Microbial Translocation Is Associated with Increased Monocyte Activation and Dementia in AIDS Patients

Petronela Ancuta,Tauheed Zaman,David Stone,Eun-Young Kim,Kevin J Kunstman,Anupa Kamat,Steven M Wolinsky,Dana Gabuzda,Alysse Wurcel,Patrick Autissier,Elyse J Singer,Susan Morgello,Megan Mefford,Derya Unutmaz

doi:10.1371/journal.pone.0002516

Abstract

Elevated plasma lipopolysaccharide (LPS), an indicator of microbial translocation from the gut, is a likely cause of systemic immune activation in chronic HIV infection. LPS induces monocyte activation and trafficking into brain, which are key mechanisms in the pathogenesis of HIV-associated dementia (HAD). To determine whether high LPS levels are associated with increased monocyte activation and HAD, we obtained peripheral blood samples from AIDS patients and examined plasma LPS by Limulus amebocyte lysate (LAL) assay, peripheral blood monocytes by FACS, and soluble markers of monocyte activation by ELISA. Purified monocytes were isolated by FACS sorting, and HIV DNA and RNA levels were quantified by real time PCR. Circulating monocytes expressed high levels of the activation markers CD69 and HLA-DR, and harbored low levels of HIV compared to CD4+ T-cells. High plasma LPS levels were associated with increased plasma sCD14 and LPS-binding protein (LBP) levels, and low endotoxin core antibody levels. LPS levels were higher in HAD patients compared to control groups, and were associated with HAD independently of plasma viral load and CD4 counts. LPS levels were higher in AIDS patients using intravenous heroin and/or ethanol, or with Hepatitis C virus (HCV) co-infection, compared to control groups. These results suggest a role for elevated LPS levels in driving monocyte activation in AIDS, thereby contributing to the pathogenesis of HAD, and provide evidence that cofactors linked to substance abuse and HCV co-infection influence these processes.

Highlights

IntroductionElevated plasma endotoxin (bacterial lipopolysaccharide, LPS, a component of Gram-negative bacteria), a consequence of translocation of bacterial products from a leaky gut, is a likely cause of immune activation in HIV infection [3]
Immune activation is a strong predictor of HIV disease progression [1,2]
The cohort consisted of 119 AIDS patients enrolled at the Shattuck Hospital (n = 49) or National NeuroAIDS Tissue Consortium (NNTC) (n = 70) (Table 1), and had relatively high plasma VL and low CD4 counts compared to other current cohorts, together with a high frequency of intravenous drug abuse (IVDU). 61 of 94 subjects were HAART failures

Summary

Introduction

Elevated plasma endotoxin (bacterial lipopolysaccharide, LPS, a component of Gram-negative bacteria), a consequence of translocation of bacterial products from a leaky gut, is a likely cause of immune activation in HIV infection [3]. Alterations in circulating Mo linked to HIV disease progression include increased expression of pro-inflammatory cytokines and Mo activation markers [5,6,7]. CD16/FccRIII expression on Mo distinguishes a minor CD16+ subset [8,9] that expresses higher TNF and IL-1 [5], and higher HLA-DR, CD40, and CD86 levels compared to CD162 Mo. CD16+ Mo represent 5–10% of circulating Mo in healthy individuals [8], but are dramatically expanded in HIV-infected patients [5,10], during progression to AIDS [6,7].

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Conclusion