Microbial translocation is a cause of systemic immune activation in chronic HIV infection

Jason M Brenchley¹, David A Price¹, Timothy W Schacker², Tedi E Asher¹, Guido Silvestri³, Srinivas Rao⁴, Zachary Kazzaz¹, Ethan Bornstein¹, Olivier Lambotte⁵, Daniel Altmann⁶, Bruce R Blazar⁷, Benigno Rodriguez⁸, Leia Teixeira-Johnson⁸, Alan Landay⁹, Jeffrey N Martin¹⁰, Frederick M Hecht¹⁰, Louis J Picker¹¹, Michael M Lederman⁸, Steven G Deeks¹⁰ & Daniel C Douek¹

¹  Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

²  Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA.

³  Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

⁴  Laboratory of Animal Medicine, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

⁵  University Hospital of Bicêtre, Bicêtre 94 276, France.

⁶  Department of Infectious Diseases, Hammersmith Hospital, Imperial College London, London W12 ONN, UK.

⁷  Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota 55455, USA.

⁸  Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44016, USA.

⁹  Department of Immunology and Microbiology, Rush Medical College, Chicago, Illinois 60612, USA.

¹⁰  University of California at San Francisco, San Francisco, California 90210, USA.

¹¹  Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon 97006, USA.

Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P 0.002). We show that increased lipopolysaccharide is bioactive in vivo and correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy seemed to reduce microbial translocation partially. Furthermore, in nonpathogenic SIV infection of sooty mangabeys, microbial translocation did not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide new directions for therapeutic interventions that modify the consequences of acute HIV infection.

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