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Journal of Virology, March 2005, p. 2788-2796, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2788-2796.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Establishment of a Subgenomic Replicon for Bovine Viral Diarrhea Virus in Huh-7 Cells and Modulation of Interferon-Regulated Factor 3-Mediated Antiviral Response

Nigel Horscroft,1 Dan Bellows,1 Israrul Ansari,2 Vicky C. H. Lai,1 Shannon Dempsey,1 Delin Liang,2 Ruben Donis,2 Weidong Zhong,1* and Zhi Hong1

Drug Discovery, Valeant Pharmaceuticals International Inc., Costa Mesa, California,1 Department of Veterinary and Biomedical Sciences, University of Nebraska—Lincoln, Lincoln, Nebraska2

Received 2 August 2004/ Accepted 14 October 2004

We describe the development of a selectable, bi-cistronic subgenomic replicon for bovine viral diarrhea virus (BVDV) in Huh-7 cells, similar to that established for hepatitis C virus (HCV). The selection marker and reporter (Luc-Ubi-Neo) in the BVDV replicon was fused with the amino-terminal protease Npro, and expression of the nonstructural proteins (NS3 to NS5B) was driven by an encephalomyocarditis virus internal ribosome entry site. This BVDV replicon allows us to compare RNA replication of these two related viruses in a similar cellular background and to identify antiviral molecules specific for HCV RNA replication. The BVDV replicon showed similar sensitivity as the HCV replicon to interferons (alpha, beta, and gamma) and 2'-ß-C-methyl ribonucleoside inhibitors. Known nonnucleoside inhibitor molecules specific for either HCV or BVDV can be easily distinguished by using the parallel replicon systems. The HCV replicon has been shown to block, via the NS3/4A serine protease, Sendai virus-induced activation of interferon regulatory factor 3 (IRF-3), a key antiviral signaling molecule. Similar suppression of IRF-3-mediated responses was also observed with the Huh-7-BVDV replicon but was independent of NS3/4A protease activity. Instead, the amino-terminal cysteine protease Npro of BVDV appears to be, at least partly, responsible for suppressing IRF-3 activation induced by Sendai virus infection. This result suggests that different viruses, including those closely related, may have developed unique mechanisms for evading host antiviral responses. The parallel BVDV and HCV replicon systems provide robust counterscreens to distinguish viral specificity of small-molecule inhibitors of viral replication and to study the interactions of the viral replication machinery with the host cell innate immune system.

* Corresponding author. Mailing address: Valeant Pharmaceuticals International, 3300 Hyland Ave., Costa Mesa, CA 92626. Phone: (714) 545-0100, ext. 2201. Fax: (714) 668-3141. E-mail: wzhong{at}valeant.com.

Journal of Virology, March 2005, p. 2788-2796, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2788-2796.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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