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Journal of Virology, July 2008, p. 6251-6258, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.00163-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Interferon Regulatory Factor 4 Is Involved in Epstein-Barr Virus-Mediated Transformation of Human B Lymphocytes

Nebraska Center for Virology, School of Biological Sciences, University of Nebraska, Lincoln, Nebraska 68588,¹ Institute for Molecular Virology, Saint Louis University, St. Louis, Missouri 63104,² Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania 19122³

Received 23 January 2008/ Accepted 7 April 2008

Epstein-Barr virus (EBV) infection is associated with many human malignancies. In vitro, EBV transforms primary B lymphocytes into continuously growing lymphoblastoid cell lines. EBV latent membrane protein 1 (LMP-1) is required for EBV transformation processes. Interferon regulatory factor 4 (IRF-4) is a transcription factor and has oncogenic potential. We find that high levels of IRF-4 are associated with EBV transformation of human primary B cells in vitro and with EBV type III latency in which LMP-1 is expressed. We show that EBV LMP-1 stimulates IRF-4 expression in B lymphocytes. The stimulation of IRF-4 by LMP-1 requires signaling from LMP-1 and involves cellular NF-B. The growth of EBV-transformed cells is inhibited when IRF-4 is specifically down-regulated. We further demonstrate that IRF-4 knockdown cells have lower proliferation but higher apoptotic rates than control cells. Finally, IRF-4 is expressed in significant numbers of specimens of primary central nervous system (CNS) lymphomas (12/27 [44.4%]), an EBV-associated malignancy. The association between the expression levels of LMP-1 and IRF-4 is statistically significant (P = 0.011) in these CNS lymphomas. Our data suggest that IRF-4 may be a critical factor in EBV transformation and a useful target in the therapy of EBV-mediated neoplasia.

Published ahead of print on 16 April 2008.