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

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 r 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. Chronic immune activation is a characteristic feature of progressive HIV disease. Indeed, polyclonal B-cell activation was one of the first described immunological abnormalities in HIV-infected individuals 1 . Subsequently, increased T-cell turnover 2 , increased frequencies of T cells with an activated phenotype 3 , and increased serum levels of proinflammatory cytokines and chemokines 4 were observed. Notably, the degree of immune activation is a better predictor of disease progression than plasma viral load 5 . However, the underlying causes of immune activation have remained elusive 6,7 .