Rhesus Macaque Acute SIV Infection Study
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ABSTRACT:
ORGANISM(S): Macaca mulatta
PROVIDER: GSE38917 | GEO | 2019/09/23
REPOSITORIES: GEO
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Project description:Interleukin (IL)-10 is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper cell (TFH) differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph node (LN) are induced by infection and not normalized with ART. During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were significantly correlated with the cell-associated SIV-DNA content within LN CD4+ memory subsets, including TFH, and predicted the frequency of CD4+ TFH and their cell- associated SIV-DNA content during ART, respectively. Notably, in ART-treated RMs, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B-cell follicle in close proximity to IL-10. Finally, we demonstrate that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques significantly reduces B cell follicle maintenance and, by extension, cellular sites of viral persistence, including LN TFH and memory CD4+ T-cells expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4+ T-cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.
2022-02-09 | GSE196182 | GEO
Project description:Interleukin (IL)-10 is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper cell (TFH) differentiation and germinal center formation, which we propose acts as a determinant of HIV/SIV persistence. In SIV-infected macaques, levels of IL-10 in plasma and lymph node (LN) are induced by infection and not normalized with ART. During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were significantly correlated with the cell-associated SIV-DNA content within LN CD4+ memory subsets, including TFH, and predicted the frequency of CD4+ TFH and their cell-associated SIV-DNA content during ART, respectively. Notably, in ART-treated RMs, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B-cell follicle in close proximity to IL-10. Finally, we demonstrate that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques significantly reduces B cell follicle maintenance and, by extension, cellular sites of viral persistence, including LN TFH and memory CD4+ T-cells expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4+ T-cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.
2022-02-09 | GSE196436 | GEO
Project description:Live-attenuated SIV vaccines (LAVs) remain the most efficacious of all vaccines in nonhuman primate models of HIV/AIDS, yet the basis of their robust protection remains poorly understood. Here, we demonstrate that the degree of LAV-mediated protection against intravenous (IV) wildtype (wt) SIVmac239 challenge strongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in lymph node (LN), but not with such T cell responses in blood or with other cellular, humoral and innate immune parameters. Maintenance of protective T cell responses was associated with persistent LAV replication in LN, which occurred almost exclusively in follicular helper T cells. Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells that intercept and suppress early wt SIV amplification and, if present in sufficient frequencies, can completely control and perhaps clear infection -- an observation that provides rationale for development of safe, persistent vectors that can elicit and maintain such responses. There are two protection outcome groups, complete protect (CP) and non-protect (NP) animals. Memory T cells (CD4+ or CD8+) were sorted for three time points, seven days pre-challenge, four days post-challenge and fourteen days post-challenge.
2012-08-08 | E-GEOD-39968 | biostudies-arrayexpress
Project description:T follicular helper cells (TFH) are critical for the development and maintenance of germinal centers (GC) and humoral immune responses. During chronic HIV/SIV infection TFH accumulate, possibly as a result of antigen persistence. The HIV/SIV-associated TFH expansion may also reflect lack of regulation by suppressive follicular regulatory CD4+ T-cells (TFR). TFR are natural regulatory T-cells (TREG) that migrate into the follicle and, similarly to TFH, up-regulate CXCR5, Bcl-6, and PD1. Here we identified TFR as CD4+CD25+FoxP3+CXCR5+PD1hiBcl-6+ within lymph nodes of rhesus macaques (RM) and confirmed their localization within the GC by immunohistochemistry. RNA sequencing showed that TFR exhibit a distinct transcriptional profile with shared features of both TFH and TREG, including intermediate expression of FoxP3, Bcl-6, PRDM1, IL-10, and IL-21. In healthy, SIV-uninfected RM, we observed a negative correlation between frequencies of TFR and both TFH and GC B-cells as well as levels of CD4+ T-cell proliferation. Following SIV infection, the TFR/TFH ratio was reduced with no change in the frequency of TREG or TFR within the total CD4+ T-cell pool. Finally, we examined whether higher levels of direct virus infection of TFR were responsible for their relative depletion post-SIV infection. We found that TFH, TFR and TREG sorted from SIV- infected RM harbor comparable levels of cell-associated viral DNA. Our data suggests that TFR may contribute to the regulation and proliferation of TFH and GC B-cells in vivo and that a decreased TFR/TFH ratio in chronic SIV infection may lead to unchecked expansion of both TFH and GC B-cells. TFR, TFH, TREG and bulk CD4 cells were sorted from spleens of 5 uninfected and 5 infected RM.
2015-09-02 | E-GEOD-69756 | biostudies-arrayexpress
Project description:Here we use RNAseq and ATACseq to study the transcriptomics and epigenetic landscape of longitudinally sampled naïve and memory CD4+ and CD8+ T cells in two species of non-human primates prior to SIV infection, during chronic SIV infection, and after administration of ARVs. We find that SIV infection leads to significant alteration to the transcriptomic profile of all T cell subsets that are only partially reversed by administration of ARVs. Epigenetic changes were more apparent in animals with longer periods of untreated SIV infection and correlated well with changes in corresponding gene expression. Known SIV integration sites did not vary due to SIV status but did contain more open chromatin in rhesus macaque memory T cells, and the expression of proteasome-related genes at the pre-SIV timepoint correlated with subsequent viremia.
2024-05-10 | GSE264657 | GEO
Project description:Here we use RNAseq and ATACseq to study the transcriptomics and epigenetic landscape of longitudinally sampled naïve and memory CD4+ and CD8+ T cells in two species of non-human primates prior to SIV infection, during chronic SIV infection, and after administration of ARVs. We find that SIV infection leads to significant alteration to the transcriptomic profile of all T cell subsets that are only partially reversed by administration of ARVs. Epigenetic changes were more apparent in animals with longer periods of untreated SIV infection and correlated well with changes in corresponding gene expression. Known SIV integration sites did not vary due to SIV status but did contain more open chromatin in rhesus macaque memory T cells, and the expression of proteasome-related genes at the pre-SIV timepoint correlated with subsequent viremia.
2024-05-10 | GSE264656 | GEO
Project description:T follicular helper cells (TFH) are critical for the development and maintenance of germinal centers (GC) and humoral immune responses. During chronic HIV/SIV infection TFH accumulate, possibly as a result of antigen persistence. The HIV/SIV-associated TFH expansion may also reflect lack of regulation by suppressive follicular regulatory CD4+ T-cells (TFR). TFR are natural regulatory T-cells (TREG) that migrate into the follicle and, similarly to TFH, up-regulate CXCR5, Bcl-6, and PD1. Here we identified TFR as CD4+CD25+FoxP3+CXCR5+PD1hiBcl-6+ within lymph nodes of rhesus macaques (RM) and confirmed their localization within the GC by immunohistochemistry. RNA sequencing showed that TFR exhibit a distinct transcriptional profile with shared features of both TFH and TREG, including intermediate expression of FoxP3, Bcl-6, PRDM1, IL-10, and IL-21. In healthy, SIV-uninfected RM, we observed a negative correlation between frequencies of TFR and both TFH and GC B-cells as well as levels of CD4+ T-cell proliferation. Following SIV infection, the TFR/TFH ratio was reduced with no change in the frequency of TREG or TFR within the total CD4+ T-cell pool. Finally, we examined whether higher levels of direct virus infection of TFR were responsible for their relative depletion post-SIV infection. We found that TFH, TFR and TREG sorted from SIV- infected RM harbor comparable levels of cell-associated viral DNA. Our data suggests that TFR may contribute to the regulation and proliferation of TFH and GC B-cells in vivo and that a decreased TFR/TFH ratio in chronic SIV infection may lead to unchecked expansion of both TFH and GC B-cells.
2015-09-02 | GSE69756 | GEO
Project description:Impact of CD8 depletion on peripheral CD4+ T cells transcriptome during ART-treated SIV infection of rhesus macaques. Analysis of CD8+ T cells, CD4+ T cells, and NK cell transcriptomes following administration of HIV/SIV latency reversing agent IL-15 superagonist N-803 in ART-suppressed SIV infected rhesus macaques. Methods: RNA-Seq of sorted CD4+ T cells from SIV-infected, ART-suppressed rhesus macaques before intervention with the anti-CD8a depleting antibody MT807R1 and then again on day 3, week 2, and week 4 following the start of intervention. Some animals also had an intervention that includes four weekly administrations of the IL-15 superagonist complex N-803 initiated at the time of CD8 depletion. Methods: RNA-Seq of sorted CD4+ T cells, CD8+ T cells, and NK cells from SIV-infected, ART-suppressed rhesus macaques before intervention with four weekly administrations of the IL-15 superagonist complex N-803, then again on day 3, week 2, and week 4 following the start of intervention. Methods: RNA from sorted cells was collected and extracted and DNA was digested. Libraries were prepared and normalized, pooled, and clustered on a flow cells for sequencing. RNAseq data were aligned to the MacaM v7.8 assembly of the Indian rhesus macaque genome. To identify pathways differentially modulated, Gene Set Enrichment Analysis (GSEA)34 was performed on the ranked transcript lists using 1000 phenotype permutations and random seeding. Gene sets used included the MSigDB H (hallmark) gene sets
2020-01-06 | GSE128415 | GEO
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:This study describes a circulating miRNA signature of acute retroviral infection, which may include candidate diagnostic or prognostic miRNAs for lentivirus-associated neurologic conditions. Plasma samples were taken from six macaques prior to infection and at ten days post-infection. Three macaques each went on to develop no or severe encephalitis. miRNA profiles were generated for each animal before and 10 days after SIV infection.
2011-09-14 | E-GEOD-26057 | biostudies-arrayexpress