JVI Accepts, published online ahead of print on 20 September 2006

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J. Virol. doi:10.1128/JVI.01570-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The Epstein-Barr virus-encoded LMP-1 oncoprotein negatively affects Tyk2 phosphorylation and interferon signaling in human B cells

Timothy R. Geiger and Jennifer M. Martin^*

Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, 80309

^* To whom correspondence should be addressed. Email: jm{at}colorado.edu.

Epstein-Barr virus (EBV) establishes a persistent infection in the human host and is associated with a variety of human cancers. Persistent infection results from a balance between the host immune response and viral immune evasion mechanisms. EBV infection is controlled initially by the innate immune response and later by T cell-mediated adaptive immunity. EBV has evolved mechanisms to evade the host immune response so that it can persist for the lifetime of the host. Latent membrane protein-1 (LMP-1) is the EBV oncoprotein essential for B cell immortalization by EBV. We show here that LMP-1 interacts with Tyk2, a signaling intermediate in the IFN signaling pathway, via a previously uncharacterized LMP-1 signaling domain. LMP-1 prevents Tyk2 phosphorylation and inhibits IFN-stimulated STAT2 nuclear translocation and ISRE transcriptional activity. Long-term culture of EBV⁺ lymphoblastoid cells in IFN is associated with outgrowth of a population expressing elevated LMP-1 protein levels, suggesting that cells expressing higher levels of LMP-1 survive the anti-proliferative selective pressure imposed by IFN. These results show that LMP-1 can protect EBV⁺ cells from the IFN-stimulated antiviral/antiproliferative response and suggest that chronic IFN treatment may encourage the outgrowth of cells expressing elevated, and therefore potentially oncogenic, LMP-1 levels in EBV⁺ individuals.

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