OVERALL – PROJECT SUMMARY/ABSTRACT Molecular Biology and Genetics of Human Tumor Viruses Paul F. Lambert, PI Viruses cause approximately 15% of human cancers. A viral etiology to a human cancer can have substantive consequences on its treatment and prevention. For example, many virally-caused human cancers express virally encoded products, which are potential targets for anti-viral, tumor-specific therapies. In addition, unique sets of cellular genes and pathways contribute to virally-associated cancers, many of which are currently being pursued as targets for anti-cancer therapies. This program project grant (PPG), now in its 45th year of continual funding, has two major objectives: to use molecular biology and genetics to elucidate the life cycles of and transformation by human tumor viruses and to translate this understanding into the identification of targets for specific anti-viral, anti-tumor therapies. The PPG has seven lead investigators who share these research goals in studying multiple human tumor viruses in two different virus families: papillomaviruses, and herpesviruses. Together, these viruses cause the vast majority of virally-associated human cancers. The PPG has been highly productive over the current funding period with 88 studies published of which 33% involve two or more labs, reflecting on the strong synergies arising from the PPG. Our PPG has a unique organization in which each of four projects have two or more labs working together on a common theme in human tumor virology. Cross-fertilization of ideas and expertise between projects is fostered by having many of the seven investigators participating in multiple projects. This interactive and collaborative organization has been highly fruitful over the current funding period in several regards. Firstly, each project has been productive and has collaborated with other projects. Secondly, innovative new ideas and approaches have arisen, many of which are now being used across multiple projects. Thirdly, the collaborative environment created by this PPG has spawned new interactions that have brought additional expertise to the PPG. The specific themes of this PPG are: 1) Characterize the Mechanism by Which Papillomaviruses Evade Host Immunity; 2) Uncovering Mechanisms of the Lymphoid Oncogenesis of Epstein-Barr Virus and Kaposi’s Sarcoma Herpesvirus; 3) Latent and Lytic EBV Infection in Epithelial Cells; and 4) Defining the Role of EBV in DLBCL Pathogenesis and Identification of Therapeutic Targets. Three cores provide expertise in A) administration, statistics and bioinformatics, B) instrumentation, microscopy and histology, and C) virus engineering and production.