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Journal of Virology, April 2005, p. 3969-3978, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.3969-3978.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibition of RIG-I-Dependent Signaling to the Interferon Pathway during Hepatitis C Virus Expression and Restoration of Signaling by IKK{varepsilon}

Adrien Breiman,1 Nathalie Grandvaux,2 Rongtuan Lin,2 Catherine Ottone,1 Shizuo Akira,3 Mitsutoshi Yoneyama,4 Takashi Fujita,4 John Hiscott,2* and Eliane F. Meurs1*

Unité Hépacivirus, Institut Pasteur, Paris, France,1 Lady Davis Institute for Medical Research and Departments of Microbiology & Immunology and Medicine, McGill University, Montreal, Canada,2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka,3 Department of Tumor Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Bunkyo-ku, Japan4

Received 18 August 2004/ Accepted 6 November 2004

Interferon (IFN) is one important effector of the innate immune response, induced by different viral or bacterial components through Toll-like receptor (TLR)-dependent and -independent mechanisms. As part of its pathogenic strategy, hepatitis C virus (HCV) interferes with the innate immune response and induction of IFN-ß via the HCV NS3/4A protease activity which inhibits phosphorylation of IRF-3, a key transcriptional regulator of the IFN response. In the present study, we demonstrate that inhibition by the protease occurs upstream of the noncanonical IKK-related kinases IKK{varepsilon} and TBK-1, which phosphorylate IRF-3, through partial inhibition of the TLR adapter protein TRIF/TICAM1-dependent pathway. Use of TRIF–/– mouse embryo fibroblasts however revealed the presence of a TRIF-independent pathway involved in IFN induction that was also inhibited by NS3/4A. Importantly, we show that NS3/4A can strongly inhibit the ability of the recently described RIG-I protein to activate IFN, suggesting that RIG-I is a key factor in the TRIF-independent, NS3/4A-sensitive pathway. Expression of IFN signaling components including IKK{varepsilon}, TBK-1, TRIF, and wild type or constitutively active forms of RIG-I in the HCV replicon cells resulted in IFN-ß promoter transactivation, with IKK{varepsilon} displaying the highest efficiency. Subsequently, overexpression of IKK{varepsilon} resulted in 80% inhibition of both the positive and negative replicative strands of the HCV replicon. The partial restoration of the capacity of the host cell to transcribe IFN-ß indicates that IKK{varepsilon} expression is able to bypass the HCV-mediated inhibition and restore the innate antiviral response.

* Corresponding author. Mailing address for E. Meurs: Unité Hépacivirus, Institut Pasteur, 75724 Paris Cedex 15, France. Phone: 33145688777, Fax: 33140613012. E-mail: emeurs{at}pasteur.fr. Mailing address for J. Hiscott: Lady Davis Institute, McGill University, Montreal H3T 1E2, Quebec, Canada. Phone: (514) 340-8222, ext. 5265. Fax: (514) 340-7576. E-mail: john.hiscott{at}mcgill.ca.

Journal of Virology, April 2005, p. 3969-3978, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.3969-3978.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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