Distinct SIV-specific lymphoid tissue CD8 T cells exhibit simultaneous effector and stem-like profiles and associate with limited SIV persistence
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ABSTRACT:
ORGANISM(S): Macaca mulatta
PROVIDER: GSE266576 | GEO | 2024/05/29
REPOSITORIES: GEO
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Project description:HIV cure efforts are increasingly focused on harnessing CD8 T cell functions; however, a deeper understanding of CD8 T cells promoting HIV control is necessary to properly inform therapeutic approaches. Here, we identified a novel TOX-expressing CD8 T cell population associated with control of SIV infection in lymphoid tissue of rhesus macaques defined as an antigen-responsive TCF1+ CD39+ subset expressing high levels of TOX and inhibitory receptors but lower levels of canonical cytolytic molecules such as granzyme B, granzyme A, and perforin. Transcriptional analysis of SIV-specific CD8 T cells, as well as proteomic analysis of purified CD8 T cell subsets, revealed these TCF1+ CD39+ cells as an intermediate effector population retaining stem-like features while maintaining a lineage relationship with terminal effector cells. TCF1+ CD39+ CD8 T cells expressed higher levels of CXCR5 than terminally differentiated cells, were found at higher frequency in follicular micro-environments, and were preferentially located in the proximity of SIV-RNA+ cells both in lymph node T cell zone and B cell follicles. Importantly, their frequency was strongly associated with reduced plasma viremia and lower reservoir size. Finally, we confirmed the presence of a highly similar TOX-enriched TCF1+ CD39+ cell population in lymph node biopsies from ART-naïve and ART-treated people living with HIV. Collectively, these data identify a unique population of lymphoid CD8 T cells possessing both stem-like and effector properties that contribute to limiting HIV/SIV persistence.
2024-06-11 | PXD050498 | Pride
Project description:Therapeutic strategies that enhance anti-viral immunity and reduce the viral reservoir are critical to achieving durable remission of HIV. The co-inhibitory receptor programmed death-1 (PD-1) regulates CD8+ T cell dysfunction during chronic HIV and SIV infections 1-4. In addition, PD-1+ CD4+ T cells constitute a significant fraction of the HIV/SIV viral reservoir5-7. We previously demonstrated that in vivo blockade of PD-1 during chronic SIV infection improves the function of anti-viral CD8+ T cells and B cells 4,8. However, the immunological effects of PD-1 blockade during anti-retroviral therapy (ART) and the potential to destabilize the persistent HIV/SIV reservoir have not been studied. Here, we show that administration of anti-PD-1 antibody (PD-1 Ab) 10 days prior to initiation of ART rapidly enhanced anti-viral CD8+ T cell function and diminished interferon stimulated genes (ISGs) that resulted in markedly improved viral suppression in plasma and better Th17 cell reconstitution in the rectal mucosa following ART initiation. In addition, PD-1 blockade during suppressive ART resulted in transient increases in plasma viremia, induction of gene signatures associated with effector CD8+ T cell function and ISGs, and lower levels of cell associated replication-competent virus suggesting destabilization of the viral reservoir. Following ART interruption, PD-1 Ab treated animals showed markedly higher expansion of proliferating CXCR5+ Perforin+ Granzyme B+ effector CD8+ T cells and lower regulatory T cells that resulted in delayed viral rebound and better control of viremia. PD-1 blockade administered only during suppressive ART however was only partially effective. Our results indicate an optimal regimen of PD-1 blockade administered in combination with ART, that augments anti-viral CD8+ T cell function and reduces the viral reservoir leading to improved control of viral rebound after ART interruption. These results have important implications for developing novel therapeutic interventions to achieve durable remission of HIV.
2021-02-24 | GSE111435 | 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:Some viruses have established an equilibrium with their host. African green monkeys (AGM) display persistent high viral replication in blood and intestine during Simian immunodeficiency virus (SIV) infection but resolve systemic inflammation after acute infection and lack intestinal immune or tissue damage during chronic infection. We show that NKG2 a/c + CD8 + T cells increase in blood and intestine of AGM in response to SIVagm infection in contrast to SIVmac infection in macaques, the latter modeling HIV infection. NKG2 a/c + CD8 + T cells were not expanded in lymph nodes and CXCR5 + NKG2 a/c + CD8 + T cell frequencies further decreased after SIV infection. Genome-wide transcriptome analysis of NKG2 a/c + CD8 + T cells from AGM revealed the expression of NK cell receptors, and of molecules with cytotoxic effector, gut homing, immunoregulatory and gut barrier function, including CD73. NKG2 a/c + CD8 + T cells correlated negatively with IL-23 in the intestine during SIVmac infection. The data suggest a potential regulatory role of NKG2 a/c + CD8 + T cells in intestinal inflammation during SIV/HIV infections.
2021-03-11 | E-MTAB-8664 | biostudies-arrayexpress
Project description:Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. CD8+ T cells from subjects with HCV infection were sorted and pelleted and re-suspended in TRIzol (Invitrogen). RNA extraction was performed using the RNAdvance Tissue Isolation kit (Agencourt). Concentrations of total RNA were determined with a Nanodrop spectrophotometer or Ribogreen RNA quantification kits (Molecular Probes/Invitrogen). RNA purity was determined by Bioanalyzer 2100 traces (Agilent Technologies). Total RNA was amplified with the WT-Ovation Pico RNA Amplification system (NuGEN) according to the manufacturer's instructions. After fragmentation and biotinylation, cDNA was hybridized to HG-U133A 2.0 microarrays (Affymetrix).
2015-09-08 | E-GEOD-72752 | biostudies-arrayexpress
Project description:Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion.
2015-09-08 | GSE72752 | GEO
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:The study describes miRNA expression in Gingival tissue of chronically SIV-infected rhesus macaques. HIV/SIV-associated periodontal disease (gingivitis/periodontitis) (PD) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Employing a systems biology approach, we report molecular changes underlying PD and its modulation by phytocannabinoids [delta-9-tetrahydrocannabinol (9-THC)] in uninfected and SIV-infected rhesus macaques (RMs) untreated (VEH-untreated/SIV) or treated with vehicle (VEH/SIV) or 9-THC (THC/SIV). VEH- untreated/SIV but not THC/SIV RMs showed significant enrichment of genes linked to anti-viral defense, interferon-beta, NFkB, RIG-1, and JAK-STAT signaling. We focused on the anti-microbial DUOX1 and immune activation marker IDO1 that were reciprocally regulated in gingiva of VEH-untreated/SIV RMs. Both proteins localized to the gingival epithelium and CD163+ macrophages, and showed differential expression in the gingiva of THC/SIV and VEH/SIV RMs. Additionally, inflammation-associated miR-21, miR-142-3p, miR-223, and miR-125a-5p showed significantly higher expression in the gingiva of VEH/SIV RMs. In human primary gingival epithelial cells, miR-125a-5p post-transcriptionally downregulated DUOX1 These findings strongly support a role for differential miRNA expression associated with HIV/SIV induced gingival mucosal dysfunction.
2021-11-30 | GSE181541 | GEO
Project description:The study describes miRNA expression changes in basal ganglia (BG) of chronically SIV-infected rhesus macaques. HIV/SIV-associated neurological disorder (HAND) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Employing a systems biology approach, we report molecular changes underlying HAND and its modulation by phytocannabinoids [delta-9-tetrahydrocannabinol (9-THC)] in uninfected and SIV-infected rhesus macaques (RMs) treated with vehicle (VEH/SIV) or 9-THC (THC/SIV). VEH/SIV but not THC/SIV RMs showed significant enrichment of genes linked to anti-viral defense, interferon-beta, NFkB, RIG-1, and JAK-STAT signaling. We focused on the anti-endoplasmic reticulum (WFS1) and anti-oxidative stress (CRYM) proteins that were significantly downregulated in BG of VEH/SIV RMs. Both proteins localized to the BG neurons, and showed differential expression in the BG of THC/SIV and VEH/SIV RMs. Additionally, inflammation-associated miR-155 and miR-142-3p showed significantly higher expression in the BG of VEH/SIV RMs. In human primary HCN2 neuronal cells, miR-142-3p post-transcriptionally downregulated WFS1. These findings strongly support a role for differential miRNA expression associated with HIV/SIV induced neurological dysfunction.
2023-02-28 | GSE220709 | 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