Increasing evidence suggests human cytomegalovirus (HCMV) infection contributes to the development of atherosclerosis. Because the type of immune response (cellular vs humoral) to infectious agents can determine disease expression or containment, we are in the process of testing the following hypotheses: 1) In healthy and atherosclerotic populations there is a spectrum of humoral vs cellular immunodominant responses to HCMV infection. 2) An immunodominant cellular phenotype conveys resistance to coronary artery disease, while an immunodominant humoral phenotype conveys susceptibility. If these hypotheses are correct, we will investigate whether the susceptible humoral phenotype can be switched to the resistant cellular phenotype with gene therapy, using adenoviral vectors that contain the IL-12 transgene. (This cytokine has been shown, in other settings, to be able to switch a humoral to a cellular immunodominant response). We are also investigating the vaccine straties against CMV and whether such strategies can reduce CMV-mediated vascular disease. Specifically: 1) We have demonstrated that CMV infection of rats increases the response to vascular injury. We are now initiating studies to determine whether vaccination with a cDNA encoding rat CMV IE proteins will prevent the neointimal response to vascular injury in the rat carotid-injury model. 2) We are initiating studies to determine whether ApoE knockout mice, which develop spontaneous atherosclerosis, will develop an increased rate of atherogenesis when infected with mouse CMV. If this turns out to be the case, we will embark on gene delivery studies to determine whether vaccine therapy, augmented by cytokine gene delivery, will protect against CMV-mediated atherogenesis. Mechanisms by which HCMV may increase SMC accumulation a) Can HCMV infection inhibit apoptosis in SMCs and, if so: 1) does it inhibit p53-dependent or independent pathways?; 2) which viral gene products are responsible for anti-apoptotic effects? b) SMC migration from the media and/or adventitia is believed to play an important role in the development of both restenosis and atherosclerosis. Does HCMV infection of SMCs increase the ability of SMCs to migrate? The immune response to HCMV a) Immunodominant cellular and humoral responses to HCMV and their relation to vascular disease.
