Role of NKG2a/c + CD8 + T cells in pathogenic versus non-pathogenic SIV infections
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ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 2500
ORGANISM(S): Chlorocebus sabaeus
SUBMITTER: Nicolas Huot
PROVIDER: E-MTAB-8664 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:High levels of HIV-1 replication during the chronic phase of infection are usually associated with rapid disease progression (RP). However, a minority of HIV-infected individuals remain asymptomatic and show persistently high CD4+ T cell counts despite high viremia for many years (viremic non progressors, VNP). The latter profile is reminiscent of the non-pathogenic model of SIV infection in natural hosts such as the sooty mangabey. We used various genomic approaches to examine 66 RP and 6 VNP defined according to strict criteria. RP were characterized by depletion of protective HLA alleles, enrichment of HLA alleles associated with disease progression, and a characteristic transcriptome profile of CD4+ and CD8+ T cells similar to that observed in pathogenic SIV infection of rhesus macaque. In contrast, VNPs presented lower expression of interferon stimulated genes than RP, and shared with SIV-infected sooty mangabeys a common profile of regulation of a set of genes that includes CASP1, CD38, LAG3, TNFSF13B, SOCS1 and EEF1D. The estimated 8% of RP and 0.1% of VNP in human cohorts represent two subsets of HIV-infected individuals whose analysis may inform our understanding of HIV pathogenesis. Selection criteria rapid progressors (RP): HIV seroconversion window <1 year WITH documented negative and positive serology or biological proof of primary infection. AND One of A) or B) A) >2 CD4+ T cell counts below 350 cells/µl within 3 years of seroconversion AND no subsequent rise of CD4+ T cells above 350 cells/µl in the absence of ART. B) ART initiated within 3 years of seroconversion AND CD4+ T cell count within 1 month of ART-start <350 cells/µl. Selection criteria viremic non progressors (VNP): > 3 years of follow-up AND median HIV viremia from >3 measurements >100'000 viral RNA copies/ml AND HIV viremia consistently above 10’000 copies/ml AND CD4+ T cell count above 350 cells/µl AND no ART during follow-up. Selection criteria elite/viremic controllers (EC): see Casado et al. 2010. Host and viral genetic correlates of clinical definitions of HIV-1 disease progression. PLoS ONE 5:e11079. Total RNA from 41 samples obtained from CD4 T cells from HIV infected individuals to identify associations between gene expression and different distinct patterns of disease progression Total RNA from 38 samples obtained from CD8 T cells from HIV infected individuals to identify associations between gene expression and different distinct
2011-06-03 | E-GEOD-28128 | biostudies-arrayexpress
Project description:Infections with mycobacteria, including Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis (M. bovis) BCG, are a leading cause of morbidity and mortality for HIV-infected persons. In contrast to HIV, SIV infection of sooty mangabeys is nonpathogenic, characterized by a lack of clinical disease including an absence of opportunistic infections. The goal of this study was to identify innate immune responses to M. bovis BCG maintained during nonpathogenic lentiviral infections, through a comparison of functional responses during pathogenic HIV or nonpathogenic SIV infections. Monocytes were evaluated for their ability to express key anti-mycobacterial cytokines TNF-α and IL-12 following a six-hour ex vivo BCG exposure. While HIV-infection was associated with a decreased percentage of IL-12-producing monocytes, nonpathogenic SIV-infection was associated with an increased percentage of monocytes producing both cytokines. Gene expression analysis of PBMC following ex vivo BCG exposure identified differential expression of NK cell-related genes and several cytokines, including IFN-γ and IL-23, between HIV-infected and control subjects. In contrast, SIV-infected and uninfected-control mangabeys exhibited no significant differences in gene expression after BCG exposure. Finally, differential gene expression patterns were identified between species, with mangabeys exhibiting lower IL-6 and higher IL-17 in response to BCG when compared to humans. Overall, this comparison of immune responses to M. bovis BCG identified unique immune signatures (involving cytokines IL-12, TNF-α, IL-23, IL-17, and IL-6) that are altered during HIV, but maintained or increased during nonpathogenic SIV infections. These unique cytokine and transcriptome signatures provide insight into the differential immune responses to Mycobacteria during pathogenic HIV-infection of humans or nonpathogenic SIV-infection of mangabeys.
2016-05-27 | GSE81926 | GEO
Project description:HIV reservoirs in tissues form the major hurdle to an HIV cure. Despite major progress made on the understanding of the establishment and persistence of viral reservoirs, the characterization of composition and dynamics of the viral reservoir is still uncomplete. In addition, most studies in HIV infection are limited to blood. Here we take advantage of non-human primate models to provide a longitudinal analysis on potential viral target cells in distinct body compartments : blood, lymph nodes (LN), spleen ileum, jejunum and liver. We observed an increase in CD32+CD4+ T cells in secondary lymphoid tissues and intestine during primary and chronic pathogenic SIVmac infection. In the natural host (African green monkey, AGM), increase of the CD4+CD32+T cell levels was observed in tissues with higher replication and immune activation. CD32+CD4+ T cells expressed more often markers associated with HIV infected and/or reservoir cells (PD-1, CXCR5 for TFH cells in SLT, and CXCR3 for Th1 cells) than CD32- cells. The tissue CD32+CD4+T cells displayed higher levels of actively transcribed SIV RNA than CD32-CD4+T cells. The genome-wide transcriptome of CD32+CD4+ T cells in spleen from SIV-infected animals indicated that the CD32+CD4+ T cells shared B cell markers. The CD20+ expressing CD32+CD4+ T cells were increased in the tissues but not in the blood during SIV infection. Altogether, the study showed that SIV infection increases the frequencies of CD32+CD4+ T cells in tissues more than in blood. These cells might represent a not well-described subpopulation of activated CD4+ T cells.
2021-04-16 | GSE169736 | GEO
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163442 | GEO
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163441 | GEO
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163440 | GEO
Project description:We examined the gene expression profiles in ex vivo human CD4+ and CD8+ T cells from untreated HIV-infected individuals at different clinical stages and rates of disease progression. Profiles of pure CD4+ and CD8+ T cells subsets from HIV-infected nonprogressors who controlled viremia were indistinguishable from HIV-uninfected individuals. Similarly, no gene clusters could distinguish T cells from individuals with early from chronic progressive HIV infection, whereas differences were observed between uninfected or nonprogressors versus early or chronic progressors. In early/chronic HIV infection, three characteristic gene expression signatures were observed: (1) CD4+ and CD8+ T cells showed increased expression of interferon stimulated genes (ISGs). However, some ISGs including CXCL9, CXCL10, and CXCL11, and the IL15R? in both CD4+ and CD8+ T cells and the anti-HIV ISG APOBEC3G in CD4+ T cells, were not upregulated. (2) CD4+ and CD8+ T cells showed a cluster similar to that observed in thymocytes, and (3) more genes were differentially regulated in CD8+ T cells than in CD4+ T cells, including a cluster of genes downregulated exclusively in CD8+ T cells. In conclusion, HIV infection induces a persistent T cell transcriptional profile, early in infection, characterized by a dramatic but potentially aberrant interferon response, and a profile suggesting an active thymic output. We studied a cohort of HIV infected individuals with various clinical stages of HIV infection and healthy uninfected volunteers as a control group (Table 1). We included 5 individuals with early HIV infection (A), five with chronic progressive HIV infection (C), five individuals with non-progressive HIV infection with low or undetectable viral loads (L) and five HIV uninfected individuals (N). The HIV infected individuals were never on therapy prior to entering the study. Samples were taken once from each donor.
2007-11-11 | E-GEOD-6740 | biostudies-arrayexpress
Project description:CD8+ T-cells inhibit virus replication in SIV-infected rhesus macaques (RM). However, it is not clear how SIV infection is controlled in germinal center during chronic SIV infection and limited information exists on the characteristics of CXCR5+ CD8 T cells during chronic SIV/HIV infection. In this study, we used functional genomics to investigate characteristic features and potential mechanisms of CXCR5+ and CXCR5- SIV specific CD8 T cells for the control of pathogenic SIV infection. Six chronically SIV infected RMs, three SIVE660 infected and three SIV mac251 infected that are positive for Mamu A01 allele were selected and SIV-specific CXCR5+ and CXCR5- CD8 T cells were sorted based on CXCR5 expression. RNA from sorted cells were extracted and microarray were performed and analysed. Principal component analysis demonstrated that overall gene expression difference between CXCR5+ and CXCR5- SIV-specific CD8 T cells. Interestingly, the CXCR5+ CD8 T cells revealed a distinct gene signature pattern when compared to CXCR5- CD8 T cells. Unlike the CXCR5- CD8 T cells, the CXCR5+ CD8 T cells expressed higher levels of genes associated with Tfh CD4 T cells such as the master transcription factor Bcl6, CD200, and CTLA4 as well as markers associated with Th2 CD4 T cells such as IL-4R (CD124), CCR4, STAT6, NFATC, and IL-10. Effector molecules typically observed in cytotoxic CD8 T cells such as granzyme A, B, and K were expressed at lower levels on CXCR5+ CD8 T cells compared to their CXCR5- counterparts. CXCR5+ CD8 T cells also expressed higher levels of molecules associated with co-stimulation/antigen presentation such as CD40, CD83, 41BBL and MAMU-DRA. The CXCR5+ CD8 also expressed higher levels of inhibitory receptors such as CD200 and SPRY2 but lower levels of other inhibitory receptors CD160 and CD244. The functional consequence of the expression of these molecules is yet to be determined. Additionally, CXCR5+ CD8 T cells expressed higher levels of the anti-apoptotic gene Bcl-2 and lower levels of the pro-apoptotic gene annexin, suggestive of their better survival potential during chronic SIV infection. Collectively, these results demonstrate that SIV specific CXCR5+ CD8 T cells possess a unique gene expression signature compared to SIV-specific CXCR5- CD8 T cells.
2017-03-07 | GSE74751 | GEO
Project description:CD8+ T-cells inhibit virus replication in SIV-infected rhesus macaques (RM). However, it is unclear to what extent the viral suppression mediated by CD8+ T-cells reflects direct killing of infected cells as opposed to indirect, non-cytolytic mechanisms. In this study, we used functional genomics to investigate potential mechanisms of in vivo viral suppression mediated by CD8+ lymphocytes. Eight chronically SIVmac239-infected RMs underwent CD8+ lymphocyte depletion, and RNA from whole blood was obtained prior to depletion, at the nadir of CD8+ lymphocytes (5 days post-depletion), and during the repopulation phase (11 days post-depletion). Principal components analysis demonstrated that overall gene expression during the nadir of CD8+ T-cells was highly divergent from other intervals. Conversely, the genomic signature of samples from the CD8+ cell rebound phase was similar to that of pre-depletion samples. During CD8+ lymphocyte depletion we detected a strongly significant decrease in the expression of the genes encoding CD8α and CD8β chains, consistent with the near complete CD8+ T-cell depletion measured by flow cytometry. Of note, we observed significant down-regulation of the expression of genes encoding for factors that can suppress SIV replication, including the CCR5-binding chemokine CCL5/Rantes, several retroviral restriction factors (TRIM10, TRIM15, APOBEC3G/H) and defensins. Reduced expression of various genes related to T cell activation and proliferation was also observed. Collectively, these data indicate that depletion of CD8+ lymphocytes in SIV-infected RMs is associated with the establishment of a pattern of gene expression that may result in increased intrinsic permissivity to virus replication. A total of 60 RNA samples were hybridized on to Rhesus Affymetrix 3' Expression arrays. The study was composed of 8 replicate rhesus macaques subjected to SIVmac239 infection and followed over infection, during subsequent treatment with monocloncal antibody OKT8F to deplete CD8+ T lymphocytes, antiretroviral therapy to suppress virus. Samples were taken at various time points during acute and chronic infection, after CD8+ cell depletion, after CD8+ cell reconstition, and during ART suppression of virus.
2013-02-08 | E-GEOD-37834 | biostudies-arrayexpress
Project description:Hyperimmune activation is one of the strong predictors of disease progression during pathogenic immunodeficiency virus infections and is mediated in part by sustained type I interferon (IFN) signaling. Combination antiretroviral therapy suppresses hyperimmune activation only partially in HIV-infected individuals. Here, we show that blockade of Programmed Death-1 (PD-1) during chonic SIV infection significantly reduces the expression of transcripts associated with type I IFN signaling in the blood and colorectal tissue of rhesus macaques (RM). The effect of PD-1 blockade on type I IFN signaling was durable and persisted under high viremia, a condition that is seen in nonprogressive SIV infection in their natural hosts. The reduced type I IFN signaling was associated with enhanced expression of some of the junction-associated genes in the colorectal tissue and a profound decrease in LPS levels in plasma suggesting a possible repair of gut associated junctions and decreased microbial translocation. The reduced type I IFN signaling was also associated with enhanced immunity against gut resident pathogenic bacteria, control of gut associated opportunistic infections and survival of SIV-infected RMs. These results reveal novel mechanisms by which PD-1 blockade enhances survival of SIV-infected RMs and have implications for development of novel therapeutic approaches to control HIV/AIDS.
2012-04-27 | GSE33933 | GEO