In this collaborative series of projects, we 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), we propose prospective, mechanistic studies to elucidate lipoprotein and adipose tissue metabolism during protease inhibitor treatment in African American and Hispanic HIV-infected men and women. We 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), we will prospectively evaluate hyperlipidemia and insulin resistance in Caucasian HIV+ and HIV- subjects in response to protease inhibitor treatment. We 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, we will perform interventions for lipids and insulin resistance in protease inhibitor-treated HIV-infected patients. In our multitiered collaborations we 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 lipoproteins and atherosclerosis. Importantly, collaborations have been established and efforts are already under way to address the specific hypotheses in the three applications. We 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065938-02
Application #
6390917
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M2))
Program Officer
Applebaum-Bowden, Deborah
Project Start
2000-07-12
Project End
2002-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$323,559
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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Enkhmaa, Byambaa; Anuurad, Erdembileg; Zhang, Wei et al. (2013) HIV disease activity as a modulator of lipoprotein(a) and allele-specific apolipoprotein(a) levels. Arterioscler Thromb Vasc Biol 33:387-92
Anuurad, Erdembileg; Bremer, Andrew; Berglund, Lars (2010) HIV protease inhibitors and obesity. Curr Opin Endocrinol Diabetes Obes 17:478-85
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Dodell, G B; Kotler, D P; Engelson, E S et al. (2009) Intermuscular and subcutaneous adipose tissue distributions differ in HIV+ versus HIV-men and women. Int J Body Compos Res 7:73-78
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Zou, Wei; Berglund, Lars (2007) HIV and highly active antiretroviral therapy: dyslipidemia, metabolic aberrations, and cardiovascular risk. Prev Cardiol 10:96-103;quiz 104-5
Hyson, Dianne; Rutledge, John C; Berglund, Lars (2003) Postprandial lipemia and cardiovascular disease. Curr Atheroscler Rep 5:437-44
Rubin, Jill; Berglund, Lars (2002) Apolipoprotein E and diets: a case of gene-nutrient interaction? Curr Opin Lipidol 13:25-32