MECHANISMS BY WHICH CMV MAY CONTRIBUTE TO ATHEROGENESIS AND RESTENOSIS

越来越多的证据表明人类巨细胞病毒（HCMV）感染 导致动脉粥样硬化的发展。 因为， 对感染因子的免疫应答（细胞与体液）可以决定 疾病表达或遏制，我们正在测试的过程中， 以下假设： 1)在健康和动脉粥样硬化人群中， 对HCMV感染的体液与细胞免疫显性应答。 2)免疫显性细胞表型传递对冠状动脉粥样硬化的抵抗， 动脉疾病，而免疫显性体液表型传递 易感性 如果这些假设是正确的，我们将调查是否 敏感的体液表型可以转换为耐药的细胞表型， 表型与基因治疗，使用腺病毒载体，含有 IL-12转基因。(This在其他环境中，细胞因子已经显示出， 能够将体液免疫应答转换为细胞免疫显性应答）。 我们也在研究CMV的疫苗策略， 这些策略可以减少CMV介导的血管疾病。具体而言： 1)我们已经证明，巨细胞病毒感染的大鼠， 对血管损伤的反应。我们现在开始研究， 用编码大鼠CMV IE蛋白的cDNA接种是否 预防大鼠血管损伤的新生内膜反应 颈动脉损伤模型 2)我们正在启动研究，以确定是否ApoE敲除小鼠， 自发性动脉粥样硬化， 感染小鼠CMV时动脉粥样硬化发生率。 如果这 在这种情况下，我们将着手进行基因传递研究，以确定 通过细胞因子基因传递增强的疫苗治疗是否会 防止CMV介导的动脉粥样硬化形成。 HCMV可能增加SMC积聚的机制 a）HCMV感染能否抑制SMC中的细胞凋亡，如果是， 1)它是否抑制p53依赖性或非依赖性途径？ 2)哪些病毒基因产物负责抗凋亡 影响？ B）SMC从中膜和/或外膜的迁移被认为是 在再狭窄和 动脉粥样硬化 人巨细胞病毒感染是否增加平滑肌细胞的增殖能力？ SMC迁移？ 对HCMV的免疫应答 a）对HCMV的免疫显性细胞和体液应答及其免疫应答 与血管疾病有关。

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.