Cardiovascular disease (CVD) contributes substantially to the overall morbidity of HIV-infected individuals. Factors that epidemiologically and prospectively are the strongest predictors of .atherosclerosis are dyslipidemia and impairmen of intracellular cholesterol metabolism. Dyslipidemia in HIV-infected patients has been attributed mainly to antiretroviral drugs, in particular protease inhibitors, but specific mechanisms responsible for dyslipidemia have not been fully characterized. Even less is known about changes in lipid metabolism induced by HIV infection itself. In this application we propose a prospective study with HIV-infected patients to characterize changes in metabolism and functionality of High Density Lipoprotein (HDL), the key anti-atherogenic lipoprotein in the blood, associated with HIV-1 infection and anti-retroviral drugs. We will also correlate these changes with the surrogate measures of progression of atherosclerosis in these patients. Studies in vitro will address the mechanism of HIV-mediated effect on HDL The following Specific Aims are proposed: .
Specific Aim 1 : To characterize effects oLHIV disease on atherosclerosis and metabolic dysregulation. .
Specific Aim 2 : To characterize the effect of HIV disease on HDL composition and structure.
Specific Aim 3 : To characterize effects of HIV disease on HDL functionality.
Specific Aim 4 : To characterize cellular mechanisms responsible for impairment of HDL metabolism. . Research described in this proposal is a mUlti-PI program that will rely on collaborative efforts of clinical cardiologists, basic science cardiovascular researchers and virologists at three sites: the George Washington University, Harvard University and BakerlDI Heart and Diabetes Research Institute.

Public Health Relevance

The proposed research is highly relevant to Public Health as it investigates the reason for high risk of atherosclerosis in HIV-infected subjects. Given that 10-30% of HIV-infected individuals present evidence of some form of cardiovascular disease, and atherosclerosis is the main underlying cause of cardiovascular disease, atherosclerosis becomes one of the main complications of HIV disease. However, mechanisms connecting HIV infection and anti-HIV treatment with development of atherosclerosis are not fully understood, making proposed study highly significant both for basic science and clinical research.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL101274-02
Application #
8121644
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Mcdonald, Cheryl
Project Start
2010-08-15
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$716,126
Indirect Cost
$98,385
Name
George Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Low, Hann; Cheng, Lesley; Di Yacovo, Maria-Silvana et al. (2016) Lipid metabolism in patients infected with Nef-deficient HIV-1 strain. Atherosclerosis 244:22-8
Zimmer, Sebastian; Grebe, Alena; Bakke, Siril S et al. (2016) Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Sci Transl Med 8:333ra50
Meikle, Peter; Low, Hann; Churchill, Melissa J et al. (2016) Lipidomic dataset of plasma from patients infected with wild type and nef-deficient HIV-1 strain. Data Brief 6:168-75
Hunegnaw, Ruth; Vassylyeva, Marina; Dubrovsky, Larisa et al. (2016) Interaction Between HIV-1 Nef and Calnexin: From Modeling to Small Molecule Inhibitors Reversing HIV-Induced Lipid Accumulation. Arterioscler Thromb Vasc Biol 36:1758-71
Mukhamedova, Nigora; Brichacek, Beda; Darwish, Christina et al. (2016) Analysis of ABCA1 and Cholesterol Efflux in HIV-Infected Cells. Methods Mol Biol 1354:281-92
Sakae, Nobutaka; Liu, Chia-Chen; Shinohara, Mitsuru et al. (2016) ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology. J Neurosci 36:3848-59
Mukhamedova, Nigora; Hoang, Anh; Cui, Huanhuan L et al. (2016) Small GTPase ARF6 Regulates Endocytic Pathway Leading to Degradation of ATP-Binding Cassette Transporter A1. Arterioscler Thromb Vasc Biol 36:2292-2303
Siegel, Marc O; Borkowska, Alison G; Dubrovsky, Larisa et al. (2015) HIV infection induces structural and functional changes in high density lipoproteins. Atherosclerosis 243:19-29
Tamehiro, Norimasa; Park, Min Hi; Hawxhurst, Victoria et al. (2015) LXR Agonism Upregulates the Macrophage ABCA1/Syntrophin Protein Complex That Can Bind ApoA-I and Stabilized ABCA1 Protein, but Complex Loss Does Not Inhibit Lipid Efflux. Biochemistry 54:6931-41
Prasad, Vinayaka R; Bukrinsky, Michael I (2014) New clues to understanding HIV nonprogressors: low cholesterol blocks HIV trans infection. MBio 5:e01396-14

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