Generalized immune activation and innate immune responses in simian immunodeficiency virus infection

Bosinger, Steven E.a; Sodora, Donald L.b; Silvestri, Guidoa

doi: 10.1097/COH.0b013e3283499cf6
Innate immunity: Edited by William A. Paxton and Teunis B.H. Geijtenbeek

Purpose of review: Chronic immune activation is a key factor driving the immunopathogenesis of AIDS. During pathogenic HIV/simian immunodeficiency virus (SIV) infections, innate and adaptive antiviral immune responses contribute to chronic immune activation. In contrast, nonpathogenic SIV infections of natural hosts such as sooty mangabeys and African green monkeys (AGMs) are characterized by low immune activation despite similarly high viremia. This review focuses on the role of innate immune responses in SIV infection.

Recent findings: Several studies have examined the role of innate immune responses to SIV as potential drivers of immune activation. The key result of these studies is that both pathogenic SIV infection of macaques and nonpathogenic SIV infections of natural hosts are associated with strong innate immune responses to the virus, high production of type I interferons by plasmacytoid dendritic cells, and upregulation of interferon-stimulated genes (ISGs). However, SIV-infected sooty mangabeys and AGMs (but not SIV-infected macaques) rapidly downmodulate the interferon response within 4–6 weeks of infection, thus resulting in a state of limited immune activation during chronic infection.

Summary: Studies in nonhuman primates suggest that chronic innate/interferon responses may contribute to AIDS pathogenesis. Further, the ability of natural host species to resolve innate immune responses after infection provides a novel avenue for potential immunotherapy.

aYerkes National Primate Research Center, and Emory Vaccine Center, Emory University, Atlanta, Georgia

bSeattle Biomedical Research Institute, Seattle, Washington, USA

Correspondence to Guido Silvestri, MD, Yerkes National Primate Research Center, Emory University School of Medicine, 3014 EVC Building, 954 Gatewood Rd NE, Atlanta, GA 30329, USATel: +1 404 7279139; fax: +1 404 7277768; e-mail:

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The nonhuman primate models of simian immunodeficiency virus (SIV) or simian/human immunodeficiency virus (SHIV) infection represent the most biologically relevant and widely used animal model for HIV infection and AIDS. There are two basic types of SIV/SHIV infections – the pathogenic infection of experimental (i.e. nonnatural) Asian macaque hosts and the nonpathogenic infection of African natural hosts such as sooty mangabeys, African green monkeys (AGMs), and numerous others. Experimental SIV infection of macaques results in a disease characterized by high-level virus replication, progressive CD4+ T-cell depletion, chronic immune activation, and establishment of a mucosal and systemic immunodeficiency that closely resembles human AIDS. For this reason, pathogenic SIV infection of macaques has been used in many studies of HIV transmission, pathogenesis, prevention, and therapy that have been extremely influential in the field. In contrast, SIV infection of natural hosts is typically nonpathogenic despite robust virus replication, and results in preservation of the immune system, lack of chronic immune activation, and a lifespan similar to SIV-uninfected individuals [1,2]. An exception to the rule that natural SIV infections are nonpathogenic is the relatively understudied natural SIVcpz infection of chimpanzees that can progress to AIDS, albeit at a lower frequency than HIV-1-infected humans or SIV-infected macaques [3]. Over the past decade, many studies have investigated the factors underlying the benign nature of natural SIV infections, with numerous mechanisms proposed including lack of chronic immune activation, reduced infection of central memory CD4+ T cells, preserved or enhanced immune regeneration, absence of microbial translocation, and ability to mediate T helper function by CD3+CD4CD8 T cells [1,2]. In this review, we will discuss the role of chronic, generalized immune activation as a factor discriminating pathogenic and nonpathogenic SIV infections, and analyze in detail the similarities and differences between these two models in terms of innate immune responses to the virus.

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Chronic immune activation in pathogenic HIV and simian immunodeficiency virus infections

Chronic immune activation was proposed as a key determinant of AIDS pathogenesis in the late 1980s/early 1990s [4–6]. Shortly thereafter, Giorgi et al.[7] reported that the level of immune activation, as determined by the fraction of CD8+ T cells expressing CD38, is a very strong and independent correlate of disease progression. Strong support for the crucial role of immune activation in AIDS pathogenesis was then provided by studies of nonpathogenic SIV infections of natural hosts, in which high levels of virus replication are associated with low levels of immune activation [8]. The HIV-associated chronic immune activation is characterized by a constellation of immunological signs including increased frequency of lymphocytes expressing activation markers, high levels of activation-induced apoptosis, accelerated T-cell turnover as measured by direct labeling, and high plasma and tissue levels of pro-inflammatory mediators (reviewed in [9]). Importantly, these signs of chronic immune activation are clearly present during pathogenic SIV infection of macaques, thus emphasizing the relevance of this model in terms of HIV immunopathogenesis [9]. Whereas there is a broad consensus that chronic immune activation is a consistent feature of pathogenic HIV/SIV infections and plays an important role in the pathogenesis of AIDS, there is still controversy as to what causes the HIV-associated immune activation. Factors that have been proposed to contribute to this phenomenon include the direct effect of specific virus proteins (Env, Nef, Tat, etc.); the generation of innate and adaptive immune responses to the virus; an ineffective regulation of antiviral immune responses; a bystander activation of T and B lymphocytes caused by increased production of pro-inflammatory cytokines (e.g. TNF-α, IL-1, IL-6, and several others); the translocation of microbial products from the intestinal lumen to the systemic circulation, in which they can activate the immune system by binding to certain Toll-like receptors (TLRs); and the presence of clinical or subclinical coinfections [10]. More recently it was proposed that preferential infection of central-memory CD4+ T cells (as opposed to effector-memory CD4+ T cells) is a factor favoring the maintenance of chronic immune activation by concentrating the bulk of antigenic load in central lymphoid tissues [2]. Regardless of the mechanisms responsible for its establishment, chronic immune activation is thought to disrupt CD4+ T-cell homeostasis and overall immune function by several mechanisms including increased number of available target cells for the virus (i.e. activated CD4+ T cells); exhaustion of antiviral CD8+ T cells; excessive lymphocyte apoptosis; suppression of T-cell regeneration; accelerated proliferative senescence of lymphocytes; and disruption of the lymphoid tissue niche necessary for the proper functioning of naive and central-memory T cells [10,11].

In the following sections of this article we will focus on the potential role of innate antiviral immune responses as key mediators of the chronic immune activation associated with pathogenic SIV infection of macaques, and how rapid regulation of these responses may be responsible for the low immune activation found in the chronic phase of infection of natural SIV hosts.

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Innate immune responses in simian immunodeficiency virus-infected Asian macaques

The role of the innate immune response to HIV has been the subject of intense study over the past few years. In SIV-infected macaques, recent studies have examined the role of specific innate leukocyte subsets and/or effector molecules [macrophages, natural killer (NK) T cells, γδ T cells, defensins, etc.]. Here we will mainly discuss the contribution to AIDS pathogenesis of the axis of innate antiviral immunity represented by plasmacytoid dendritic cells (pDCs), type I interferon production, and upregulation of interferon-stimulated genes (ISGs). In both humans and nonhuman primates, pDCs represent approximately 0.2–0.5% of total peripheral blood mononuclear cells and are identified phenotypically as lineage-HLADR+CD123+/BDCA2+ and functionally as producing type I interferons (α, β) as well as a number of pro-inflammatory cytokines and chemokines (i.e. TNF-α, IL-6, CXCL10, CCL4, and CCL5) [12]. It should be noted that BDCA2 is not commonly used to define pDCs in macaques due to poor cross-reactivity of reagents, but has been used successfully in other non-human primate (NHP) species. Importantly, pDCs express high levels of two key TLRs, TLR-7 and TLR-9 [13–15], that mediate the response to viral ssRNA and DNA, respectively, with the production of type I interferons in response to TLR-7/9 stimulation being dependent on the phosphorylation and nuclear translocation of the transcription factor IRF7 [16]. Upon activation in vivo, pDCs upregulate CCR7 and CD62L, migrate to lymph nodes, and mature into typical antigen-presenting cells [17,18]. Whereas pDCs are not the only cell type capable of producing type I interferons, most studies indicate that they are the key cells that dictate the tempo and magnitude of the in-vivo type I interferon response to a viral infection.

In HIV-infected humans, the observations that pDCs are both depleted and dysfunctional when compared to uninfected controls led to the formulation of a model in which pDCs contribute to the immune control of HIV via their ability to induce antiviral responses and augment cytotoxic T-lymphocyte (CTL) and NK responses [19]. The longitudinal kinetics of pDC levels were more rigorously defined in SIV-infected macaques, in which these cells increase rapidly in blood during the first few days of infection, then rapidly decline to levels approximately 50% of baseline by the time of peak viremia (days 10–14 after infection) and remain reduced throughout the chronic phase of SIV infection [20–24]. Of note, the SIV-associated decline of circulating pDCs is associated with increased levels of these cells in lymph nodes [22–25]; however, it remains unclear whether this increased pDC homing to lymph nodes persists during the chronic phase of SIV infection [21–24]. Collectively, these studies of pDCs in SIV-infected macaques appeared to support the model in which these cells play a protective role against disease progression.

Several recent findings, however, have suggested that pDC activation and type I interferon responses may not be wholly beneficial to the HIV/SIV-infected host and, in fact, may be detrimental by promoting immune activation and/or bystander apoptosis. First, the observation that ISGs are upregulated during chronic SIV infection of macaques indicated that even though pDCs are partially depleted from the blood and/or lymph nodes, they (or complementing cell types) are able to promote strong type I interferon responses [26–28]. Second, in-vitro and ex-vivo studies have shown that HIV-activated pDCs may acquire the ability to induce apoptosis of CD4+ T cells via a TRAIL/DR5-dependent mechanism [29,30]. Third, stimulation of human pDCs with HIV RNA induces the production of indoleamine 2,3 dioxygenase (IDO), thereby promoting the differentiation of T-regulatory cells, thus potentially suppressing a number of antiviral immune responses [31]. Fourth, acute SIV infection is associated with significant migration of pDCs to the intestinal mucosa, in which these cells persist throughout the chronic phase of infection in association with high levels of local immune activation [32•–34•]. A recent study has suggested that during macaque SIV infection virtually complete depletion of pDCs occurs and, therefore, these cells could not contribute to immunopathogenesis [35]. In this regard, the observations that pDCs localize in the gut after infection are particularly important because they indicate that the depletion of pDCs from peripheral blood during SIV infection is likely due to mucosal retention, rather than to a net loss of pDCs due to cell death; and pDCs remain in the gut well into chronic infection and cannot be ruled out as candidate drivers of immune activation. Finally, as discussed in detail in the next section, natural SIV hosts display robust pDC activation and interferon production during acute SIV infection that is rapidly resolved upon the transition to chronic infection (reviewed in [36]). In light of these data, and in combination with recent human studies demonstrating chronic activation and dysregulation of pDCs in HIV infection [37,38••,39••], an alternative model has been proposed by several investigators in which pDCs and/or the type I interferon response may represent a major cause of immune activation and immunopathogenesis during pathogenic HIV and SIV infections [40,41].

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Innate immunity in nonpathogenic simian immunodeficiency virus infection of African natural hosts

The role of innate immune responses to SIV during nonpathogenic infections of sooty mangabeys and AGMs has been the subject of several recent studies aimed at testing the hypothesis that attenuated innate immunity to the virus is responsible for, or at least associated with the low levels of immune activation observed during the chronic phase of these infections. In this regard, all published works indicate that, despite robust virus replication, the key markers of innate immune activation, such as production of type I interferons by pDCs, upregulation of ISGs, and activation of macrophages and natural killer cells, are not elevated during chronic SIV infection of natural hosts [25,42••,43••,44,45,46••,47•]. A number of hypotheses have been proposed to explain this intriguing phenomenon, including an intrinsic defect in the ability of pDCs to respond to TLR-7 and TLR-9 signaling, the presence of active inhibitory mechanisms (acting either at the level of pDCs or through cross-talk with other cell types), and features of the maturation and/or anatomical distribution of these cells that limit their interaction with viral products (reviewed in [10]).

The possibility that innate immune responses to SIV are intrinsically muted in natural SIV hosts was proposed by Mandl et al.[25] based on a comparative in-vitro study of pDC function in sooty mangabeys and macaques. This study described a reduced production of IFN-α protein in response to TLR-7 and TLR-9 stimulation of sooty mangabey pDCs when compared to the same cells of macaques [25]. These authors concluded that divergent TLR-7 and TLR-9 signaling was present in sooty mangabeys compared with macaques, even though they observed a similarly strong upregulation of type I interferon mRNAs in response to inactivated SIV in both species [25]. More recently, several independent in-vivo studies conducted using different groups of animals have more reliably assessed the dynamics of innate immune responses to SIV in natural hosts using various assays including high-throughput genomics, multiparametric flow cytometry, detection of plasma levels of cytokines, and immunohistochemistry [42••,43••,44,45,46••,47•]. These studies have conclusively shown that, in both pathogenic infections of macaques and nonpathogenic infections of sooty mangabeys and AGMs, the acute phase of SIV infection is associated with a robust innate immune response to the virus. This response involves major changes in the transcriptome consistent with activation of the innate immune system, including a massive upregulation of ISGs in both peripheral blood and lymphoid tissues [42••,43••,44,45]. Consistent with these observations is the fact that high levels of IFN-I-producing pDCs can be detected by immunohistochemistry in the lymph nodes of SIV-infected sooty mangabeys and AGMs during acute infection [46••]. This large set of in-vivo studies indicates that an intrinsic inability to generate a strong type I interferon-mediated response to the virus is neither a feature of natural SIV infections nor a requirement to reach a state of nonpathogenicity.

Importantly, a key difference between pathogenic SIV infection of macaques and nonpathogenic SIV infection of natural hosts is that the latter resolve the widespread expression of innate effector molecules during the postacute phase of infection (i.e. by day 30–45 after infection) [42••,43••] (reviewed in [48]). The observed similarities in the overall pattern of SIV-induced transcriptional changes in sooty mangabeys and AGMs suggest a common evolutionary pathway of disease resistance in natural hosts that relies on the rapid resolution of an otherwise normal innate immune response to the virus [36]. In stark contrast, SIV-infected macaques maintain their elevated expression of innate immune response genes, including ISGs, throughout the chronic phase of infection [42••,43••]. The observation of chronically high levels of ISGs in SIV-infected macaques is consistent with the finding of high levels of ISG mRNAs during chronic HIV infection in humans [49,50]. In addition, recent work characterizing the transcriptomes of a rare population of chronically HIV-infected humans that do not exhibit CD4+ T-cell depletion despite plasma viremia exceeding 100 000 RNA copies/ml demonstrated remarkable overlap with those of sooty mangabeys, including a reduced ISG response compared with patients with a rapid progressor phenotype [51••]. Collectively, these comparative studies of innate immune responses during pathogenic and nonpathogenic SIV infections delineate a model in which natural SIV infections are characterized by a robust and extensive innate immune response to the virus that – in contrast to pathogenic infections – resolves during the transition from acute to chronic infection despite ongoing virus replication (Fig. 1). This model of immune resolution also suggests that active immune regulatory mechanisms are responsible for the low immune activation of chronically SIV-infected sooty mangabeys and AGMs. Whereas resolution of the pDC/interferon response was reported by multiple groups, the mechanism by which natural hosts arrest IFN-α production despite persistent virus replication remains a key unanswered question. Several recent studies detailing virus/dendritic cell interplay at the cellular level provide intriguing potential mechanisms by which natural hosts may halt the interferon response (summarized in Fig. 2) including active immunoregulatory mechanisms; restriction of infection of dendritic cells [57]; reduced dendritic cell trafficking to mucosal tissues [32•,33•]; desensitization/maturation of pDCs [39••]. Consistent with a mechanism of immune regulation is the observation that the return to baseline expression levels of innate immunity genes in SIV-infected sooty mangabeys is temporally coincident with a marked upregulation of immune regulatory genes such as IDO and ADAR [42••]. An intriguing, nonmutually exclusive possibility is that the rapid regulation of pDC and type I interferon-mediated responses in SIV-infected sooty mangabeys is related to the low levels of virus replication in the lymph node-resident central-memory CD4+ T cells of these animals [58]. Further studies will hopefully elucidate the role of these and other factors in determining the low immune activation state of chronically SIV-infected sooty mangabeys and AGMs.

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The role of innate immunity and chronic immune activation in the immunopathogenesis of AIDS has been recently investigated by comparative studies of experimental, pathogenic SIV infection of Asian macaques and natural, nonpathogenic SIV infection of African nonhuman primates. These studies have shown that both pathogenic and nonpathogenic SIV infections are characterized by a robust innate immune response to the virus. However, this response is transient in natural hosts, but persistent in Asian macaques, thus suggesting that this downregulation of innate immunity may protect sooty mangabeys and AGMs from chronic immune activation and progression to AIDS. Importantly, it is hoped that further elucidation of the genes and molecular pathways involved in maintenance of a state of low immune activation in chronically SIV-infected sooty mangabeys and AGMs will identify targets for therapeutic interventions aimed at limiting or abrogating the aberrant immune activation that is associated with HIV infection in humans.

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The authors would like to thank Michaela Müller-Trutwin, Rama Rao Amara, Sue-Fen Kwa and Ann Chahroudi for helpful discussion.

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Conflicts of interest

There are no conflicts of interest.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

* • of special interest

* •• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 447–448).

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This study discusses comprehensively the recruitment of pDCs to the gut during acute and chronic HIV/SIV infection in rhesus macaques, sooty mangabeys and humans. They demonstrated that pDCs drive an interferon response in the gut that correlates with immune activation measured by CD8+Ki67+ levels, which was abrogated by blockade of mucosal homing. They also demonstrated a lack of mucosal homing by pDCs in SIV+ sooty mangabeys.

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This study demonstrated the mucosal recruitment of pDCs to the gut, and demonstrated that pDCs are not depleted during SIV infection.

34•. Ansari AA, Reimann KA, Mayne AE, et al. Blocking of alpha4beta7 gut-homing integrin during acute infection leads to decreased plasma and gastrointestinal tissue viral loads in simian immunodeficiency virus-infected rhesus macaques. J Immunol 2011; 186:1044–1059.

This study utilized in-vivo antibody mediated blockade of the alpha4beta7 integrin to abrogate gut homing of multiple leukocyte subsets in SIV infection, including pDCs, during SIV infection demonstrating remarkable decreases in viremia, and lowered ISG responses in gut.

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This study characterized pDC responses in primary HIV infection, and demonstrated, in contrast to classical human studies, that pDCs had an elevated, not attenuated, IFN-α response to viral stimulation.

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This study was the first study of high-throughput transcript profiling of SIVsmm-infected sooty mangabeys and demonstrated that sooty mangabeys have a massive innate response to SIV in acute infection that subsequently resolves before chronic infection, in striking contrast to control rhesus macaques infected with SIVsmm or SIVmac239, in which the ISG response persisted indefinitely. A companion paper by Jacquelin and colleagues demonstrated parallel findings in African green monkeys.

43••. Jacquelin B, Mayau V, Targat B, et al. Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest 2009; 119:3544–3555.

This study comprehensively characterized genome-wide expression in several tissues in SIV-infected African green monkeys and observed a marked induction in innate responses shortly after infection, but returned to baseline within 2 months after infection; these results mirrored findings in a companion paper by Bosinger et al. in sooty mangabeys.

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This study definitively demonstrates the production of IFN-α in situ in CD123+ cells in the lymph nodes of acutely infected sooty mangabeys and AGMs.

47•. Campillo-Gimenez L, Laforge M, Fay M, et al. Nonpathogenesis of simian immunodeficiency virus infection is associated with reduced inflammation and recruitment of plasmacytoid dendritic cells to lymph nodes, not to lack of an interferon type I response, during the acute phase. J Virol 2010; 84:1838–1846.

This study definitively demonstrates the in-vivo production of IFN-α in SIV-infected AGMs and confirms their ability to respond to TLR7/TLR8 ligands.

48. Manches O, Bhardwaj N. Resolution of immune activation defines nonpathogenic SIV infection. J Clin Invest 2009; 119:3512–3515.
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This study is among the first to characterize the viremic nonprogressor (VNP) human phenotype, in which immune activation is absent despite long-term, high-level viremia (HIV RNA copies >100,000 per ml plasma). Extensive genomic characterization was performed and demonstrated that transcriptomes of VNPs shared characteristics of that of SIV+ sooty mangabeys, including reduced ISG expression (compared with rapid progressors) despite increased viral load.

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African green monkey; chronic immune activation; HIV; IFNa; innate immunity; interferon stimulated genes; plasmacytoid dendritic cells; review; simian immunodeficiency virus; sooty mangabey type I interferon

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