MECHANISMS OF CMV LATENCY IN ACCELERATED VASCULAR DISEASE

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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.