infection is characterized by a peak of virus replication occurring between one and two weeks post-inoculation [12, 31, 45]. This peak is followed by a relatively rapid decline to levels ranging around 104–106 in SMs and 105–107 in SIVmac-infected RMs. While set-point viremia in SIVmac239- or SIVmac251-infected RMs is usually higher than in SMs, relatively lower levels of viremia are observed in RMs infected with uncloned SIVsmm who can still progress to AIDS [45]. The fact that the viremia of SIV-infected SMs is at least as high – or perhaps even higher – than that observed in untreated HIV-infected individuals (and in SIVsmm-infected RMs) indicates very clearly that the non-progressing phenotype of SMs cannot be simply attributed to lower levels of virus replication. In addition, if that were the case, one would expect some signs of disease progression in the animals with higher viremia – in analogy to what has been observed in HIV-infected humans [28, 29]. However, several studies have shown that there is no tendency to develop AIDS even in the SMs with highest viral load [44, 48]. Interestingly, in both SMs and RMs the transition from the acute to the chronic phase of infection results in a (quasi) steady state of virus replication and CD4+ T cell homeostasis – with the important difference, however, that CD4+ T cell counts progressively decline overtime in the vast majority of RMs but only in a small minority of SMs. The determinants of the level of set-point viremia are still poorly understood in both species, with the relative contribution of immune control versus target cell availability remaining still unknown. Interestingly, the effect of CD8+ T cell deletion seem to be more dramatic in RMs than in SMs, thus suggesting that CTLs may be more important in these animals in determining the setpoint viremia [1, 20, 25, 26, 42]. A caveat of these experiments is that the mechanisms by which CD8+ cell depletion is followed by increased viral load are complex and not well understood, particularly as it has become 7 AIDS pathogenesis: a tale of two monkeys clear that CD8 depletion results in a change of the activation state of CD4+ T cells which may have a direct effect on virus replication [1; Picker personal communication]. Interestingly, the level of SIV-specific CD8+ T cell responses measured by intracellular cytokine staining in response to ex vivo stimulation with SIV peptides appears to be similar in SMs and RMs [8, 51] and, for both species, lower than what has been observed in HIV-infected humans [2]. The lack of any evidence that the AIDS-resistant naturally SIV-infected SMs have ‘better’ or ‘stronger’ SIV-specific adaptive immune responses when compared to HIV-infected humans or SIV-infected RMs has profound theoretical implications, as it indicates that natural SIV hosts have evolved to a non-pathogenic type of infection independent of immune control of virus replication. From a more practical point of view, this observation emphasizes the tremendous challenge of artificially inducing, with an AIDS vaccine, a type of protective immunity that has not been selected for in many thousands of years of evolutionary pressure posed by lentiviruses on the primate immune system. In both SMs and RMs (as well as African green monkeys), the main cell type supporting virus replication appears to be a population of short-lived, activated CD4+ T cells [13, 32, 38]. In SIV-infected SMs, this conclusion is supported by at least four different lines of evidence. First, histological studies where virus replication is assessed by in situ hybridization in conjunction with staining for T cell markers indicate that the majority of infected cells are CD3+CD4+ [Estes and Silvestri, unpublished observations]. Second, the kinetics of plasma viral load decline after treatment with antiretroviral drugs indicates that 90%–99% of virus replication in SMs occurs on short-lived cells, thus compatible with activated CD4+ T cells [13]. Third, depletion of CD4+ T cells with an anti-CD4 monoclonal antibody that does not deplete macrophages is associated with marked decline in viral load [22]. Fourth, CD4+ T cells are severely depleted in mucosal tissues of SIV-infected SMs during the acute phase of infection, likely due to direct cytopathic effect of the virus [12]. Collectively these observations indicate that the nonpathogenic phenotype of SMs is not related to differences in the spectrum of target cells for virus replication. That SIV-infected SMs experience a rapid and dramatic deletion of mucosal CD4+ T cells whose kinetics is similar to that observed in SIVinfected RMs [12] is an observation of great interest, and suggests that the differences in mucosal immune function between pathogenic and non-pathogenic primate lentiviral infection develop during the chronic phase of infection [33]. Consistent with this hypothesis 8 Silvestri is the observation that the level of mucosal CD4+ T cells remains stable in chronically SIV-infected SMs while it progressively declines coincident with development of AIDS in SIV-infected RMs. The fact that SMs are able to deal with a rapid and significant depletion of mucosal CD4+ T cells is also consistent with the possibility that these animals have evolved to become less dependent on these cells to maintain an intact mucosal immunity. An alternative – but not mutually exclusive hypothesis – is that additional factors (i.e., lack of local immune activation, see next paragraph) may protect the CD4+ T cell-depleted mucosal immune system of natural SIV hosts. In this context, it is interesting to note that, in contrast to SIV-infected RMs and HIV-infected humans, SIVinfected SMs do not show any signs of microbial translocation from the intestinal lumen to the circulation [4]. As microbial translocation may be a key determinant of the generalized immune activation that is thought to cause systemic CD4+ T cell depletion and progression to AIDS in HIV-infected individuals, it is possible that, in SIV-infected SMs, a preserved mucosal immune function explains the paradox of a selective depletion of CD4+ T cells in the MALT but not in the blood or lymph nodes. Differences between non-pathogenic SIV infection of SMs and pathogenic SIV infection of RMs There are three main and consistent immunological differences between SIV-infected RMs and SMs, with the latter typically showing: (i) preservation of peripheral CD4+ T cell homeostasis; (ii) lower levels of immune activation; (iii) lower expression of CCR5 on CD4+ T cells (reviewed in 14). Normal or near normal levels of CD4+ T cells (i.e., >500/cm3) are observed in 85%–90% of naturally SIV-infected SMs despite many years of infection with a highly replicating virus [48]. It should be noted that the disconnection between peripheral CD4+ T cell counts (that are mostly normal) and mucosal CD4+ T cell levels (that are decreased after infection) is a typical feature of SIV-infected SMs that is not found in RMs or humans. Interestingly, moderate to severe systemic CD4+ T cell depletion is observed in 10%–15% of naturally SIV-infected SMs as well as a subset of experimentally SIV-infected SMs that developed a dual-tropic (i.e., CCR5 and CXCR4-using) variant of SIVsmm [30, 48]. The fact that even these animals with a persistently severe CD4+ T-cell depletion J Med Primatol 37 (Suppl 2) (2008) 6–12 ª 2008 The Author Journal compilation ª 2008 Blackwell Munksgaard Silvestri (i.e., CD4+ T cell counts <50/cm3 for over five years) do not progress to AIDS is a finding whose importance, in my opinion, is hard to overestimate, and which raises fundamental questions on the nature of lentivirus pathogenesis and the function of CD4+ T cells in primates. Does this observation indicate that in absence of other factors (i.e., immune activation? depletion of other cell types?) the immune system can successfully cope with a massive and persistent depletion of CD4+ T cells? Does it mean that CD4 depletion is more of a marker, rather than a cause, of the HIV-induced immunodeficiency? It is my hope that these unconventional and somewhat provocative hypothesis be taken very seriously by the scientific community as their testing might reveal previously unappreciated but in fact highly significant aspects of HIV/AIDS pathogenesis. The fact that SIV-infected SMs show markedly lower levels of immune activation when compared to SIV-infected RMs or HIV-infected humans has been shown in a fairly large number of studies [5, 6, 12, 21, 31, 44, 45, 48]. Consistent with their lower levels of immune activation, naturally SIV-infected SMs show low levels of bystander apoptosis and cell cycle dysregulation when compared to RMs [35]. While a previous study from our group suggested that differences in T cell activation and proliferation are apparent since the acute phase of infection [45], more recent studies indicate that the main differences in the level of immune activation between SMs and RMs are manifest during the chronic phase of infection [12]. The observation that natural, non-pathogenic SIV infection is characterized by low levels of immune activation has also been made in other species such as chimpanzees, AGMs and mandrills [5, 14, 23, 34, 36]. Collectively, these studies led several authors to hypothesize that attenuated immune activation protects natural SIV hosts from progression to AIDS in the face of chronic infection with a highly replicating cytopathic retrovirus [46, 49]. This hypothesis is clearly consistent with the finding that immune activation is a strong correlate of diseases progression in HIV-infected humans (reviewed in 8). The cellular and molecular mechanisms responsible for the low levels of immune activation in SIVinfected SMs are still poorly understood and likely complex. As mentioned above, a preserved integrity of the mucosal barrier with low levels of microbial translocation may provide significant protection from Toll-like receptor (TLR)-mediated activation of macrophages and dendritic cells with consequent downstream bystander activation of T cells [3, 4]. Also, a better ability of SIVsmm Nef to down-regulate CD3-TCR in infected CD4+ T cells may be instrumental to reduce J Med Primatol 37 (Suppl 2) (2008) 6–12 ª 2008 The Author Journal compilation ª 2008 Blackwell Munksgaard AIDS pathogenesis: a tale of two monkeys T cell activation – particularly in comparison with HIV-infected humans [41]. In addition, in SIV-infected SMs a lower production of IFN-a by plasmacytoid dendritic cells in response to certain viral TLR ligands may also set the tone for a less vigorous T cell response to SIV antigens [26]. At least in SIV-infected African green monkeys, increased activity of regulatory T cells during acute infection may also contribute to the attenuated immune phenotype [23]. While the hypothesis that low immune activation is the key to maintaining a healthy immune system in natural SIV hosts is supported by very strong correlative evidence, the ultimate proof of the ‘immune activation’ hypothesis would come from in vivo experiments wherein induction of AIDS in natural hosts is achieved by increasing their level of immune activation. The third main difference between SMs and RMs (and, more generally, between natural and non-natural hosts for primate lentiviral infections) is in the expression of CCR5 by CD4+ T cells. In RMs and humans, the fraction of CD4+ T cells expressing CCR5 is approximately 10%–20% in blood and >50% in mucosal tissues [37]. The enrichment in CD4 + CCR5 + T cells in the MALT is consistent with the known role of CCR5 as a marker of effector/effector memory T cell differentiation [40]. Intriguingly, the fraction of CD4+CCR5+ T cells in SMs – both uninfected and SIV-infected – is much lower, that is, in the range of 1%–5% in both blood and MALT [37, 50]. This low expression of CCR5 in SMs is specific for CD4+ T cells as levels comparable to those observed in RMs and humans are found in CD8+ T cells. While this finding is absolutely unequivocal, its precise pathophysologic meaning – particularly in the context of the non-pathogenicity of natural SIV infection – is still unclear. Obviously, the low expression of CCR5 on CD4+ T cells does not protect SMs from either horizontal transmission or virus replication in infected animals. Similarly, this low CCR5 expression does not protect CD4+ T cells from direct infection in vivo, as several lines of evidence indicate that CD4+ T cells, rather than macrophages or other non-CD4 cell types, produce the bulk of virus in SIV-infected SMs. A more likely possibility is that a restriction of CCR5 expression to more differentiated (i.e., effector/activated) CD4+ T cells will limit SIV replication to a subset of more ‘expendable’ CD4+ T cells – that is, cells that are likely doomed to die of activation-induced apoptosis regardless of their being infected or not. In this context, a significant beneficial effect in preserving CD4+ T cell homeostasis may result from protecting the pool of central memory CD4+ T cells from the 9 AIDS pathogenesis: a tale of two monkeys direct effect of virus replication [46]. An additional, non-mutually exclusive possibility is that low CCR5 expression on CD4+ T cells may protect SIV-infected SMs from immune activation, as CD4+CCR5+effector T cells may be less able to home to inflamed tissues and thus provide less of a substrate for SIV replication and further inflammation. This latter hypothesis is consistent with recent work indicating that, in HIVinfected humans, specific CCR5 genotypes protect from progression to AIDS independently of both viral load and cellular immune responses to HIV [9]. Finally, it is possible that low CCR5 expression on CD4+ T cells is involved in the resistance of SMs (and natural SIV hosts in general) from vertical transmission of the infection [46]. Implications in terms of HIV pathogenesis, therapy, and vaccines Understanding how primates and their lentiviruses have co-evolved to reach a pacific co-existence in nature will continue to provide crucial insights into human AIDS pathogenesis that, ultimately, may have important implications for the therapy and prevention of HIV infection and AIDS. In terms of therapeutic implications, I believe that defining the cellular and molecular mechanisms that dictate the obvious differences in immune activation and CCR5 expression between natural and non-natural hosts will aid in the design of new, immune-based therapies to be used, in addition to HAART, in the treatment of HIV infection. In terms of AIDS vaccine, the first major conclusion that can be drown from these studies of natural SIV infections is that thousands of years of co-evolution of African primates and their lentiviruses have resulted in a state of apathogenicity wherein virus replication is not controlled by the host immune system, thus emphasizing how daunting is the task of developing an AIDS vaccine. The second major implication of these studies is that the dissociation between virus replication and disease progression typical of SIV-infected natural hosts is an invitation to explore potential alternative strategy of AIDS prevention that will result in delayed disease progression without suppressing virus replication. Conflicts of interest The author has no conflict of interest. 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J Med Primatol 37 (Suppl 2) (2008) 6–12 ª 2008 The Author Journal compilation ª 2008 Blackwell Munksgaard