CHARACTERIZATION OF THE GAMMA HERPES VIRUS HV68 V CYCLIN

点击翻译按钮获取中文摘要

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. This research investigates the mechanisms by which cyclin homologs encoded by g-herpesviruses (v-cyclin) contribute to gammaherpesvirus pathogenesis and latency. The human gammaherpesviruses, KSHV and EBV, are important causes of cancer, especially in immunocompromised individuals. Because of the specificity of these viruses, in vivo studies of the pathogenesis have been limited. We and others have been developing a small animal model system, infection of inbred mice with gHV68, for analysis of the pathogenesis of gammaherpesvirus infection and the role of individual gammaherpesvirus genes in latency and tumor induction. gHV68 infection is associated with the development of lymphoma and lymphoproliferative disease, severe vasculitis of the great elastic vessels and splenic fibrosis. Studies to date indicate that gHV68 share pathogenetic mechanisms with EBV, KSHV and HVS, validating it as a model for analysis of important questions in gammaherpesvirus pathogenesis. This work is focused on the role of the gHV68 v-cyclin in disease pathogenesis. Notably, the g2-herpesvirus (HVS, KSHV and gHV68) all encode homologs of D-type cyclins, while EBV infection up regulates expression of host d-type cyclins. We have shown that the gHV68 v-cyclin is an oncogene that promotes cell cycle progression in primary lymphocytes and that a gHV68 v-cyclin mutant reacts inefficiently from latently infected MM and or B cells. These observations lead to the following 3 specific aims. Aim 1. Determine the role(s) of the gHV68 v-cyclin in latency and reactivation. Aim 2. Characterized regulation of gHV68 v-cyclin expression. Aim 3. Define the structural and biochemical basis of differences in the functions of the gHV68 v-cyclin and host D and E type cyclins.