Human immunodeficiency virus (HIV) infection is a growing epidemic within today's world population. Highly active antiretroviral therapies (HAART) are becoming increasingly effective at decreasing or even eliminating the serum viral load of HIV positive individuals, resulting in increased life spans. Unfortunately, long-term harmful side effects (hyperlipidemias, lipodystrophy and insulin resistance) of HAART therapeutics are becoming evident. The mechanism(s) by which HIV protease inhibitors (PI) therapy leads to dysregulation of sterol and lipid metabolism is unclear. The liver is the major organ responsible for maintaining lipid homeostasis in the body. The proposed experiments in this new application will explore the mechanism(s) by which different HIV PIs alter hepatic cholesterol, bile acid and fatty acid metabolism.
The specific aims of this application are: 1) Determine the effects of the most commonly used HIV PI (ritonavir, indinavir, nelfinavir, Iopinavir, atazanavir) on cholesterol, bile acids and fatty acid metabolism using primary adult rat hepatocytes as a model system; 2) Determine the effects of HIV PI on hepatic cholesterol, fatty acid, and bile acid metabolism and lipoprotein profiles in a mouse in vivo model 3) Elucidate the mechanism(s) where by indinavir (and other HIV PIs) alters hepatic cholesterol and bile acid metabolism in primary rat hepatocytes. Test the hypothesis that HIV PIs alters the intracellular movement of cholesterol and/or protein turnover rates of sterol responsive element binding proteins (SREBPs). Knowledge of how HIV PI alter lipid metabolism may allow for more effective, long term approaches for treating HIV infected individuals. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057189-05
Application #
7371133
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Brobst, Susan W
Project Start
2004-03-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2008
Total Cost
$308,676
Indirect Cost
Name
Virginia Commonwealth University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Wu, Xudong; Sun, Lixin; Zha, Weibin et al. (2010) HIV protease inhibitors induce endoplasmic reticulum stress and disrupt barrier integrity in intestinal epithelial cells. Gastroenterology 138:197-209
Lei, Bokai; Zha, Weibin; Wang, Yun et al. (2010) Development of a novel self-microemulsifying drug delivery system for reducing HIV protease inhibitor-induced intestinal epithelial barrier dysfunction. Mol Pharm 7:844-53
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Chen, Li; Jarujaron, Sirikalaya; Wu, Xudong et al. (2009) HIV protease inhibitor lopinavir-induced TNF-alpha and IL-6 expression is coupled to the unfolded protein response and ERK signaling pathways in macrophages. Biochem Pharmacol 78:70-7
Wu, Xudong; Zhang, Luyong; Gurley, Emily et al. (2008) Prevention of free fatty acid-induced hepatic lipotoxicity by 18beta-glycyrrhetinic acid through lysosomal and mitochondrial pathways. Hepatology 47:1905-15

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