Atherosclerosis is the major cause of cardiovascular disease (CVD) leading to myocardial infarction and stroke. An abundance of evidence indicates that atherosclerosis is an inflammatory disorder involving endothelial cell (EC) dysfunction, and infiltration of macrophages and lymphocytes into the arterial wall;however, the events responsible for the chronic inflammation remain elusive. HIV-infected persons have an increased risk for CVD, and have more advanced subclinical cardiac findings than matched uninfected persons. Moreover, an increasing number of clinical studies has demonstrated the presence of early markers of vascular disease, including carotid intimal thickening (cIMT), in HIV-infected persons without any overt signs of disease. The link of chronic inflammation to CVD has led investigators to examine the association of numerous infectious agents as possible cofactors with HIV to increase the risk for the CVD. Of the potential co- infecting pathogens, human cytomegalovirus (CMV) has consistently been identified as the leading candidate. Of note, elevated immune responses to CMV have been repeatedly identified as potential independent risk factors for CVD in HIV-infected and uninfected populations. In this proposal, we hypothesize that infection of ECs and generation of a strong immune response to CMV including CMV specific T cell responses contribute to the increased risk of CVD in HIV-infected persons.
The specific aims are to determine:
Aim 1 : To identify the association of increased carotid intima-media thickness (cIMT) in HIV-infected persons and markers of CMV immune response;
Aim 2 : Elucidation of how CMV infection of ECs and differential adhesion of CMV- immunologically primed and nave PBMCs from HIV-infected women and perinatally-infected youth under different flow conditions contribute to EC dysfunction;
and Aim 3 : Association of non-lipid lowering benefits of statins with inhibition of CMV infection. This proposal uniquely combines a clinical study of HIV-infected women and perinatally-infected youth that will correlate the immune responses to CMV with echocardiographic evidence of early CVD, and determine the pathogenetic mechanisms responsible for the cardiac findings in an original in vitro model. This innovative model uses a multifaceted approach to study interactions among HIV, CMV, ECs, and PBMCs under conditions of flow and shear stress that closely mirror conditions in arteries susceptible to atherosclerosis. This research will provide novel insights into the pathogenesis of atherosclerosis and CVD in HIV-infected women and perinatally-infected youth, and will lead to new approaches for treatment and prevention strategies to improve cardiovascular health in HIV-infected persons.

Public Health Relevance

Premature cardiovascular disease (CVD) has become an important medical problem for HIV-infected persons receiving effective antiretroviral therapy. Hemodynamic factors are major regulators of atherosclerosis, and human cytomegalovirus (CMV) infection has emerged as a potential important risk factor for CVD. The proposed research will examine the role of CMV in the development of early CVD as measured by carotid intima media thickness in HIV-infected women and perinatally-infected youth, and will utilize a novel dynamic flow model to identify the immunologic, virologic and molecular mechanisms linking CMV to HIV-associated endothelial cell inflammation and damage indicative of CVD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZHL1-CSR-B (M2))
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Kirby, Ruth
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University of California San Diego
Schools of Medicine
La Jolla
United States
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