A Dual Role for APOBEC Counteraction in EBV Infection ABSTRACT Epstein-Barr Virus (EBV) is an oncogenic virus responsible for ~200,000 new cases of cancer each year. EBV-associated cancers include a highly aggressive type of nasopharyngeal carcinoma (NPC) that is endemic to regions of SE Asia. Studies on EBV biology and NPC pathogenesis have failed to establish a mechanistic explanation for why people in these geographic areas have a 50-fold increase in EBV-positive NPC in comparison to Western countries. A major requirement for the development of this malignancy is overcoming the growth arrest induced by EBV infection in epithelial cells, thereby allowing longer-term virus persistence. Thus, it is possible that genetic alterations in SE Asians may promote cell cycle progression and favor the development of NPC. Our lab has recently discovered a novel role for the EBV protein BORF2, which had previously been implicated in causing growth arrest during lytic infection. We found that BORF2 mediates evasion of intracellular immunity by directly binding to the antiviral DNA deaminase APOBEC3B (A3B). This interaction causes both proteins to relocalize to cytoplasmic aggregates and effectively protects the viral genome from A3B-catalyzed mutation. In independent work, we have also shown that A3B binds the cyclin-dependent kinase CDK4. Taken together, these studies lead me to hypothesize a dual role for BORF2 in nasopharyngeal epithelial cells – protecting the EBV genome from deamination by A3B and promoting cell cycle arrest through simultaneous sequestration of CDK4. This hypothesis will be tested through two Specific Aims. The first will focus on fully characterizing the BORF2-A3B interaction through genetic, biochemical, and cell biological studies. The second will determine the role of the BORF2-A3B interaction in causing cell cycle arrest and promoting EBV lytic infection. In this aim I will also analyze genomic datasets to determine whether a SE Asia-biased A3B- deletion allele predisposes to NPC. These studies will elucidate the mechanism through which BORF2 relocalizes A3B to avoid restriction, as well as reveal a novel role for this interaction in cell cycle modulation. A clear delineation of these molecular mechanisms will advance knowledge and aid in the development of therapies to EBV infection. Equally important, defining a role for this interaction in shaping EBV infection trajectories may establish a geographically-biased A3B deletion allele as an NPC susceptibility marker.