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。 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以终生潜伏的形式在宿主中持续存在，但在具有免疫能力的个体中不会发生病理性的HCMV感染。然而，在免疫缺陷和炎症情况下，尤其是在接受免疫抑制治疗的移植受者中，这种病毒会重新激活，以减弱与急性/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HCMV重新激活是病毒感染的主要原因。人巨细胞病毒从潜伏状态到激活状态再到血管疾病的加速发展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反应模型，该模型显示了 电视在人类身上的特征。我们发现，在大鼠心脏移植模型中，大鼠巨细胞病毒(RCMV)感染显著地加速了TVS的发展和慢性排斥反应的发生。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，接受更昔洛韦治疗并不能阻止RCMV潜伏感染同种异体移植物中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. 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.