The human cytomegalovirus (HCMV) is a ubiquitous pathogen linked with a high risk of morbidity in immunologically suppressed and immunodeficient patients. Furthermore, HCMV is one of major viral causes of congenital infections. HCMV infections are also implicated in several chronic diseases. The strategies to cope with the consequences of HCMV infection are limited by the lack of complete understanding of the viral pathogenesis. Cytomegaloviruses (CMV) are characterized by strict species specificity. Infection of mice with mouse CMV (MCMV) has been particularly informative as a model of HCMV infection in dissecting the role of innate and adaptive immune responses. Primary CMV infections are efficiently controlled in immunocompetent hosts;however, the viral genome remains in a state of latency from which periodic reactivation may occur. The most important question is why the mammalian immune system fails to effectively resolve these infections. A large number of CMV genes modulate the innate and adaptive host immune response. The team of scientists proposing this project has characterized several MCMV genes that play a role in the subversion of NK cell response by downmodulation of cellular ligands for the NKG2D receptor expressed on NK cells and CD8+ T cells. Mutant viruses lacking these viral immunoevasion genes are attenuated in vivo. Because of the importance of the NKG2D receptor in controlling both NK- and T cell-mediated immunity, it is of paramount importance to understand the mechanisms and consequences of viral regulation of the NKG2D ligands. In this project, the regulation of the expression of MCMV immunoevasion proteins that target NKG2D ligands and the molecular mechanisms by which these viral proteins disrupt NKG2D ligand expression will be studied. Cellular proteins that interact with viral immunoevasins will be identified and the impact of viral regulation of NKG2D ligands on the efficacy of NK and memory T cell responses in controlling latency, and in resolving the recurrent virus infection, will be evaluated. This research will aid at gaining insight on how CMV persists for the lifetime in the infected hosts and may lead to the development of novel probes to characterize the cellular mechanisms that control the expression of NK receptor ligands. PUBLIC HEALTH RELEVANCE: The significance of this research lies both in the advancement of our basic knowledge of persistent virus infections, and in the possibility of designing new and more efficient anti-viral treatments. The study will serve to advance our understanding of the biology and natural history of the cytomegalovirus by characterizing the regulation of important viral immunoregulatory genes and their protein products. Considering that clinical diseases associated with cytomegalovirus infections are dominantly caused by recurrent infection and that current drug treatments suffer from the emergence of drug resistant virus strains, there is an urgent need to develop new anti-viral regimens for which the mouse model of infection is optimal to experimentally define critical parameters affecting recurrent herpes virus infections.