PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques.

TitlePD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques.
Publication TypeJournal Article
Year of Publication2012
AuthorsDyavar Shetty R, Velu V, Titanji K, Bosinger SE, Freeman GJ, Silvestri G, Amara R R
JournalJ Clin Invest
Volume122
Issue5
Pagination1712-6
Date Published2012 May 1
ISSN1558-8238
KeywordsAnimals, Antibodies, Neutralizing, Antiviral Agents, Bacteremia, Bacterial Translocation, Campylobacter, Chronic Disease, Feces, Gene Expression Profiling, Humans, Interferon Type I, Intestinal Mucosa, Intestine, Large, Lipopolysaccharides, Macaca mulatta, Opportunistic Infections, Programmed Cell Death 1 Receptor, Salmonella, Shigella, Signal Transduction, Simian Acquired Immunodeficiency Syndrome, Simian immunodeficiency virus, Transcription, Genetic, Trichuris
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.

DOI10.1172/JCI60612
Alternate JournalJ. Clin. Invest.
PubMed ID22523065