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

ABSTRACT: 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.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE163442 | GEO | 2021/02/22

REPOSITORIES: GEO

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

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

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

2021-02-22 | GSE163440 | GEO

Wound healing mechanisms in pathogenesis control in natural SIV host species [monocytes]

Project description:We devised a systems biology approach to investigate the early host response to high-dose rectal SIV transmission, by transcriptomic comparative analysis of a natural reservoir host SIV model species, African green monkeys (AGMs – Chlorocebus sabaeus, N=28) and a pathogenic model, rhesus macaques (RMs - Macaca mulatta, N=24).on rectal tissues for both AGMs and RMs.

2018-09-20 | GSE111233 | GEO

Wound healing mechanisms in pathogenesis control in natural SIV host species [rectal tissue]

2018-09-20 | GSE111077 | GEO

Interleukin-10 contributes to 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. 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

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

Short-term pIFN-α2a treatment does not significantly reduce the viral reservoir of SIV-infected, ART-treated rhesus macaques

Project description:Objective: To evaluate the effect of short-term type I IFN treatment on the latent viral reservoir in SIV-infected rhesus macaques on ART; Methods: We infected twelve RMs intrarectally with 10,000 TCID of SIVmac239. After 6 weeks of infection, all RMs started a three-class, four-drug ART regimen. Once viral loads were consistently undetectable, six animals were administered 1 dose of pegylated IFN-α2a per week for 4 weeks with each weekly intramuscular application being 6 µg/kg.

2018-05-17 | GSE114561 | GEO

IFNalpha-blockade during ART-treated SIV infection lowers tissue vDNA, rescues immune function, and improves overall health

Project description:The induction of type I interferons during acute viral infections drives local and systemic anti-viral responses. However, in chornic virus infection these type I interferon driven responses can be detrimental and can be characterized impaired immune responses (greater T cell exhaustion) and an overall decline in health outcomes. To parse out the role of type I IFN and assess the therapeutic impact of blocking type I IFN, we administered IFN-a blocking antibody to a cohort of SIV-infected ART treated Maccaca mulata. After 9 weeks of treatment (1 injection per week), we observed a significant reduction in the SIV-DNA levels in the lymphnode. This reduced SIV reservoir was seem with a systemic increase in immune cell subset signatures associated with better CD8 T cell function and lower plasma levels of TGF-beta. In addition, upon interruption of ART (16 weeks after ART initiation and after 16 rounds of anti-IFNa infusion), we observed that the non-human primates that underwent type I interferon blockade maintained better overall health and hemoglobin levels.

2021-09-27 | GSE184495 | GEO

Microarray Expression Analysis of SIV infection of Sooty Mangabeys

Project description:Natural SIV infection of sooty mangabeys (SMs) does not progress to disease despite chronic virus replication. In contrast to pathogenic SIV infection of rhesus macaques (RMs), chronic SIV infection of SMs is characterized by low immune activation. To elucidate the mechanisms underlying this phenotype, we longitudinally assessed host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs is consistently associated with a robust innate immune response, including widespread up-regulation of interferon-stimulated genes (ISGs). Our findings indicate that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low immuneactivation of chronically SIV-infected SMs. We infected 5 SMs with SIVsmm and assessed their gene expression in RNA derived from whole blood at 3,7,10,14,30 and 180 days post-infection using Rhesus Affymetrix GeneChips. As a comparison, we also analyzed gene expression in 4 RMs infected with SIVsmm, and 8 RMs infected with SIVmac239, a classical pathogenic SIV.

2010-03-08 | E-GEOD-16147 | biostudies-arrayexpress

Type I IFN signaling blockade during ART-treated and untreated chronic SIV infection suppresses inflammation but does not increase virus replication

Project description:Objective: Determine how admnistration of type I IFN antagonist influences the expression levels of interferon stimulated genes (ISG) during ART-treated or untreated chronic SIV infection. Methods: SIVmac251 infectected animals on or off ART received 3.5mg/kg pasylated-IFN-Iant two or three times a week from week 16 to 24 post-infection. RNA was rextracted from PBMC collected at several timepoints around IFN-Iant trearment and analyzed by RNA sequencing to compare transcription between IFN-Iant or placebo animals. Results: ISG, which are involved in control of virus replication, were increased upon SIV challenge and reduced by ART. Administration of IFN-Iant to ART-treated animals resulted in further reduction of ISG expression. Blocking IFN-I signaling in ART-untreated animals resulted in the most prominent reduction of ISG expression. Conclusion: These findings indicate that administration of an antagonist during ART-treated and untreated chronic SIV infection significantly impact IFN-I signalling.

2018-08-10 | GSE112148 | GEO

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