Polymorphisms in HIV-1nefare associated with plasma concentration of biomarkers of endothelial activation

Abstract

Infection with HIV is associated with an increased risk of cardiovascular disease (CVD), which may be mediated by the effect of the viral proteins, Nef and Tat, on inflammation and endothelial activation. The viral genes coding for Nef and Tat contain numerous polymorphisms, which we hypothesised may be differentially associated with endothelial activation. Therefore, our aim was to assess the association of these polymorphisms with endothelial activation and inflammation in subjects infected with HIV-1. The HIV-1 nef and tat genes were sequenced from clinical isolates from 31 and 34 patients, respectively. Plasma concentration of biomarkers of endothelial activation; intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (E-selectin), monocyte chemoattractant protein-1 (MCP-1) and von Willebrand factor (vWF), and biomarkers of inflammation; tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8), were compared across Nef and Tat by varying amino acid substitutions. Analysis of HIV-1 nef gene sequences identified five polymorphisms (V16I, H40Y, T50A,H, S169N and H188Q,S) that were each significantly (p<0.05) associated with ICAM-1 plasma concentration. An additive effect of these variants on plasma ICAM-1 concentration (p=0.004 for trend), was observed. No significant associations were seen between Tat amino acid residues and plasma concentration of markers of endothelial activation and inflammation. These are the first human in vivo data that support the hypothesis that Nef polymorphisms impact endothelial function.