Role of Telomere maintenance in HIV-Associated Cardiovascular Disease

Jue Lin, PhD, Recipient

HIV-infected individuals are at increased risk for a number of diseases typically associated with aging, including cardiovascular disease. It is now well accepted that poorly defined HIV-associated immunologic perturbations, in addition to traditional risk factors and antiretroviral therapy toxicity, contribute to this risk. This study will explore the pathogenesis of HIV-associated cardiovascular disease with a focus on telomere maintenance and aging. The central hypothesis of this study is that chronic exposure to HIV virus results in premature "aging" of the immune system manifested by shorter telomeres and lower telomerase activity in immune cells, and that these immunologic perturbations are associated with cardiovascular disease. Telomeres are repeated DNA sequences at the end of chromosomes. As cells proliferate, telomeres shorten, resulting eventually in cellular senescence. This process can be delayed by increases in telomerase, an enzyme that can lengthen telomeres. Among HIV uninfected individuals, shorter telomere length and lower telomerase activity have been associated with risks of cardiovascular events. In this study, we will analyze telomere length and telomerase activity in peripheral blood mononuclear cells that have already been collected from a large well-characterized cohort of HIV infected and uninfected adults (70 HIV non-controllers, 70 untreated HIV "elite" controllers, 70 highly active anti-retroviral therapy responders and 70 HIV-seronegative controls). We will evaluate the association between telomere length, telomerase activity and HIV-associated cardiovascular disease. We hypothesize that HIV infected patients will have shorter telomere length and reduced telomerase activity compared to well-matched controls. We also hypothesize that untreated noncontrollers will have shorter telomere length and reduced telomerase activity compared to HAART responders and elite controllers. Finally, we hypothesize that shorter telomere length and lower telomerase activity will be associated with increased cardiovascular risk as assessed by endothelial function, carotid artery intima-media thickness and coronary artery calcification in the HIV patients.