Transcription and Replication of Oncogenic Viruses in Hypoxia

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Summary Oncogenic viruses are major contributors to approximately 20% of human cancers, with about 8 well-known viruses directly shown to be causative agents. Our program will focus on examining cellular processes that are usurped by these viral agents to drive the oncogenic phenotype. The transcription and replication of oncogenic viruses in the hypoxic microenvironment has not been extensively explored and here we will explore the mechanisms controlled by Merkel Cell Polyoma Virus (MCPyV), Epstein Barr virus (EBV) and Kaposi’s Sarcoma Associated Herpesvirus (KSHV). MCPyV is the causative agent of Merkel cell carcinomas, EBV is the causative agent linked to Nasopharyngeal carcinomas, Burkitt’s lymphomas, Hodgkin’s lymphomas, non- Hodgkin’s lymphomas, post-transplant lymphoproliferative disease in HIV patients that are immunocompromised, and KSHV is the causative agent for Kaposi’s sarcoma and pleural effusion lymphomas and is also associated with Multi-centric Castleman’s disease. These viral agents have been the focus of decades of studies but their function has not been examined extensively in hypoxia. The focus of this application is to bring together four prominent groups, led by investigators within the University of Pennsylvania community to join their scientific expertise to address the mechanism of viral-mediated oncogenesis. The overall goal will investigate the mechanism of transcription and replication control by viral-encoded antigens and the metabolic changes that are required for their function in hypoxia. These fundamental cellular processes targeted in hypoxia will provide novel information for successful establishment of viral infection in hypoxia. The program consists of four scientific projects, an administrative core, a virus, vector and cell culture core and a next generation sequencing core. The scientific projects are: 1. KSHV reprograms transcription and replication in hypoxia; 2. KSHV induces tumorigenesis by harnessing differentiation in hypoxia; 3. Skin hypoxia, MCPyV infection and MCC tumorigenesis; and 4. Regulation of EBV latency and oncogenesis by oxygen metabolism. The success of these projects will establish a comprehensive mechanistic view of oncogenic viral infection and pathogenesis in hypoxia, and provide new clues for the development of strategies to prevent and treat the associated cancers in HIV patients. In addition, the accumulation of new information on the biology of these viruses will be critical for insights into their mechanism of oncogenesis and so reduce the burden of disease in HIV infected, transplants and other immunocompromised patients.