The development of highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality in HIV-infected patients, yet the regimen also often results in chronic metabolic diseases. Dyslipidemia, insulin resistance, and lipodystrophy observed in patients receiving HAART have been linked to HIV protease inhibitors (PI). Previous studies have shown that HIV Pis activate ER stress, which underlies inflammatory responses and dysregulation of lipid metabolism in macrophages and hepatocytes. Within adipocytes, key players in both body lipid storage and inflammation, HIV Pis have been shown to activate ER stress, increase proinflammatory cytokine secretions, alter lipid metabolism, and inhibit differentiation of pre-adipocytes to mature adipocytes. Yet, the cellular mechanisms of HIV Pl-induced dysregulations have not been elucidated. We hypothesize that HIV Pis disrupt lipid metabolism by activating ER stress and inflammatory responses in adipocytes. We will test this hypothesise through three specific aims.
AIM 1 is to elucidate the mechanism of HIV Pl-induced ER stress in adipocytes. We will accomplish this by studying protein and mRNA level changes in pre- and differentiated murine, as well as human, cultured adipocytes.
AIM 2 is to define the role of ER stress in HIV Pl-induced dysregulation of adipocyte lipid metabolism and induction of the inflammatory response. We will first focus on the effects of HIV Pis in these processes and then knock down key players of the ER stress pathway to test how these effects are altered.
Aim 3 is to characterize the contribution of HIV Pl-induced macrophage cytokine secretions play in adipocyte ER stress activation, adipocyte cytokine secretion, and adipose tissue inflammation. We will treat co-cultures of macrophages and adipocytes to analyze differences in UPR activation and cytokine secretions versus cells cultured and treated alone. We will follow this by in vitro studies to determine the extent HIV PI treatment has on adipose tissue inflammation. By understanding how HIV Pis disrupt normal function in key cells of metabolic disease, we can learn to prevent the onset of these diseases by using concurrent alternative therapies with HAART in HIV patients. Public Health Relevance: HAART-induced dylipidemia and lipodystrophy are two major side effects of a pivotal drug regimen used for treating HIV-infected patients. Determining the underlying cellular/molecular mechanisms by which some of these drugs cause devastating metabolic diseases can allow us to develop new therapies that will counteract induction of these chronic illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DK085856-02
Application #
8016576
Study Section
Special Emphasis Panel (ZDK1-GRB-W (O1))
Program Officer
Castle, Arthur
Project Start
2009-09-25
Project End
2013-09-24
Budget Start
2010-09-25
Budget End
2011-09-24
Support Year
2
Fiscal Year
2010
Total Cost
$32,724
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