MECHANISMS OF CMV LATENCY IN ACCELERATED VASCULAR DISEASE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 临床研究表明，人巨细胞病毒（HCMV）与移植血管硬化（TVS）的加速有关，我们的目标是确定HCMV在这一过程中的作用。虽然CMV在宿主中以终身潜伏形式存在，但在免疫活性个体中不会发生病理性HCMV感染。然而，这种病毒在免疫缺陷事件期间和炎症状态期间重新激活，特别是在接受免疫抑制治疗的移植受者中，以减轻与急性/慢性同种异体移植物排斥相关的主动免疫应答。在这些患者中，HCMV从潜伏期重新激活是病毒感染的主要原因。HCMV从潜伏期到激活状态演变以及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，该模型表现出人类TVS的所有特征。我们已经表明，大鼠CMV（RCMV）感染显着加速发展的TVS和时间的大鼠心脏移植模型中的慢性排斥反应。我们还观察到，与临床情况相似，与未感染对照组相比，来自潜伏感染供体大鼠的心脏同种异体移植物发生慢性排斥反应加速。有趣的是，接受更昔洛韦治疗并不能阻止RCMV潜伏感染的同种异体移植物中TVS的加速。这些结果表明，完全的病毒复制是不需要的疾病的加速和病毒的表达限于CMV立即早期（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. Clinical studies have associated human cytomegalovirus (HCMV) with the acceleration of transplant vascular sclerosis (TVS) and our goal is to determine the role of HCMV in this process. While CMV persists in the host in a life-long latent form, a pathologic HCMV infection does not occur in the immunocompetent individual. However, this virus reactivates during events of immunodeficiency and during inflammatory conditions especially in transplant recipients undergoing immunosuppressive therapy to abate the active immune response associated with acute/chronic allograft rejection. In these patients, HCMV reactivation from latency is the major cause of virus infection. 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. We have shown that rat CMV (RCMV) infection significantly accelerates both the development of TVS and time to chronic rejection in the rat heart allograft model. 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 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.