In this collaborative series of projects, this investigation will characterize the underlying mechanisms for the metabolic complications (hyperlipidemia/body fat redistribution/insulin resistance) associated with protease inhibitors in HIV-infected subjects. Exposure of HIV-infected patients to this atherogenic metabolic state could lead to atherosclerosis and vascular disease. In one of the applications (Berglund L, PI), this project proposes perspective, mechanistic studies to elucidate lipoprotein and adipose tissue metabolism during protease inhibitor treatment in African-American and Hispanic HIV- infected men and women. This investigation 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 (Shachter N, PI), where existing, well-characterized cell culture and mouse models of hyperlipidemia 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), will prospectively evaluate hyperlipidemia and insulin resistance in Caucasian HIV+ and HIV- subjects in response to protease inhibitor treatment. The study 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, this study will perform interventions for lipids and insulin resistance in protease inhibitor-treated HIV-infected patients. In the multi tiered collaborations the study 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 covers broad areas relevant to the RFA, such as HIV treatment expertise, expertise in body composition, adipose tissue metabolism and lipoprotein and atherosclerosis. Importantly, collaborations have been established and efforts are already under way to address the specific hypotheses in the three applications. The PI expects 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.
|Liu, Yanzhu; Yang, Lin; Conde-Knape, Karin et al. (2004) Fatty acids increase presenilin-1 levels and [gamma]-secretase activity in PSwt-1 cells. J Lipid Res 45:2368-76|
|Liang, J S; Distler, O; Cooper, D A et al. (2001) HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. Nat Med 7:1327-31|