Recent studies suggest that HIV patients are at increased risk for cardiovascular events; however, the mechanisms underlying this increased risk remain unclear. Our group was one of the first to demonstrate that HIV infection is independently associated with accelerated atherosclerosis, as measured by carotid artery-intima media thickness (IMT), and that HIV- associated inflammation may be driving this accelerated atherosclerosis. The mechanism by which HIV disease independent of any drug-specific toxicity increases the risk of cardiovascular disease during HAART is not known. We hypothesize that even well controlled HIV infection is independently associated with cardiovascular risk and that further decreasing HIV-associated inflammation adding newer antiretroviral agents will also decrease cardiovascular risk. We will perform a cross-sectional study of 300 treated and suppressed HIV-infected patients and 75 uninfected controls (Aim 1) and two small clinical trials of 50 HIV-infected patients each (Aims 2,3) to study the relationship between HIV infection, inflammation, thrombosis, atherogenic lipoproteins, and measures of atherosclerosis. We propose the following specific aims: Aim 1: To determine the influence of traditional and novel markers of inflammation on endothelial function and IMT progression; Aim 2: To determine if "intensification" with raltegravir in subjects on long-term antiretroviral therapy with clinically undetectable HIV RNA levels will improve endothelial function, and to determine if this effect is mediated by alterations in inflammatory markers, lipoproteins and/or thrombotic factors; and Aim 3: To determine the potentially beneficial aspects of CCR5 inhibition on inflammation and endothelial function as measured by brachial artery reactivity. This application combines (1) the ability to rapidly recruit subjects from existing cohorts of HIV-infected subjects; (2) a dedicated and successful cardiology research imaging laboratory, (3) a laboratory that pioneered study of pro-atherosclerotic lipoprotein in infection, and (4) the collaboration of senior investigators from NIAID performing innovative immunology assays.

Understanding cardiovascular disease pathogenesis in HIV infection will provide essential information for the prediction, management, and therapy of HIV and HAART- associated complications, an increasingly important issue as aging occurs.