Microbial Translocation is a Cause of Systemic Immune Activation in Chronic HIV Infection

Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Medicine (Impact Factor: 27.36). 12/2006; 12(12):1365-71. DOI: 10.1038/nm1511
Source: PubMed


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 <or= 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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    • "Unhealthy alcohol use may amplify the effects of HIV on translocation of microbial products such as lipopolysaccharide (LPS) across the gastrointestinal tract (Brenchley et al., 2006), which predicts greater immune activation and faster clinical progression among those not receiving ART (Marchetti et al., 2011). In fact, prior research has established that "
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    • "This T-cell subset is known to contribute to the recruitment of neutrophils (Ye et al., 2001) which produce antimicrobial and anti-HIV-1 molecules such as defensins (Chang and Klotman, 2004; Chang et al., 2005; Wu et al., 2005), and remove bacteria and products thereof by phagocytosis (Dobmeyer et al., 1995). Neutrophils in GALT appear to slow the progression of HIV- 1 pathogenesis by opposing microbial translocation (Ancuta et al., 2008; Brenchley et al., 2006). Furthermore, the ability of neutrophils to undergo rapid apoptosis is important for the resolution of inflammation (El Kebir and Filep, 2010; El Kebir et al., 2012; McGrath et al., 2011), and our present results indicate that exosomes released from HIV-1-infected cells likely interfere with this process. "
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    • "In line with this, low levels of immune activation were observed in chronically infected natural hosts of SIV, such as African green monkeys and Sooty mangabeys who do not progress to diseases despite high levels of virus replication (Pandrea et al., 2008; Silvestri et al., 2003). Microbial translocation from the intestinal lumen to the systemic circulation appears to be a key factor underlying the chronic immune activation, and it is supposed to be the consequence of intestinal mucosal barrier dysfunction (Brenchley et al., 2006; Klatt et al., 2012). However, the underlying mechanisms such as the causal relationships between virus infection , intestinal mucosal barrier dysfunction and translocation of microbes and microbial products, and when and how the earliest gut barrier dysfunction occurred have not been completely understood. "
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