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.
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