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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-{kappa}B Signaling and Stabilizes Latent Virus Persistence{triangledown} ,{dagger}

Fang Lu,1 Andreas Weidmer,1 Chang-Gong Liu,2 Stefano Volinia,2 Carlo M. Croce,2 and Paul M. Lieberman1*

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-{kappa}B signaling pathways and is essential for EBV immortalization of B lymphocytes. An inhibitor to miR-155 further stimulated NF-{kappa}B responsive gene transcription, and IKK{varepsilon} 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-{kappa}B signaling and the suppression of host innate immunity to latent viral infection.

* 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

{triangledown} Published ahead of print on 27 August 2008.

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

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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