Mechanisms of CMV latency in accelerated vascular disease

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DESCRIPTION (provided by applicant): The goal of this project is to determine the viral mechanisms involved in cytomegalovirus (CMV)-accelerated transplant vascular sclerosis (TVS), which is the hallmark vascular disease associated with chronic rejection of solid organ grafts. 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. 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 observed that similar to what is observed in the clinical setting that heart allografts from latently infected donor rats undergo acceleration of chronic rejection compared to uninfected controls. Interestingly, we have also observed that treatment with ganciclovir, which is a viral DMA polymerase inhibitor that blocks viral late gene expression, did not prevent the acceleration of TVS in RCMV latently infected allografts transplanted into sero-negative recipients. 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. In this study, we will determine the viral load and cell types infected in the allograft. In addition, we will determine the viral genes that are expressed in the allografts from latently infected donors prior to and following transplantation and then determine whether these gene products contribute to the acceleration of TVS? To achieve these objectives we plan the following specific aims: 1. What are the RCMV latently infected cell types as well as the viral expression profile in the allograft prior to transplantation? A. What are the RCMV latently infected cell types in the donor hearts prior to transplantation? B. Which RCMV genes are expressed in the latently infected donor hearts? 2. What are the characteristics of RCMV acceleration of TVS in allografts from latently infected donors? A. What are the kinetics of TVS formation in allografts from latently infected donors? B. Does the spectrum of RCMV gene expression change in the latently infected allografts during the development of TVS in the presence of ganciclovir? 3. Which RCMV gene(s) expressed in latently infected allografts are required for the acceleration of TVS? A. Does mutation of the RCMV genes expressed in the latently infected allografts alter virus-induced acceleration of disease? B. What is the function of RCMV genes expressed in latently infected allografts?