In this collaborative series of projects, the investigators will characterize the underlying mechanisms for the metabolic complications (hyperlipidemia/body fat redistribution/insulin resistance) associated with protease inhibitors in HIV-infected subjects. In one of the applications (Berglund L, PI), the investigators propose pro- spective, mechanistic studies to elucidate lipoprotein and adipose tissue metabolism during protease inhibitor treatment in African American and Hispanic HIV-infected men and women. They will also determine baseline predictors of body fat redistribution and hyperlipidemia, and prospectively address adipose tissue lipolysis in response to protease inhibitors. These studies will be complemented by the basic science project (Schacter N, PI), where existing, well-characterized cell culture and mouse models of hyper- lipidemia will be used to explore mechanisms behind protease inhibitor- associated hyperlipidemia. In both proposals, the same fundamental hypotheses will be explored (increased lipoprotein secretion and/or decreased clearance). Further, intervention experiments will be initiated to abrogate protease inhibitor-induced hyperlipidemia using genetic approaches. In the third proposal (Carr A, PI), they will prospectively evaluate hyperlipidemia and insulin resistance in Caucasian HIV+ and HIV- subjects in response to protease inhibitor treatment. They will address effects of protease inhibitors on adipose tissue signaling pathways and on the complement system and determine the association between these factors and fat redistribution. Finally, the investigators will perform interventions for lipids and insulin resistance in protease inhibitor-treated HIV-infected patients. In their multitiered collaborations, they will compare results in different ethnic groups, address protease inhibitor treatment in HIV-infected and HIV-noninfected subjects, do detailed adipose tissue and plasma lipoprotein characterizations and test specific hypotheses simultaneously in humans and in animal models. The expertise of the collaborative research teams cover broad areas relevant to the RFA, such as HIV treatment expertise, expertise in body composition, adipose tissue metabolism and lipoproteins and atherosclerosis. Importantly, collaborations have been established and efforts are already under way to address the specific hypotheses in the three applications. The investigators expect that the synergisms and interactions between the three collaborating R01 applications will provide a framework for development of new approaches to correct metabolic derangements in HIV-infected subjects treated with protease inhibitors, will impact on future drug development and reduce the risk of cardiovascular disease.
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