DESCRIPTION (provided by applicant): This program project grant application focuses on the human oncogenic herpesviruses, Epstein- Barr Virus (EBV) and Kaposi Sarcoma-associated Herpesvirus (KSHV), to identify the critical mechanisms by which these agents induce cancer and deregulate cell growth. EBV and KSHV are linked to multiple cancers in the human population. This proposal will study the role of several viral and cellular genes and proteins in modulating EBV- and KSHV-mediated oncogenesis. To identify the mechanisms responsible for the oncogenic properties of these viruses, the projects will characterize the basic molecular properties of viral proteins and their interactions with cellular proteins. The experiments will identify how viral proteins interact with cellular proteins to change their function. Furthermore, the potential therapeutic benefits of targeting viral and cellular proteins will be tested in cell culture assays and animal models. This application consists of five projects and two cores. Project 1 will utilize electron microscopy to analyze the structure of KSHV proteins and replication complexes. Project 2 will elucidate the role of a cellular deubiquitinase, UCHL1, in membrane trafficking and cell-cell communication of EBV-infected cells. Project 3 will investigate how KSHV modulates the tumor microenvironment and the cellular and viral proteins involved in these processes. Project 4 will examine KSHV carcinogenesis using novel mouse models and cell culture assays, and Project 5 will investigate how the EBV oncoproteins, LMP1 and LMP2, modulate the cellular proteome and cellular pathways to contribute to EBV-associated malignancies. Core A provides administrative support for the overall program, while Core B provides state-of-the-art genomics and viral and cellular gene profiling, as well as biostatistics support for all the projects in this application.