The Role of Human Cytomegalovirus in Vascular Pathogenesis

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) has been proposed to be a risk factor for transplant-associated atherosclerosis, restenosis, and atherosclerosis in some individuals with no known risk factors. This hypothesis has received increasing support as a result of epidemiological data, clinical observations, animal research, and in vitro studies with smooth muscle cells, endothelial cells, and monocyte/macrophages. The long term goals of this study are to determine how HCMV mediates this process. This study will focus on how IE2 86, an essential viral protein, affects signaling pathways in human aortic endothelial cells. The first aim of this study is to examine how two specific IE2 86 mutants will affect signaling pathways in human aortic endothelial cells. The three major pathways of interest include the endothelial nitric oxide synthase pathway, the regulation of the endothelial cell protein C receptor, and the regulation of p53 localization and activity. These pathways will be examined by generating recombinant viruses as BACs in the TR clinical isolate of HCMV and examining the effects in human aortic endothelial cells. The second aim is to examine which viral and cellular proteins interact with IE2 86. This will be achieved by introducing a tandem affinity purification tag into the endogenous IE2 86 protein. These interactions will be further elucidated by examining the two specific IE2 86 mutants studied in Aim 1. It is believed that human cytomegalovirus (HCMV) plays a role in vascular diseases such as atherosclerosis. Because the virus affects between 60-90% of the U.S. population it is important to determine how HCMV causes vascular disease.