title: PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques.
abstract: Hyperimmune activation is a strong predictor of disease progression during pathogenic immunodeficiency virus infections and is mediated in part by sustained type I IFN signaling in response to adventitious microbial infection. The immune inhibitory receptor programmed death-1 (PD-1) regulates functional exhaustion of virus-specific CD8(+) T cells during chronic infections, and in vivo PD-1 blockade has been shown to improve viral control of SIV. Here, we show that PD-1 blockade during chronic SIV infection markedly reduced the expression of transcripts associated with type I IFN signaling in the blood and colorectal tissue of rhesus macaques (RMs). The effect of PD-1 blockade on type I IFN signaling was durable and persisted even under conditions of high viremia. Reduced type I IFN signaling was associated with enhanced expression of some of the junction-associated genes in colorectal tissue and with a profound decrease in plasma LPS levels, suggesting a possible repair of gut-associated junctions and decreased microbial translocation into the blood. PD-1 blockade enhanced immunity to gut-resident pathogenic bacteria, control of gut-associated opportunistic infections, and survival of SIV-infected RMs. Our results suggest PD-1 blockade as a potential novel therapeutic approach to enhance combination antiretroviral therapy by suppressing hyperimmune activation in HIV-infected individuals.
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Dyavar Shetty
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Velu
authors.forename: Kehmia
authors.initials: K
authors.lastname: Titanji
authors.forename: Steven E
authors.initials: SE
authors.lastname: Bosinger
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.forename: Rama Rao
authors.initials: RR
authors.lastname: Amara
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016470:Bacteremia / Q000097:blood / Q000382:microbiology; D018988:Bacterial Translocation; D002167:Campylobacter / Q000276:immunology / Q000502:physiology; D002908:Chronic Disease; D005243:Feces / Q000382:microbiology / Q000469:parasitology; D020869:Gene Expression Profiling; D006801:Humans; D007370:Interferon Type I / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007420:Intestine, Large / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008070:Lipopolysaccharides / Q000097:blood; D008253:Macaca mulatta; D009894:Opportunistic Infections / Q000382:microbiology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D012475:Salmonella / Q000276:immunology / Q000502:physiology; D012760:Shigella / Q000276:immunology / Q000502:physiology; D015398:Signal Transduction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D015302:Simian Immunodeficiency Virus; D014158:Transcription, Genetic; D014258:Trichuris / Q000276:immunology / Q000502:physiology
chemical_list: D057134:Antibodies, Neutralizing; D000998:Antiviral Agents; D007370:Interferon Type I; D008070:Lipopolysaccharides; D061026:Programmed Cell Death 1 Receptor