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

J Clin Invest. 2012 May;122(5):1712-6. doi: 10.1172/JCI60612. Epub 2012 Apr 23.


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.

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology*
  • Antibodies, Neutralizing / therapeutic use
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Bacteremia / blood
  • Bacteremia / microbiology
  • Bacterial Translocation*
  • Campylobacter / immunology
  • Campylobacter / physiology
  • Chronic Disease
  • Feces / microbiology
  • Feces / parasitology
  • Gene Expression Profiling
  • Humans
  • Interferon Type I / blood
  • Interferon Type I / genetics
  • Interferon Type I / metabolism*
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Intestine, Large / drug effects
  • Intestine, Large / immunology
  • Intestine, Large / metabolism
  • Intestine, Large / microbiology
  • Lipopolysaccharides / blood
  • Macaca mulatta
  • Opportunistic Infections / microbiology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Salmonella / immunology
  • Salmonella / physiology
  • Shigella / immunology
  • Shigella / physiology
  • Signal Transduction
  • Simian Acquired Immunodeficiency Syndrome / drug therapy*
  • Simian Acquired Immunodeficiency Syndrome / immunology
  • Simian Acquired Immunodeficiency Syndrome / metabolism
  • Simian Acquired Immunodeficiency Syndrome / microbiology
  • Simian Immunodeficiency Virus
  • Transcription, Genetic
  • Trichuris / immunology
  • Trichuris / physiology


  • Antibodies, Neutralizing
  • Antiviral Agents
  • Interferon Type I
  • Lipopolysaccharides
  • Programmed Cell Death 1 Receptor