REGULATION OF THE EBV LYTIC SWITCH GENE BZLF1

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Epstein-Barr virus (EBV) is a human lymphotropic herpesvirus which is the etiologic agent of infectious mononucleosis, and is closely associated with the development of several human cancers. Like Other herpesviruses, EBV can establish either a lytic or latent infection. The proposed research involves characterizing the regulation of the EBV lytic cycle gene BZLF1, which has been shown to be important for induction of the entire lytic cascade. The long-term objectives of these studies are to understand the mechanisms whereby induction of the lytic cycle of EBV is controlled in vivo, and the importance of these mechanisms to viral survival in the host. Proper regulation of lytic induction is likely to be important both for cell-to-cell spread and for immortalization of EBV infected cells. The specific aims of this proposal are 1) Analysis of selected BZLF1 promoter and gene mutations within the context of the viral genome. Selected mutations will be made by homologous recombination, and the effects on induction of the lytic cycle, the formation of immortalized cell lines, and infectivity will be studied. 2) Characterization of the efficiency of induction of the BZLF1 gene in latently infected cells. In situ techniques will be used to compare expression of the BZLF1 gene product with other lytic antigens and with cellular inducible genes to determine whether induction of the lytic cycle is blocked specifically at BZLF1 gene expression. The applicant has developed this proposal with an objective to become an established, independent investigator of the Epstein-Barr virus. The applicant will devote 100% effort to the proposed research for the duration of this award, in order to maximize the potential to realize this objective. The sponsor's laboratory was chosen on the basis of scientific merit, enthusiasm, knowledge of EBV, availability of resources, and dedication to the applicant; in addition there is a strong Community of virologists and immunologists at this institution whose expertise will be invaluable to the applicant's scientific development.