Human cytomegalovirus (HCMV) causes one of the most common opportunistic infections in immunocompromised individuals, including organ transplant recipients and AIDS patients. Moreover, HCMV has also been implicated as a possible etiologic factor in the pathogenesis of vascular diseases, including atherosclerosis, arterial restenosis following angioplasty, and solid organ transplant vascular sclerosis. CMV infection in the aorta plays a key role in the development of viral-associated vascular diseases. The great vessels can be the sites for both acute and latent viral infections. Ongoing infections in the vessels facilitate the development of vascular diseases by (a) generating local lesions and injury of the endothelium, (b) up-regulating the expression of cell adhesion molecules and chemokines that induce inflammatory response, and (c) enhancing proliferation and migration of smooth muscle cells. Protection of patients, especially those who are immunocompromised, from developing CMV-associated vascular diseases requires eliminating HCMV infection from the blood vessels and blocking viral replication in these tissues. Understanding the mechanism of CMV infections in the vessels will provide insight into treatment and prevention of CMV-associated vascular diseases. Using murine CMV (MCMV) as a model system, the proposed study is to identify the viral genes required for CMV replication in the aorta and to study the functions of these viral determinants in supporting CMV infections in the vascular wall. We have recently generated a pool of MCMV mutants that contain a transposon sequence. We have also isolated a viral mutant that is attenuated in replication in the aorta and is defective in inducing viral-associated vascular diseases including acute arteritis and atherosclerosis. In the proposed research, mice will be infected with viral mutants and those mutants that are defective in replicating in the aorta will be isolated. The pathogenecity of these mutants will be studied, and the genes that are mutated will be identified. Moreover, the mechanism of how the identified viral determinants function in supporting MCMV infections in the aorta and promoting vascular diseases will be investigated. These studies will lead to the identification of viral determinants for infection in the aorta and the investigation of the functions of these genes in the development of CMV-associated vascular diseases. Understanding the mechanism of CMV infection in blood vessels will facilitate the development of novel strategies for treatment and prevention of CMV-associated vascular diseases as well as viral systemic infections.
