Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus virus that can infect both B lymphocytes andepithelial cells. Depending upon the cell type and its state of differentiation, infection by EBV leads to eitherlytic replication with cell death or a latent infection. Latent EBV infections are associated with several B-celland epithelial-cell malignancies including Burkitt's lymphoma, Hodgkin's disease, non-Hodgkin's lymphomasin immunocompromised individuals, nasopharyngeal carcinoma, and some gastric carcinomas. Thus,understanding regulation of EBV latency versus lytic replication is crucial for developing therapies to treatthese diseases. The BZLF1 and BRLF1 genes of EBV encode multifunctional proteins essential for lyticreplication. While the BZLF1 and BRLF1 promoters are inactive in latently infected cells, cell differentiationand activators of certain cell signaling pathways can induce BZLF1 and BRLF1 expression, promoting EBVreactivation into lytic replication. In this Project, we will (i) identify cellular factors that play key roles inregulating expression of these two immediate-early genes in both B cells and epithelial cells, and (ii)examine how these factors contribute to controlling the balance between latent and lytic EBV infection in avariety of cell types and during cellular differentiation. In conjunction with Project 5, these results may leadto new therapies for treating EBV-associated cancers.
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