(C) LBP levels were compared between AIDS patients classified into 5 groups based on the level of NCI as inFigure 1Cor (DE) classified into groups based on patterns of substance abuse as inFigure 2AB. 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 computer 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. == Introduction == Immune activation is a strong predictor of HIV disease progression[1],[2]. Elevated plasma endotoxin (bacterial lipopolysaccharide, LPS, a component of Gram-negative bacteria), a consequence of translocation of bacterial products from a leaky gut, is usually a likely cause of immune activation in HIV contamination[3]. LPS triggers monocyte (Mo) activation via CD14 and TLR4-mediated signaling, resulting in release of soluble CD14 and pro-inflammatory cytokines. Sustained Mo stimulation leads to LPS tolerance[4]. Brenchley et al. found correlations between plasma LPS levels, Mo tolerance to LPS ex vivo, and T-cell activation markers, and proposed that T-cell activation is an indirect consequence of LPS-mediated Mo stimulation[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/FcRIII expression Lentinan 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 CD16Mo. CD16+Mo represent 510% of circulating Mo in healthy individuals[8], but are dramatically expanded in HIV-infected patients[5],[10], particularly during progression to Lentinan AIDS[6],[7]. Although Mo do not support productive HIV contamination in vitro[11]and represent a minor viral reservoir in HIV-infected patients[12],[13],[14], CD16+Mo may be preferentially susceptible to contamination[14],[15],[16]. Furthermore, CD16+Mo-derived macrophages form conjugates with T-cells Rabbit Polyclonal to CCDC45 that promote T-cell activation and HIV replication[17],[18]. Activated Mo play a key role in the pathogenesis of HIV-associated dementia (HAD) and minor cognitive motor disorder (MCMD)[7],[19],[20],[21],[22]by carrying virus into the CNS, supporting productive contamination upon differentiation into macrophages, and producing neurotoxic factors[7],[21]. An increased frequency of CD16+/CD69+activated Mo[5]was associated with Lentinan HAD in the pre-HAART era[6],[7]. HAART decreases the frequency of CD16+Mo[10], reduces HIV levels in brain, and improves neurocognitive function[19], but neurocognitive impairment (NCI) still occurs in 1020% of AIDS patients[19],[20],[21]. Host factors that drive Mo activation in patients who develop HAD have not been defined. Here we investigated the relationship between plasma LPS, alterations in circulating Mo, and HAD in AIDS patients. High plasma LPS and LPS-binding protein (LBP) levels, together with low endotoxin core antibody (EndoCAb) levels, were associated with increased soluble markers of Mo activation and HAD. Plasma LPS levels were higher in AIDS subjects with IV heroin or ethanol abuse, or co-infection with Hepatitis C computer virus (HCV) compared to control groups. These findings suggest a role for elevated LPS levels in triggering Mo activation during HIV contamination, thereby contributing to HAD pathogenesis, and identify cofactors that may influence these processes. == Materials and Methods == == Subjects == AIDS patients with CD4 counts <300 cells/l were recruited at the Lemuel Shattuck Hospital (n = 49) or at 4 sites in the National NeuroAIDS Tissue Consortium (NNTC) (Manhattan HIV Brain Bank, National Neurological AIDS Lender, California NeuroAIDS Tissue Network, Texas NeuroAIDS Research Center) (n = 70) with written informed consent and IRB approval. HIV-/HCV-uninfected Lentinan blood was from Research Blood Components (Brighton, MA). Shattuck Hospital subjects were recruited based on presence or absence of an HAD diagnosis. NNTC subjects were selected by database searches based on patterns of substance abuse (determined by PRISM (psychiatric research interview for material and mental disorders) diagnoses and urine tox screens) irrespective of HAD or other forms of NCI..