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J. Biol. Chem., Vol. 279, Issue 44, 46335-46342, October 29, 2004

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The Latent Membrane Protein 1 of Epstein-Barr Virus Establishes an Antiviral State via Induction of Interferon-stimulated Genes^*

Jun Zhang, Subash C. Das, Catherine Kotalik¶, Asit K. Pattnaik, and Luwen Zhang¶||

From the Nebraska Center for Virology, the ^¶School of Biological Sciences, and the Department of Veterinary and Biomedical Science, University of Nebraska, Lincoln, Nebraska 68588

Epstein-Barr virus (EBV) infection is associated with several 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. In this report, we show that LMP-1 is able to induce the expression of several interferon (IFN)-stimulated genes (ISGs) with antiviral properties such as 2'-5' oligoadenylate synthetase (OAS), stimulated trans-acting factor of 50 kDa (STAF-50), and ISG-15. LMP-1 inhibits vesicular stomatitis virus (VSV) replication at low multiplicity of infection (0.1 pfu/cell). The antiviral effect of LMP-1 is associated with the ability of LMP-1 to induce ISGs; an LMP-1 mutant that cannot induce ISGs fails to induce an antiviral state. High levels of ISGs are expressed in EBV latency cells in which LMP-1 is expressed. EBV latency cells have antiviral activity that inhibits replication of superinfecting VSV. The antiviral activity of LMP-1 is apparently not related to IFN production in our experimental systems. In addition, EBV latency is responsive to viral superinfection: LMP-1 is induced and EBV latency is disrupted by EBV lytic replication during VSV superinfection of EBV latency cells. These data suggest that LMP-1 has antiviral effect, which may be an intrinsic part of EBV latency program to assist the establishment and/or maintenance of EBV latency.

Received for publication, April 9, 2004 , and in revised form, July 27, 2004.

^* This work was supported in part by National Institutes of Health Grant AI34956 (to A. K. P.) and by grants from the Tobacco Settlement Biomedical Research Enhancement Fund, the Layman Foundation, the Nebraska Center for Virology funded by National Institutes of Health (RR15635) from the COBRE Program of the National Center for Research Resources (to L. Z and A. K. P.), and a UCARE grant (to C. K.). 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.

^|| To whom correspondence should be addressed: E141 Beadle Center, Nebraska Center for Virology, University of Nebraska, 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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