MECHANISMS OF CMV LATENCY IN ACCELERATED VASCULAR DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的长期目标是确定病毒病原体在血管疾病的发展和加速中的作用。临床研究表明，人巨细胞病毒(HCMV)与移植血管硬化(TVS)、血管成形术后血管再狭窄以及动脉粥样硬化的发生有直接关系。CMV侵染宿主，并以潜伏的形式存活。病毒的终生持久性给巨细胞病毒带来了巨大的压力，要求其发展逃避免疫系统识别和消除的机制。病理性巨细胞病毒感染不会发生在免疫功能正常的个体中，然而，这种病毒在免疫缺陷事件和炎症条件下会重新激活。移植受者接受免疫抑制治疗，以减轻与急性和慢性同种异体移植排斥反应相关的主动免疫反应。在这些患者中，潜伏期的重新激活被认为是病毒感染的主要原因。到目前为止，HCMV从潜伏状态演变到激活状态并随后加速血管疾病的病毒机制尚不清楚。为了解决这个问题，我们开发了一种大鼠心脏移植慢性排斥模型，该模型显示了电视在人类身上的所有特征。我们等人的研究表明，在大鼠心脏移植模型中，大鼠巨细胞病毒(RCMV)感染显著加速了TVS的发展和慢性排斥反应。我们已经证明，这种疾病过程的一部分是由病毒编码的趋化因子受体R33介导的。然而，其他RCMV基因似乎也有助于电视病毒的发展，因为R33突变仍然会加速疾病，尽管速度较慢(Strelow等人)。我们还观察到，与临床上发生的情况类似，来自潜伏感染的供体大鼠的同种异体心脏移植与未感染的对照组相比，经历了慢性排斥反应的加速。有趣的是，受体接受更昔洛韦治疗，这是一种病毒DNA聚合酶抑制剂，可以阻断病毒晚期基因的表达，但并没有阻止潜伏感染的RCMV同种异体移植物中TVS的加速。这些结果表明，病毒的完全复制不是疾病加速所必需的，病毒的表达仅限于CMV即刻早期(IE)或早期基因产物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of this project is to determine the role of viral pathogens in the development and acceleration of vascular diseases. Clinical studies have directly associated human cytomegalovirus (HCMV) with the acceleration of transplant vascular sclerosis (TVS) and vascular restenosis following angioplasty, as well as atherosclerosis. CMV infects the host and persists in a latent form for life. Life-long viral persistence puts an immense pressure on HCMV to develop mechanisms to escape recognition and elimination by the immune system. A pathologic HCMV infection does not occur in the immunocompetent individual, however, this virus reactivates during events of immunodeficiency and also during inflammatory conditions. Transplant recipients undergo immunosuppressive therapy to abate the active immune response associated with acute and chronic allograft rejection. In these patients, reactivation from latency is thought to be the major cause of virus infection. To date the viral mechanisms involved in the evolution of HCMV from latency to the state of activation and subsequent acceleration of vascular disease are unknown. To address this issue we have developed a rat heart transplant chronic rejection model that exhibits all of the hallmarks of TVS in humans. Studies by our group and others have shown that rat CMV (RCMV) infection significantly accelerates both the development of TVS as well as chronic rejection in the rat heart allograft model. We have shown that part of this disease process is mediated by a virally encoded chemokine receptor r33. However, other RCMV genes also appear to contribute to the development of TVS since an r33 mutant still accelerates disease even though at a reduced rate (Streblow et al.). We have also observed that, similar to what occurs in the clinical setting, heart allografts from latently infected donor rats undergo acceleration of chronic rejection compared to uninfected controls. Interestingly, treatment of a recipient with ganciclovir, a viral DNA polymerase inhibitor that blocks viral late gene expression, did not prevent the acceleration of TVS in RCMV latently infected allograft. These results indicate that complete viral replication is not required for the acceleration of disease and that virus expression is restricted to CMV immediate early (IE) or early gene products.