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.
Bibliographical noteFunding Information:
We would like to thank G. Barclay for information on the origins of EndoCab. The authors would like to acknowledge the Bad Boys of Cleveland (BBC), J. Spritzler, R. Seder and R. Koup for advice and discussion. This study was supported by grants from the US National Institutes of Health (AI 25879, AI 38858 and AI 36219 to M.M.L.; ROI AI052755 and AI066998 to G.S.; and AI052745, AI41531, P30 AI27763, P30 MH62246 and MO1-RR0083-37 to the UCSF cohort study) and the Yerkes Primate Center (RR-00165 to G.S.). O.L. is supported by grants from the French National Agency for Research on Aids and Viral Hepatitis (ANRS) and is a member of the ANRS EP36 study group. D.A.P. is a Senior Clinical Fellow of the Medical Research Council (UK). This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health.