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

University of California, San Francisco, San Francisco, California, United States
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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    • "That is, a precocious development of type 2 diabetes, dislipidemia, cardiovascular diseases, osteoporosis and frailty syndrome. Such diseases have been related to structural or metabolic perturbations in the gut microbiota of non-HIV-infected subjects (Claesson et al., 2012; Koeth et al., 2013; Le Chatelier et al., 2013; Tang et al., 2013) whereas, in PLWH, have been linked to chronic inflammation, immune activation and endotoxemia (Brenchley et al., 2006; Douek, 2003; Sandler and Douek, 2012). Thus there is considerable interest in understanding the role of the human gut microbiome in HIV pathogenesis and, in particular, its ability to perpetuate chronic inflammation and foster immune senescence. "
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    ABSTRACT: The human intestinal microbiota is essential for human health and well-being and is driven by genetic, lifestyle and environmental factors. Here, we show in two independent cohorts of HIV-1-infected subjects and HIV-1-negative controls in Europe that gay men often have a distinct composition of the human fecal microbiota, with increased microbial richness and diversity and enrichment in the Prevotella enterotype. This is independent of HIV-1 status, and with only a limited contribution of diet effects. After accounting for sexual orientation, however, HIV-1 infection remains associated to reduced bacterial richness, more so in subjects with suboptimal CD4 + T-cell count recovery under antiretroviral therapy. Future studies should evaluate if interventions to increase gut bacterial richness could improve HIV-associated immune dysfunction.
    Full-text · Article · Jan 2016 · EBioMedicine
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    • "Two types of clinical consequences of the maintained intestinal permeability have been described: (1) A poor immune recovery in those patients with higher values of bacterial translocation parameters. An inverse correlation between serum concentrations of barrier damage or immune activation markers and the magnitude of recovery of peripheral blood CD4+ T cell count has been demonstrated in ART-treated individuals[109,110,126,133]; and (2) Increased morbidity and mortality from non-AIDS defining causes, such as neurocognitive impairment or cardiovascular diseases, in those patients with a more pathological bacterial translocation and immune activation[113]. In ART-treated patients, causes of death are different of those classically associated with AIDS: most of patients in the Hunt's study[134]died by non- AIDS related causes, such as cardiovascular diseases (19%-27%), non-AIDS related cancer (11%-13%) and end-stage liver disease (8%-11%), among others. "

    Preview · Article · Jan 2016 · World Journal of Gastroenterology
    • "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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    ABSTRACT: Background: Alcohol use may accelerate HIV disease progression, but the plausible biological mechanisms have not been clearly elucidated. Methods: HIV-positive persons who were not on antiretroviral therapy (ART) completed the baseline assessment for a longitudinal study examining the association of alcohol use with HIV disease markers. Oversampling drinkers, baseline samples were tested for markers of monocyte activation (soluble CD14 [sCD14]), inflammation (interleukin-6 [IL-6]-6), and coagulation (d-dimer). We defined "unhealthy alcohol use" as testing positive using the Alcohol Use Disorders Identification Test-Consumption (≥3 for women and ≥4 for men) in the past 3 months or testing positive using a biomarker of heavy drinking, phosphatidylethanol (≥50 ng/ml). Multiple linear regression was used to examine the associations of unhealthy alcohol use with sCD14, log10 IL-6, and d-dimer. Results: Compared to those who were abstinent from alcohol, unhealthy drinkers had significantly higher sCD14 levels (mean = 1,676 vs. 1,387 ng/ml; mean difference [95% confidence interval (CI)] = 289 [83, 495], p < 0.01). In analyses adjusted for demographic factors, current cigarette smoking, and HIV disease markers, unhealthy drinkers continued to display significantly higher sCD14 levels compared to those who were abstinent from alcohol (adjusted mean = 1,670 vs. 1,406 ng/ml; adjusted mean difference [95% CI] = 264 [47, 480], p = 0.02). Unhealthy alcohol use was not significantly associated with IL-6 or d-dimer levels. Conclusions: Unhealthy alcohol use was independently associated with a marker of monocyte activation (i.e., higher sCD14) that predicts mortality in treated HIV infection. Longitudinal research should examine whether unhealthy alcohol use predicts changes in sCD14 prior to and following ART initiation.
    No preview · Article · Oct 2015 · Alcoholism Clinical and Experimental Research
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