With advent of HAART, life expectancy for HIV-infected patients has greatly increased, making HIV disease a chronic illness. Consequently, a number of slowly developing side effects of HIV infection are becoming apparent and constitute a significant clinical problem. Many of these co-morbidities, such as cardiovascular disease, dyslipidemia, and metabolic syndrome, are caused by virus- and anti-HIV treatment-mediated impairment of normal metabolism of cholesterol. Importantly, metabolic changes occur not only in HIV-infected cells, which are relatively few in HAART-treated subjects, but also in uninfected cells and tissues. Our studies performed in both in vitro and in vivo models of HIV infection have established that HIV protein Nef released from infected cells impairs activity of cholesterol transporter ABCA1 and interferes with ABCA1-dependent cholesterol efflux in uninfected cells. These effects of extracellular Nef on uninfected tissues may be responsible for metabolic co-morbidities (atherosclerosis, dyslipidemia, diabetes) in HIV-infected patients. However, the mechanism of cholesterol metabolism impairment induced by extracellular Nef and the contribution of this impairment to metabolic complications of HIV infection are not fully understood. This project will address these questions by pursuing the following Specific Aims: 1) To determine how extracellular Nef affects cholesterol metabolism in uninfected cells; 2) To characterize metabolic effects of extracellular Nef; 3) To test the anti-pathogenic effect of drugs targeting cholesterol metabolism. Proposed studies are highly significant as they address pathogenesis of HIV-associated metabolic complications, a leading co-morbidity in HIV disease. This proposal has a significant translational component, as in Aim 3 we will investigate a new therapeutic strategy to treat HIV infection and its metabolic complications using drugs affecting lipid metabolism. The proposal utilizes the expertise of two co-PIs, who have a long history of successful collaboration and complementary expertise in HIV virology (Dr. Bukrinsky) and cholesterol metabolism (Dr. Sviridov).

Public Health Relevance

A number of co-morbidities in HIV-infected individuals are caused by metabolic abnormalities. The proposed project will determine how extracellular Nef affects cellular and systemic cholesterol metabolism causing metabolic complications, such as atherosclerosis and diabetes, in HIV-infected subjects. In addition, the proposed studies may contribute to development of new therapeutic agents to prevent and treat HIV infection and its complications by targeting cholesterol metabolism.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Liu, Lijuan
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George Washington University
Schools of Medicine
United States
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Kuniholm, Mark H; Liang, Hua; Anastos, Kathryn et al. (2017) Association of a 3' untranslated region polymorphism in proprotein convertase subtilisin/kexin type 9 with HIV viral load and CD4+ levels in HIV/hepatitis C virus coinfected women. AIDS 31:2483-2492
Ditiatkovski, Michael; Palsson, Jonatan; Chin-Dusting, Jaye et al. (2017) Apolipoprotein A-I Mimetic Peptides: Discordance Between In Vitro and In Vivo Properties-Brief Report. Arterioscler Thromb Vasc Biol 37:1301-1306
Kuniholm, Mark H; Liang, Hua; Anastos, Kathryn et al. (2017) Association of a 3' Untranslated Region Polymorphism in PCSK9 with HIV Viral Load and CD4+ Levels in HIV/Hepatitis C Virus Co-Infected Women. AIDS :
Low, Hann; Mukhamedova, Nigora; Cui, Huanhuan L et al. (2016) Cytomegalovirus Restructures Lipid Rafts via a US28/CDC42-Mediated Pathway, Enhancing Cholesterol Efflux from Host Cells. Cell Rep 16:186-200
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
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
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
Siegel, Johanna; Darwish, Christina; Popratiloff, Anastas et al. (2016) Live Cell Imaging of ABCA1 Downregulation by HIV-1 Nef in an Experimental Model of HeLa ABCA1-GFP. AIDS Res Hum Retroviruses 32:872-3
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