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J. Biol. Chem., Vol. 281, Issue 14, 9163-9169, April 7, 2006

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The Latent Membrane Protein 1 of Epstein-Barr Virus (EBV) Primes EBV Latency Cells for Type I Interferon Production^*

Dongsheng Xu, Kristen Brumm¹, and Luwen Zhang²

From the Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska, Lincoln, Nebraska 68588

Epstein-Barr virus (EBV) latency has been associated with a variety of human cancers. Latent membrane protein 1 (LMP-1) is one of the key viral proteins required for transformation of primary B cells in vitro and establishment of EBV latency. We have previously shown that LMP-1 induces the expression of several interferon (IFN)-stimulated genes and has antiviral effect (Zhang, J., Das, S. C., Kotalik, C., Pattnaik, A. K., and Zhang, L. (2004) J. Biol. Chem. 279, 46335–46342). In this report, a novel mechanism related to the antiviral effect of LMP-1 is identified. We show that EBV type III latency cells, in which LMP-1 is expressed, are primed to produce robust levels of endogenous IFNs upon infection of Sendai virus. The priming action is due to the expression of LMP-1 but not EBV nuclear antigen 2 (EBNA-2). The signaling events from the C-terminal activator regions of LMP-1 are essential to prime cells for high IFN production. LMP-1-mediated activation of NF-B is apparently necessary and sufficient for LMP-1-mediated priming effect in DG75 cells, a human B cell line. IFN regulatory factor 7 (IRF-7) that can be activated by LMP-1 is also implicated in the priming action. Taken together, these data strongly suggest that LMP-1 may prime EBV latency cells for IFN production and that the antiviral property of LMP-1 may be an intrinsic part of EBV latency program, which may assist the establishment and/or maintenance of viral latency.

Received for publication, November 3, 2005 , and in revised form, February 8, 2006.

^* This work was supported in part by National Institutes of Health Grants AI59132, CA108951, and P20RR15635 to the Nebraska Center for Virology and by National Institutes of Health Grant U54 AI057160 to the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by an Undergraduate Creative Activities and Research Experiences (UCARE) grant.

² To whom correspondence should be addressed: Nebraska Center for Virology, University of Nebraska, E141 Beadle Ctr., 1901 Vine St., Lincoln, NE 68588. Tel.: 402-472-5905; Fax: 402-472-8722; E-mail: lzhang2{at}unlnotes.unl.edu.

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