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

ABSTRACT: 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.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE184495 | GEO | 2021/09/27

REPOSITORIES: GEO

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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.

2018-08-10 | GSE112148 | GEO

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 [cohort3]

2021-02-22 | GSE163442 | 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

Gene expression profiling data from sooty mangabeys treated with interferon alpha

Project description:In contrast to pathogenic HIV and SIV infection of humans and macaques, SIV infection of sooty mangabeys (SMs) is typically non-pathogenic despite high virus replication. A key feature of primary SIV infection of SMs is a strong type I interferon (IFN-I) response, characterized by massive up-regulation of interferon-stimulated genes (ISG), followed by rapid resolution during the acute-to-chronic phase transition and establishment of an immune quiescent state that persists throughout the chronic infection. Based on these observations we hypothesized that low levels of IFN-I signaling may be instrumental in preventing chronic immune activation and disease progression in SIV-infected SMs. We used microarrays to characterize gene expression changes induced by IFNalpha treatment. To directly assess the effects of an experimentally-induced augmentation of IFN-I signaling in chronically SIV-infected SMs, we administered recombinant rhesus macaque IFNalpha2-IgFc (rmIFNα2) to eight naturally SIV-infected SMs weekly for 16 weeks and longitudinally monitored viral load, lymphocyte counts, immune activation, SIV-specific CD8+ T-cell responses, and gene expression profile. Administration of rmIFNα2 was bioactive in vivo with gene expression profiling revealing a strong upregulation of numerous ISGs in the blood of treated animals.

2012-07-09 | E-GEOD-35460 | biostudies-arrayexpress

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

Type I IFN responses in rhesus macaques prevent SIV transmission and slow disease progression

Project description:In acute HIV infection immune activation may provide target cells and drive virus replication, which innate immunity may limit. Thus, the net effects of inflammatory mediators, including type I interferon (IFN-I), are unclear. Here, we block IFN-I signaling during pathogenic acute SIV infection with an IFN-I receptor antagonist. Delayed antiviral gene expression, increased SIV reservoir, increased CD4 T cell depletion and accelerated progression to AIDS and death ensue despite decreased T cell activation. In contrast, IFNα2a treatment initially upregulates antiviral genes and prevents systemic SIV infection after rectal challenge. Antiviral gene expression normalizes, and infection ensues with fewer transmitted/founder variants. Continued IFNα2a treatment causes delayed antiviral gene expression, increased SIV reservoir and increased CCR5+ CD4 T cell loss. Thus, the precise timing of antiviral gene expression has a profound impact on disease course. The benefits of early antiviral activity outweigh the harms of increased immune activation in acute SIV infection. SRA Study accession: SRP034563, BioProject ID:PRJNA231884

2014-07-23 | E-GEOD-53690 | biostudies-arrayexpress

Type I IFN responses in rhesus macaques prevent SIV transmission and slow disease progression

2014-07-23 | GSE53690 | GEO

TGF-beta blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo [scRNA-seq]

Project description:HIV-1 persistence during ART is due to the establishment of long-lived viral reservoirs in resting immune cells. Using an NHP model of barcoded SIVmac239 intravenous infection and therapeutic dosing of the anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirmed the latency reversal properties of in vivo TGF-beta blockade, decreased viral reservoirs and stimulated immune responses. Eight SIV-infected macaques on suppressive ART were treated with 4 2-week cycles of galunisertib. ART was discontinued 3 weeks after the last dose, and macaques euthanized 6 weeks after ART-interruption(ATI). One macaque did not rebound, while the remaining rebounded between week 2 and 6 post-ATI. Galunisertib led to viral reactivation as indicated by plasma viral load and immunoPET/CT with the 64Cu-DOTA-F(ab')2-p7D3-probe. Half to 1 Log decrease in cell-associated (CA-)SIV DNA was detected in lymph nodes, gut and PBMC, while intact pro-virus in PBMC decreased by 3-fold. No systemic increase in inflammatory cytokines was observed. High-dimensions cytometry, bulk and single-cell RNAseq revealed a shift toward an effector phenotype in T and NK cells.

2024-01-08 | GSE244870 | GEO

TGF-beta blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo [RNA-seq]

2024-01-08 | GSE244828 | GEO

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