Epstein-Barr virus (EBV) is a human herpesvirus capable of establishing a latent state in B lymphocytes.The product of the immediate-early BZLF1 gene, Zta, is a transcriptional transactivator essential for viral DNA amplification and virion production. Previously, we identified a negative cis-acting element within the BZLF1 promoter termed ZV. ZV contains the sequence 5-CAGGTA-3 located at nucleotides ؊17 to ؊12 relative to the transcription initiation site. It sequence specifically binds a cellular factor, ZVR. Based on sequence binding specificity, we postulated that ZVR may be zinc finger E-box binding factor (ZEB) or a related zinc finger/homeodomain family member. We show here by immunoshift assays that ZVR and human ZEB specifically cross-react with an antibody to ␦EF1, the chicken homolog of ZEB. Competition electrophoretic mobility shift assays confirmed that ZEB binds to the ZV element with the same binding specificity as ZVR. Overexpression of ZEB in either B-lymphocytic DG75 cells or mammary epithelial MCF-7 cells repressed Zta-induced activation of the BZLF1 promoter four-to fivefold via the ZV site. Thus, we conclude that the previously identified cellular repressor ZVR is, in fact, ZEB. We also present evidence that other cellular factors likely affect the transcriptional activity of ZEB. Lastly, we identify a ZEB-binding site within the promoter of the lytic BRLF1 gene of EBV. We postulate that ZEB likely plays an important role in regulating the life cycle of EBV.
Epstein-Barr virus (EBV) is a human gammaherpesvirus estimated to infect 90% of the world's population (24, 25).Primary infection and replication of the virus are thought to occur in the oropharyngeal epithelium (24,25,30,45). EBV can also infect B lymphocytes, where it establishes a latent infection (1,26,40). Latent infection by EBV is associated with a number of malignancies. These include Burkitt's lymphoma (24, 25), some cases of Hodgkin's disease (1, 24), nasopharyngeal carcinoma (9) and gastric carcinoma (reference 46 and references cited therein). However, lytic replication of EBV may also be associated with human diseases in addition to infectious mononucleosis, with the presence of antibodies to EBV lytic antigens correlating with increased risk for nasopharyngeal carcinoma (7) and hairy leukoplakia (3,48,49,53).Once EBV has established a latent infection, only a small subset of EBV's approximately 100 genes are expressed: EBVencoded early antigens (EBNAs) 1 to 6, latent membrane proteins (LMP) 1 and 2, two EBV-encoded small nuclear RNAs, and the BamHIA transcripts (24, 25). The expression of a subset of these genes is sufficient to immortalize B cells and maintain the viral genome as an episome (27). However, reactivation of the viral lytic phase can occur, resulting in replication of the viral genome to a higher copy number and production of infectious virions. Treatment of certain viralgenome-harboring B cells and epithelial cells with chemical reagents (4,12,23,33,56), serum factors (2), transforming growth factor 1 (15),...