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Journal of Virology, January 2006, p. 900-911, Vol. 80, No. 2
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.2.900-911.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Amino-Terminal Domain of Bovine Viral Diarrhea Virus Npro Protein Is Necessary for Alpha/Beta Interferon Antagonism

Laura H. V. G. Gil,1,{dagger} Israrul H. Ansari,1,§ Ventzislav Vassilev,1,¶ Delin Liang,1,{ddagger} Vicky C. H. Lai,2 Weidong Zhong,2 Zhi Hong,2 Edward J. Dubovi,3 and Ruben O. Donis1*

Departments of Veterinary and Biomedical Sciences, University of Nebraska—Lincoln, Lincoln, Nebraska 68583-0905,1 Population and Diagnostic Medicine, New York State College of Veterinary Medicine, Cornell University, Ithaca, New York 18453,3 Valeant Pharmaceuticals, Valeant Plaza, 3300 Hyland Avenue, Costa Mesa, California 926262

Received 3 November 2004/ Accepted 24 October 2005

The alpha/beta interferon (IFN-{alpha}/ß) system is the first line of defense against viral infection and a critical link between the innate and adaptive immune responses. IFN-{alpha}/ß secretion is the hallmark of cellular responses to acute RNA virus infections. As part of their survival strategy, many viruses have evolved mechanisms to counteract the host IFN-{alpha}/ß response. Bovine viral diarrhea virus (BVDV) (genus Pestivirus) was reported to trigger interferon production in infected cultured cells under certain circumstances or to suppress it under others. Our studies with various cultured fibroblasts and epithelial bovine cells indicated that cytopathic (cp) BVDV induces IFN-{alpha}/ß very inefficiently. Using a set of engineered cp BVDVs expressing mutant Npro and appropriate controls, we found that the IFN-{alpha}/ß response to infection was dependent on Npro expression and independent of viral replication efficiency. In order to investigate whether the protease activity of Npro is required for IFN-{alpha}/ß antagonism, we engineered Npro mutants lacking protease activity by replacement of amino acid E22, H49, or C69. We found that E22 and H49 substitutions abolished the ability of Npro to suppress IFN, whereas C69 had no effect, suggesting that the structural integrity of the N terminus of Npro was more important than its catalytic activity for IFN-{alpha}/ß suppression. A catalytically active mutant with a change at a conserved Npro region near the N terminus (L8P) in both BVDV biotypes did not antagonize IFN-{alpha}/ß production, confirming its involvement in this process. Taken together, these results not only provide direct evidence for the role of Npro in blocking IFN-{alpha}/ß induction, but also implicate the amino-terminal domain of the protein in this function.

* Corresponding author. Mailing address: Molecular Genetics Section, Influenza Branch, DVRD, NCID, Centers for Disease Control and Prevention, Mail Stop G-16, 1600 Clifton Road, Atlanta, GA 30333. Phone: (404) 639-4968. Fax: (404) 639-2334. E-mail: rdonis{at}cdc.gov.

{dagger} Present address: Laboratory of Virology and Experimental Therapeutics, CPqAM-Fiocruz, Recife, PE 50670-420, Brazil.

{ddagger} Present address: Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033.

§ Present address: Nebraska Center for Virology and Dept. of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln, NE 68588-0666.

Present address: Viral Vaccines Research and Development, GlaxoSmithKline Biologicals, Rue de l'Institut, 89 (P31-005), B-1330 Rixensart, Belgium.

Journal of Virology, January 2006, p. 900-911, Vol. 80, No. 2
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.2.900-911.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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