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Journal of Virology, November 2008, p. 10436-10443, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00752-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus-Induced miR-155 Attenuates NF-B Signaling and Stabilizes Latent Virus Persistence ^,

Fang Lu,¹ Andreas Weidmer,¹ Chang-Gong Liu,² Stefano Volinia,² Carlo M. Croce,² and Paul M. Lieberman^1*

The Wistar Institute, Philadelphia, Pennsylvania 19104,¹ Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210²

Received 4 April 2008/ Accepted 14 August 2008

MicroRNAs have been implicated in the modulation of gene expression programs important for normal and cancer cell development. miR-155 is known to play a role in B-cell development and is upregulated in various B-cell lymphomas, including several that are latently infected with Epstein-Barr virus (EBV). We show here that EBV infection of primary human B lymphocytes leads to the sustained elevation of miR-155 and its precursor RNA, BIC. The EBV-encoded latency membrane protein 1 (LMP1) can partially reconstitute BIC activation in B lymphocytes but not in epithelial cell cultures. LMP1 is a potent activator of NF-B signaling pathways and is essential for EBV immortalization of B lymphocytes. An inhibitor to miR-155 further stimulated NF-B responsive gene transcription, and IKK was identified as a potential target of miR-155 translational repression. Remarkably, miR-155 inhibitor reduced EBNA1 mRNA and the EBV copy number in latently infected cells. This suggests that miR-155 contributes to EBV immortalization by modulation of NF-B signaling and the suppression of host innate immunity to latent viral infection.

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* Corresponding author. Mailing address: The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104-4261. Phone: (215) 898-9491. Fax: (215) 898-0663. E-mail: Lieberman{at}wistar.org

Published ahead of print on 27 August 2008.

Supplemental material for this article may be found at http://jvi.asm.org/.

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Journal of Virology, November 2008, p. 10436-10443, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00752-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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