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Interleukin-10 contributes to reservoir establishment and persistence in antiretroviral therapy-treated, SIV-infected macaques

ABSTRACT: 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.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE196182 | GEO | 2022/02/09

REPOSITORIES: GEO

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Interleukin-10 regulates reservoir establishment and persistence in antiretroviral therapy-treated, SIV-infected macaques

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

Decreased TFR/TFH ratio in SIV-infected rhesus macaques may contribute to accumulation of TFH cells in chronic infection

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

Decreased TFR/TFH ratio in SIV-infected rhesus macaques may contribute to accumulation of TFH cells in chronic infection

2015-09-02 | GSE69756 | GEO

Lymph-Node-Based CD3+ CD20+ Cells Emerge from Membrane Exchange between T Follicular Helper Cells and B Cells and Increase Their Frequency following Simian Immunodeficiency Virus Infection

Project description:CD4+ T follicular helper (TFH) cells are key targets for human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) replication and contribute to the virus reservoir under antiretroviral therapy (ART). Here, we describe a novel CD3+ CD20+ double-positive (DP) lymphocyte subset, resident in secondary lymphoid organs of humans and rhesus macaques (RMs), that appear predominantly after membrane exchange between TFH and B cells. DP lymphocytes are enriched in cells displaying a TFH phenotype (CD4+ PD1hi CXCR5hi), function (interleukin 21 positive [IL-21+]), and gene expression profile. Importantly, expression of CD40L upon brief in vitro mitogen stimulation identifies, by specific gene- expression signatures, DP cells of TFH-cell origin versus those of B-cell origin. Analysis of 56 RMs showed that DP cells (i) significantly increase following SIV infection, (ii) are reduced after 12 months of ART in comparison to pre-ART levels, and (iii) expand to a significantly higher frequency following ART interruption. Quantification of total SIV-gag DNA on sorted DP cells from chronically infected RMs showed that these cells are susceptible to SIV infection. These data reinforce earlier observations that CD20+ T cells are infected and expanded by HIV infection, while suggesting that these cells phenotypically overlap activated CD4+ TFH cells that acquire CD20 expression via trogocytosis and can be targeted as part of therapeutic strategies aimed at HIV remission.

2023-05-15 | GSE232577 | GEO

IL-21 and IFNalpha therapy rescues terminally-differentiated NK cells and limit SIV reservoir in ART-treated macaques [cohort3]

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

IL-21 and IFNalpha therapy rescues terminally-differentiated NK cells and limit SIV reservoir in ART-treated macaques [cohort2]

2021-02-22 | GSE163441 | GEO

IL-21 and IFNalpha therapy rescues terminally-differentiated NK cells and limit SIV reservoir in ART-treated macaques [cohort1]

2021-02-22 | GSE163440 | GEO

Lymph node dendritic cells harbor inducible replication-competent HIV despite years of suppressive ART

Project description:The comprehensive characterization and quantification of the HIV tissue reservoirs is required to design appropriate therapeutic intervention(s) to achieve a cure. While pioneering studies demonstrated that HIV replication and spreading mainly occur in lymphoid tissues, the identification of specific cell subsets harboring replication competent virus in lymphoid tissues has long been neglected. In this context, we and others have recently shown that gut memory CD4 T cells, lymph node T follicular helper (Tfh) cells and tissue macrophages represent major HIV/SIV tissue reservoirs. Notably, Tfh cell differentiation is a multi-stage process that requires long-lasting interactions with lymph node (LN) dendritic cells (DCs) and pre-germinal center B cells in a specific cytokine/chemokine microenvironment. Lymph node DCs are endowed with an exceptional T-cell stimulatory potential and can either migrate from the periphery to the draining lymph node (migratory DCs) or locate in the LN for their entire life span (resident DCs). On the basis of these unique properties, long-term persistence of LN DCs infected with replication competent virus may represent the initial trigger of viral rebound post ART interruption and may therefore represent a major obstacle to HIV cure. We demonstrate that LN migratory DCs are infected with replication competent virus and persist despite suppressive ART. In addition, we identified the mechanisms associated with i) LN DC susceptibility to HIV infection and ii) long term persistence of HIV-infected LN DCs i.e. proliferation of infected cells in tissue sanctuaries.

2023-09-13 | GSE196066 | GEO

Robust and persistent SIV and HIV reactivation under ART by N-803 and CD8 depletion

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

Peripheral Blood Biomarkers in ART-Suppressed, SIV-Infected Rhesus Macaques Predict Viral Rebound Following ART Discontinuation

Project description:The development of biomarkers that can predict viral rebound following discontinuation of antiretroviral therapy (ART) in HIV-1-infected humans would be an important advance in HIV-1 cure research. In a prior study, we initiated ART in 20 rhesus macaques on days 0, 1, 2, and 3 following SIVmac251 infection prior to plasma viremia1. Following 6 months of suppressive ART, we discontinued ART and observed viral rebound in 9 of 20 animals. Here we show that transcriptomic and proteomic signatures of inflammation and immune activation in peripheral blood during ART suppression predicted viral rebound following ART discontinuation. Higher levels of proinflammatory and cellular immune activation pathways, including TNF, IL-1, IL-6, monocyte, and T cell activation signaling pathways, correlated with viral rebound following ART discontinuation. Immune modulatory IL-10 and TGF-b signaling also correlated with viral rebound. We then validated these candidate biomarkers of viral rebound in a second cohort of SIV-infected, ART-suppressed macaques. Taken together, these data suggest that persistent upregulation of inflammatory and immune activation pathways despite suppressive ART may represent a peripheral blood biomarker signature of the rebound-competent viral reservoir. The development of interventions that target the viral reservoir and modulate this signature may open new avenues in HIV-1 cure research.

2023-08-30 | GSE203603 | GEO

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