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Journal of Virology, December 2006, p. 11638-11650, Vol. 80, No. 23
0022-538X/06/$08.00+0     doi:10.1128/JVI.01570-06
Copyright © 2006, American Society for Microbiology. 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, Colorado 80309

Received 21 July 2006/ Accepted 8 September 2006

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 alpha interferon (IFN-) signaling pathway, via a previously uncharacterized LMP-1 signaling domain. LMP-1 prevents Tyk2 phosphorylation and inhibits IFN--stimulated STAT2 nuclear translocation and interferon-stimulated response element 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 antiproliferative 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.

Published ahead of print on 20 September 2006.

Present address: Department of Biochemistry, Colorado State University, Fort Collins, CO 80523.

This article has been cited by other articles:

• Martin, H. J., Lee, J. M., Walls, D., Hayward, S. D. (2007). Manipulation of the Toll-Like Receptor 7 Signaling Pathway by Epstein-Barr Virus. J. Virol. 81: 9748-9758 [Abstract] [Full Text]