asnjournals.org/lookup/suppl/doi:10.1681/ASN.2012060550/-/DCSupplemental.
HIV infection has been associated with increased cardiovascular disease risk [1] but the mediators of the increased risk have not been specifically identified. Endothelial dysfunction is selleck inhibitor a critical initial step of atherogenesis which subsequently contributes to the progression and clinical manifestations of atherosclerosis [2], [3]. Long-term use of protease inhibitors (PIs) has been associated with endothelial dysfunction [4]. Factors other than PI use that may contribute to endothelial dysfunction in HIV-infected patients include untreated HIV infection itself [5] treatment-associated lipid changes [4], [6] and the lipodystrophy syndrome [7].

Mediators and markers of endothelial dysfunction have been sought, such as lipids and lipoproteins and circulating markers of inflammation and vascular activation, but the majority of these factors have not been significantly associated with endothelial function as measured by brachial flow-mediated dilation (FMD) [5], [8]. Lack of a consistent association between FMD and CD4 cell count suggests that immune status is not directly related to endothelial dysfunction [5], [8], [9], . In a large cohort study, there was also no association between CD4 cell count and risk of myocardial infarction [12]. Despite careful study, the specific mediators of HIV-associated endothelial dysfunction have not been identified CD4 T cell depletion in gut-associated lymphoid tissue (GALT) occurs within 4�C6 weeks of primary HIV infection [13].

Simian immunodeficiency virus-infected macaque models have demonstrated that gut bacteria are a source of circulating bacterial lipopolysaccharide (LPS) [14]. CD4 T-cell depletion in GALT coincides with increased expression of genes associated with inflammation and decreased expression of genes regulating epithelial barrier and digestive functions, mucosal repair and regeneration which suggests disruption of the gut microenvironment [13]. Increased levels of LPS that occur in patients with chronic progressive HIV infection decreased after 48 weeks of effective anti-retroviral therapy (ART) but did not normalize [15]. These increased levels of LPS are associated with persistent immune activation [15], so by extension persistent immune activation itself is another potential mechanism of HIV-associated endothelial dysfunction.

Gut microbial translocation leads to increased circulating levels of LPS and other microbial products. LPS activates endothelial cells via a distinct signaling pathway and this may directly influence cardiovascular disease pathogenesis [16], [17]. Soluble CD14 (sCD14) is a circulating glycoprotein that binds LPS, subsequently allowing the interaction of LPS with another signaling Cilengitide receptor.