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

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: GSE163440 | 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 [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]

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

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

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2022-02-09 | GSE196436 | GEO

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2018-05-17 | GSE114561 | GEO

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

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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.

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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.

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