Epstein Barr virus (EBV) is associated with diverse cancers, including nasopharyngeal cancer, non-Hodgkin's lymphoma occurring in immunodeficient individuals, Hodgkin's disease and Burkitt's lymphoma. In all EBV-associated tumors the virus remains in a latent state of limited gene expression. Latency is maintained by regulation of the EBV BZLF1 gene, whose product ZEBRA, a b-ZIP transcriptional activator, obligates the virus to enter lytic replication. Our global objective is to understand the mechanism of this switch between latency and the lytic cycle. Studies of the functions of ZEBRA required for activation of lytic cycle gene expression focus on two groups of mutants that are discordant in their capacity to activate transcription and to disrupt latency. These mutants, containing alterations in the DNA recognition domain or in the accessory activation domain, should point to additional functions that are needed to activate the latent virus. Analysis of the downstream targets of ZEBRA include investigations of DNA context effects that permit a promoter to respond to ZEBRA, identification of cellular genes that are activated by ZEBRA, and identification of cellular and viral proteins that directly interact with the ZEBRA protein. Experiments that explore control of expression of the BZLF1 gene include determination whether Zp and Rp, the two promoters that control BZLF1 transcription, are coordinately or sequentially regulated. Clues to the relative importance of cellular or viral factors in BZLF1 regulation should come from study of well characterized EBV transformed cell lines that differ markedly in their responses to chemical inducing stimuli. The proposed experiments take a biologic perspective and utilize molecular genetic and biochemical techniques to explore a central unsolved question in the pathogenesis of this human tumor virus.
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