Early Resolution of Acute Immune Activation and Induction of PD-1 in SIV-Infected Sooty Mangabeys Distinguishes Nonpathogenic from Pathogenic Infection in Rhesus Macaques

Estes, Jacob D.; Gordon, Shari N.; Zeng, Ming; Chahroudi, Ann; Dunham, Richard M.; Staprans, Silvija I.; Reilly, Cavan; Silvestri, Guido; Haase, Ashley T.

doi:10.4049/jimmunol.180.10.6798

Cited by 165 publications

(91 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Accumulating evidence from human and non-human primate studies supports the broad hypothesis that progression to AIDS during HIV infection is driven by chronically elevated T cell activation and systemic inflammation (1–4). While the etiology of such persistent immune activation is incompletely understood, the gastrointestinal mucosal immune disruption that follows progressive HIV and SIV infection is postulated to play a role.…”

Section: Introductionmentioning

confidence: 93%

Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism

et al. 2013

Self Cite

View full text Add to dashboard Cite

Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART) and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan metabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to metabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection, which is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease.

show abstract

Section: Introductionmentioning

confidence: 93%

Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…As a result, initial models proposed that innate pathways in the anti-SIV response of natural hosts were silenced or largely reduced. Subsequent studies took advantage of more frequent sampling during very early intervals of infection (3-30 days) and reported three key findings: (i) during acute infection, elevated levels of activation (DR) or proliferation (Ki67) markers on CD4+ T cells in SMs[27] and CD8+ T cells in AGMs[28] and SMs[29]; (ii) transient recruitment of pDCs to lymph nodes during acute SIVagm infection[30]; and (iii) recruitment of cells expressing the activation/exhaustion marker PD1 in lymph nodes after SIVsm infection[31], Despite these observations, and the assertion by the authors that timely homeostatic mechanisms were at play, the concepts that natural hosts (i) displayed an acute-phase immune response to SIV, and (ii) subsequently resolved early innate responses, were not fully appreciated. In this regard, high-throughput genomics were key, as they showed that early immune activation after SIV infection in natural hosts was not limited to isolated pathways involving the CD8+ T cell response, but was indicative of system-wide activation.…”

Section: Introductionmentioning

confidence: 99%

Systems biology of natural simian immunodeficiency virus infections

Bosinger¹,

Jacquelin²,

Benecke³

et al. 2012

Current Opinion in HIV and AIDS

Self Cite

View full text Add to dashboard Cite

Purpose of review A key factor driving AIDS-associated immunopathogenesis is chronic immune activation. SIV infection of African natural host species leads to high viremia, but low immune activation and absence of disease. Considerable progress in our understanding of pathological immune activation have come from comparative studies of SIV infection in pathogenic Asian macaque species and natural hosts. The focus of this review is to highlight recent work on the natural host model using high throughput genomics. Recent findings Several groups have independently conducted microarray gene expression profiling comparing in vivo SIV infection in natural and non-natural hosts. A consistent finding between these studies is that both pathogenic SIV infection of macaques and nonpathogenic infections of natural hosts have strong induction of interferon-stimulated genes (ISGs) early on, but a key difference was that natural hosts downmodulated the interferon response rapidly after acute infection. The development of new genome-based resources for further study of the natural host model is discussed. Summary Initial efforts using high throughput biology to study SIV infection of natural hosts have effectively identified the ability of natural hosts to resolve interferon responses and immune activation. Further application of ‘omic’-based technologies coupled with integrative systems-based analysis should continue to yield progress.

show abstract

“…Numerous studies have analyzed similarities and differences between SIV-infected natural and nonnatural hosts in an attempt to delineate the mechanisms underlying differences in pathogenicity. Similarities that have been identified include high plasma viral loads (3)(4)(5)(6), a short in vivo life span of productively infected cells (7,8), acute immune activation (9)(10)(11)(12), and depletion of mucosal CD4…”

mentioning

confidence: 99%

Simian Immunodeficiency Virus SIVagm Efficiently Utilizes Non-CCR5 Entry Pathways in African Green Monkey Lymphocytes: Potential Role for GPR15 and CXCR6 as Viral Coreceptors

Riddick

Matsuda

et al. 2016

J Virol

View full text Add to dashboard Cite

African green monkeys (AGM) are natural hosts of simian immunodeficiency virus (SIV), and infection in these animals is generally nonpathogenic, whereas infection of nonnatural hosts, such as rhesus macaques (RM), is commonly pathogenic. CCR5 has been described as the primary entry coreceptor for SIV in vivo, while human-derived CXCR6 and GPR15 also appear to be used in vitro. However, sooty mangabeys that are genetically deficient in CCR5 due to an out-of-frame deletion are infectible with SIVsmm, indicating that SIVsmm can use alternative coreceptors in vivo. In this study, we examined the CCR5 dependence of SIV strains derived from vervet AGM (SIVagmVer) and the ability of AGM-derived GPR15 and CXCR6 to serve as potential entry coreceptors. We found that SIVagmVer replicated efficiently in AGM and RM peripheral blood mononuclear cells (PBMC) in the presence of the CCR5 antagonist maraviroc, despite the fact that maraviroc was capable of blocking the CCR5-tropic strains SIVmac239, SIVsmE543-3, and simian-human immunodeficiency virus SHIV-AD8 in RM PBMC. We also found that AGM CXCR6 and AGM GPR15, to a lesser extent, supported entry of pseudotype viruses bearing SIVagm envelopes, including SIVagm transmitted/founder envelopes. Lastly, we found that CCR5, GPR15, and CXCR6 mRNAs were detected in AGM and RM memory CD4 ؉ T cells. These results suggest that GPR15 and CXCR6 are expressed on AGM CD4 ؉ T cells and are potential alternative coreceptors for SIVagm use in vivo. These data suggest that the use of non-CCR5 entry pathways may be a common feature of SIV replication in natural host species, with the potential to contribute to nonpathogenicity in these animals. IMPORTANCEAfrican green monkeys (AGM) are natural hosts of SIV, and infection in these animals generally does not cause AIDS, whereas SIV-infected rhesus macaques (RM) typically develop AIDS. Although it has been reported that SIV generally uses CD4 and CCR5 to enter target cells in vivo, other molecules, such as GPR15 and CXCR6, also function as SIV coreceptors in vitro. In this study, we investigated whether SIV from vervet AGM can use non-CCR5 entry pathways, as has been observed in sooty mangabeys. We found that SIVagmVer efficiently replicated in AGM and RM peripheral blood mononuclear cells in the presence of the CCR5 antagonist maraviroc, suggesting that non-CCR5 entry pathways can support SIVagm entry. We found that AGMderived GPR15 and CXCR6 support SIVagmVer entry in vitro and may serve as entry coreceptors for SIVagm in vivo, since their mRNAs were detected in AGM memory CD4 ؉ T cells, the preferred target cells of SIV.

show abstract

Early Resolution of Acute Immune Activation and Induction of PD-1 in SIV-Infected Sooty Mangabeys Distinguishes Nonpathogenic from Pathogenic Infection in Rhesus Macaques

Cited by 165 publications

References 52 publications

Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism

Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism

Systems biology of natural simian immunodeficiency virus infections

Simian Immunodeficiency Virus SIVagm Efficiently Utilizes Non-CCR5 Entry Pathways in African Green Monkey Lymphocytes: Potential Role for GPR15 and CXCR6 as Viral Coreceptors

Contact Info

Product

Resources

About