EBV's Plasmid Replicon: Its Synthesis, Partitioning, and Maintenance of Tumors

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DESCRIPTION (provided by applicant): Epstein-Barr Virus (EBV) is a human tumor virus causally associated with multiple types of lymphomas and carcinomas. Its genome is maintained in both normal and malignant proliferating cells as a plasmid. We have studied EBV's plasmid replicon to elucidate both its synthesis and partitioning and its contributions to EBV's tumorigenesis. Earlier we identified its cis-acting element, oriP, and its sole viral trans-acting protein, EBNA1. We recently developed a method to visualize EBV plasmid replicons in live cells, which has uncovered several fascinating properties. For example, they are duplicated each S-phase only 84% of the time; and they encode a non-random mechanism of partitioning which spatially couples partitioning to their synthesis. We propose now in Aim 1 to characterize the synthesis and partitioning of EBV genomes early after infection of primary B-cells to understand how these events contribute to EBV's establishing its stable infection of these cells. We shall in Aim 2 dissect the mechanism of EBV's partitioning to understand its coupling to its synthesis. We have also recently discovered that inhibiting EBV's plasmid replicon by inhibiting EBNA1 induces apoptosis in normal and malignant, EBV-infected B-cells. We shall extend these findings in Aim 3 to EBV-associated tumors in immunocompromised hosts such as AIDS patients. In particular, we propose to investigate the mechanisms by which EBV prevents apoptosis in these infected, malignant B-cells and identify the viral genes that allow these tumor cells to survive. PUBLIC HEALTH RELEVANCE: All of these studies will reveal the mechanisms by which EBV replicates as a plasmid in infected cells. In addition to indicating how inhibiting EBNA1 would be therapeutically beneficial, they should also identify additional targets for developing anti-viral anti-tumor drugs.