REGULATION OF REPLICATION AND LATENCY BY EBV EBNA-1

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Infection with Epstein-Barr virus (EBV) during childhood is usually asymptomatic. When primary exposure occurs in the post-adolescent years EBV causes infectious mononucleosis, a self-limiting B- lymphoproliferative disease. Once infected, an individual will carry the virus for life and over 80% of the adult population world-wide is latently infected. The most serious sequelae of primary or reactivated EBV infection occur in individuals who are immunologically compromised such as patients undergoing immunosuppressive regimes in conjunction with organ transplantation, those with genetic X-linked immunodeficiency and AIDS patients. EBV-associated B-cell lymphomas can develop in these populations and in AIDS patients, in particular, there is an increased incidence of lymphoma of the central nervous system and the occurrence of hairy leukoplakia of the tongue. EBV is associated with malignant disease in two other populations. The tumor cells of African Burkitts lymphoma and of nasopharyngeal carcinoma (which occurs primarily in those of Chinese extraction) contain EBV DNA and express EBNA-1. Currently available anti- herpetic agents have no effect on latent replication. The total dependence of EBV latency maintenance on EBNA-1 makes EBNA-1 a good candidate for anti-viral targeting. A detailed characterization of EBNA-1, its domains and functions, would provide necessary information on which to base an anti-viral strategy. The overall goal of these studies is to understand the mechanisms involved in the maintenance of latent EBV infection. The Specific Aims include: (1) Further purification of the EBNA-1 protein and development of an in vitro ori-P replication system, (2) Isolation and characterization of a cellular EBNA-1 like DNA binding protein, (3) Characterization of functional domains of EBNA-1; namely those for specific DNA-binding, nuclear localization, phosphorylation, chromosome association and transactivation, (4) Investigation of a role for the BamHI-Q-binding sites in regulation of latency gene expression, (5) Analysis of structural requirements for ori-P function, and (6) Evaluation of latent gene expression in epithelial cells.