gamma-Herpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV) are oncogenic viruses that establish life-long latency in the host. These important human pathogens are associated with lymphoproliferative disorders and numerous malignancies, particularly in individuals with acquired or inherited immunodeficiencies. gamma-Herpesviruses are extremely species specific, thus murine gamma-herpesvirus 68 (MHV-68) provides an excellent small animal model to address basic immunological questions in the host. MHV-68 and KSHV are gamma2-herpesviruses and share important biological similarities, including the lack of obvious B cell transforming activity in vitro and the capacity to infect cells of myeloid origin, macrophages and dendritic cells, in the host. In the current proposal, we will exploit this relevant mouse model, to study the interaction between gamma-herpesviruses and dendritic cells. Dendritic cells are specialized antigen presenting cells that initiate and modulate T cell immunity, playing a critical role in the response to viral infections. gamma2-Herpesviruses encode numerous genes that function to impair antigen presentation, cellular migration, cell cycle and apoptosis. Our hypothesis is that MHV-68 targets dendritic cells to interfere with their functional ability or exploit their function. This may be crucial during early pathogenesis and contribute to the establishment of infection. Our studies will address these issues by pursuing the following specific aims: 1) To determine to what extent MHV-68 alters dendritic cell function. 2) To determine the impact of MHV-68 on the functional capacity of dendritic cells early during infection in the host. 3) To determine the impact of dendritic cell infection on MHV-68 immune evasion during acute infection. It is anticipated that the information gathered in this proposal will contribute to our understanding of the immune control and evasion of gamma-herpesviruses. Our questions are also critical to understanding how immunity is generated against viruses that subvert dendritic cell function, and for the better design of immunotherapies against gamma-herpesviruses.
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