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Journal of Virology, June 2005, p. 7535-7543, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7535-7543.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mutations in the NS1 Protein of Swine Influenza Virus Impair Anti-Interferon Activity and Confer Attenuation in Pigs

Alicia Solórzano,1 Richard J. Webby,2 Kelly M. Lager,3 Bruce H. Janke,4 Adolfo García-Sastre,1 and Jürgen A. Richt3*

Dept. Microbiology, Mount Sinai School of Medicine, New York, New York 10029,1 Division of Virology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,2 Virus and Prion Diseases of Livestock Research Unit, National Animal Disease Center, USDA Agricultural Research Service, Ames, Iowa 50010,3 Dept. Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, Iowa 500114

Received 7 November 2004/ Accepted 8 February 2005

It has been shown previously that the nonstructural protein NS1 of influenza virus is an alpha/beta interferon (IFN-{alpha}/ß) antagonist, both in vitro and in experimental animal model systems. However, evidence of this function in a natural host has not yet been obtained. Here we investigated the role of the NS1 protein in the virulence of a swine influenza virus (SIV) isolate in pigs by using reverse genetics. The virulent wild-type A/Swine/Texas/4199-2/98 (TX/98) virus and various mutants encoding carboxy-truncated NS1 proteins were rescued. Growth properties of TX/98 viruses with mutated NS1, induction of IFN in tissue culture, and virulence-attenuation in pigs were analyzed and compared to those of the recombinant wild-type TX/98 virus. Our results indicate that deletions in the NS1 protein decrease the ability of the TX/98 virus to prevent IFN-{alpha}/ß synthesis in pig cells. Moreover, all NS1 mutant viruses were attenuated in pigs, and this correlated with the amount of IFN-{alpha}/ß induced in vitro. These data suggest that the NS1 protein of SIV is a virulence factor. Due to their attenuation, NS1-mutated swine influenza viruses might have a great potential as live attenuated vaccine candidates against SIV infections of pigs.

* Corresponding author. Mailing address: National Animal Disease Center, P.O. Box 70, Ames, IA 50010. Phone: (515) 663-7366. Fax: (515) 663-7458. E-mail: jricht{at}nadc.ars.usda.gov.

Journal of Virology, June 2005, p. 7535-7543, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7535-7543.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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