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Reduced chronic lymphocyte activation following Interferon-α blockade in the acute phase of SIV infection in rhesus macaques

ABSTRACT: Pathogenic HIV/SIV infection of humans and rhesus macaques (RMs) induces persistently high production of type-I interferon (IFN-I) which is thought to contribute to disease progression. To elucidate the specific role of IFN in SIV pathogenesis, 12 RMs were treated prior to i.v. SIVmac239 infection with a high or a low dose of an antibody (AGS-009) that neutralizes most IFN subtypes, and compared with six mock-infused, SIV-infected controls. Plasma viremia was measured post infection to assess the effect of IFNα blockade on virus replication, and peripheral blood and lymphoid tissue samples were analyzed by immunophenotypical staining. Consistent with the known antiviral effect of IFN-I, high-dose AGS-009 treatment induced a modest increase in acute phase viral loads vs. controls. 4 out of 6 RMs receiving a high dose of AGS-009 also experienced an early decline in CD4+ T cell counts which was associated with progression to AIDS. Interestingly, 50% of animals treated with AGS-009 (6/12) developed AIDS within one year of infection, compared with 17% (1/6) of untreated controls. Finally, blockade of IFN decreased the levels of activated CD4+ and CD8+ T cells, as well as B-cells, as measured by PD-1 and/or Ki67 expression. The lower levels of activated lymphocytes in IFN-blockade animals supports the hypothesis that IFN signaling contributes to lymphocyte activation during SIV infection, and suggests that this signaling pathway is involved in controlling virus replication during acute infection. The potential anti-inflammatory effect of IFN blockade should be explored as a strategy to reduce immune activation in HIV-infected individuals.

ORGANISM(S): Homo sapiens Macaca mulatta

PROVIDER: GSE110617 | GEO | 2018/02/19

REPOSITORIES: GEO

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Project description:Hyperimmune activation is one of the strong predictors of disease progression during pathogenic immunodeficiency virus infections and is mediated in part by sustained type I interferon (IFN) signaling. Combination antiretroviral therapy suppresses hyperimmune activation only partially in HIV-infected individuals. Here, we show that blockade of Programmed Death-1 (PD-1) during chonic SIV infection significantly reduces the expression of transcripts associated with type I IFN signaling in the blood and colorectal tissue of rhesus macaques (RM). The effect of PD-1 blockade on type I IFN signaling was durable and persisted under high viremia, a condition that is seen in nonprogressive SIV infection in their natural hosts. The reduced type I IFN signaling was associated with enhanced expression of some of the junction-associated genes in the colorectal tissue and a profound decrease in LPS levels in plasma suggesting a possible repair of gut associated junctions and decreased microbial translocation. The reduced type I IFN signaling was also associated with enhanced immunity against gut resident pathogenic bacteria, control of gut associated opportunistic infections and survival of SIV-infected RMs. These results reveal novel mechanisms by which PD-1 blockade enhances survival of SIV-infected RMs and have implications for development of novel therapeutic approaches to control HIV/AIDS. SIV negative controls (n=4); SIV infected and control antibody (SYNAGIS) treated (n=3); and SIV infected Programmed Death 1 antibody (PD-1 Ab) treated (n=3) groups of Rhesus macaques PBMCs were isolated by Ficoll-paque plus medium (Amersham) and were lysed in to RNA later reagent (Qiagen) and samples were homogenized with Qiagen Shredder (Qiagen). RNA was extracted with Rneasy mini kit (Qiagen) and was used for microarray experiments. Rhesus GeneChip assays were performed in the Yerkes Microarray Core Facility (www.microarray.emory.edu), one of the Affymetrix Microarray Core Labs.The 0.5Âµg of total RNA sample was analyzed on Rhesus Macaque Genome GeneChip that consists of over 52,000 probe sets (Affymetrix, Santa Clara, CA). Target RNA labeling, hybridization and post-hybridization processing were performed following the Affymetrix GeneChip Expression Analysis standard protocols. In brief, RNA sample was first reverse-transcribed using T7-Oligo(dT) Promoter Primer and SuperScript II in the first-strand cDNAs synthesis reaction. Following RNase H-mediated second-stranded cDNA synthesis, the double-stranded cDNAs were purified by use of a GeneChip sample clean-up module and served as templates in the generation of biotinylated complementary RNAs (cRNAs) in the presence of T7 RNA Polymerase and a biotinylated nucleotide analog/ribonucleotide mix by in vitro transcription (IVT) reaction. The biotinylated cRNAs were cleaned up, fragmented, and hybridized to the rhesus macaque expression arrays at 45Â°C for 16 h with constant rotation at 60 rpm. The gene chips were then washed and stained with Affymetrix fluidics stations 450 and scanned on Affymetrix scanner 3000. The images are processed to collect raw data with GeneChip Operating Software (GCOS) 1.4.

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Reduced chronic lymphocyte activation following Interferon-α blockade in the acute phase of SIV infection in rhesus macaques

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