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The B-Cell Specific Transcription Factor, Oct-2, Promotes Epstein-Barr Virus Latency by Inhibiting the Viral Immediate-Early Protein, BZLF1 1,2 1 1,3 Amanda R. Robinson , Swee Sen Kwek , Shannon C. Kenney * 1 Department of Oncology, McArdle Laboratory for Cancer Research , University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America, 2 Department of Cellular and Molecular Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America, 3 Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America Abstract The Epstein-Barr virus (EBV) latent-lytic switch is mediated by the BZLF1 immediate-early protein. EBV is normally latent in memory B cells, but cellular factors which promote viral latency specifically in B cells have not been identified. In this report, we demonstrate that the B-cell specific transcription factor, Oct-2, inhibits the function of the viral immediate-early protein, BZLF1, and prevents lytic viral reactivation. Co-transfected Oct-2 reduces the ability of BZLF1 to activate lytic gene expression in two different latently infected nasopharyngeal carcinoma cell lines. Furthermore, Oct-2 inhibits BZLF1 activation of lytic EBV promoters in reporter gene assays, and attenuates BZLF1 binding to lytic viral promoters in vivo. Oct-2 interacts directly with BZLF1, and this interaction requires the DNA-binding/dimerization domain of BZLF1 and the POU domain of Oct-2. An Oct-2 mutant (D262–302) deficient for interaction with BZLF1 is unable to inhibit BZLF1-mediated lytic reactivation. However, an Oct-2 mutant defective for DNA-