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Journal of Virology, February 2009, p. 1881-1891, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01805-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Novel Influenza Virus NS1 Antagonists Block Replication and Restore Innate Immune Function ^,

Dipanwita Basu,¹ Marcin P. Walkiewicz,¹ Matthew Frieman,² Ralph S. Baric,² David T. Auble,³ and Daniel A. Engel^1*

Department of Microbiology, University of Virginia School of Medicine, Charlottesville, Virginia 22908,¹ Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,² Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908³

Received 27 August 2008/ Accepted 24 November 2008

The innate immune system guards against virus infection through a variety of mechanisms including mobilization of the host interferon system, which attacks viral products mainly at a posttranscriptional level. The influenza virus NS1 protein is a multifunctional facilitator of virus replication, one of whose actions is to antagonize the interferon response. Since NS1 is required for efficient virus replication, it was reasoned that chemical inhibitors of this protein could be used to further understand virus-host interactions and also serve as potential new antiviral agents. A yeast-based assay was developed to identify compounds that phenotypically suppress NS1 function. Several such compounds exhibited significant activity specifically against influenza A virus in cell culture but had no effect on the replication of another RNA virus, respiratory syncytial virus. Interestingly, cells lacking an interferon response were drug resistant, suggesting that the compounds block interactions between NS1 and the interferon system. Accordingly, the compounds reversed the inhibition of beta interferon mRNA induction during infection, which is known to be caused by NS1. In addition, the compounds blocked the ability of NS1 protein to inhibit double-stranded RNA-dependent activation of a transfected beta interferon promoter construct. The effects of the compounds were specific to NS1, because they had no effect on the ability of the severe acute respiratory syndrome coronavirus papainlike protease protein to block beta interferon promoter activation. These data demonstrate that the function of NS1 can be modulated by chemical inhibitors and that such inhibitors will be useful as probes of biological function and as starting points for clinical drug development.

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* Corresponding author. Mailing address: Department of Microbiology, University of Virginia School of Medicine, 1300 Jefferson Park Ave., Charlottesville, VA 22908. Phone: (434) 924-8633. Fax: (434) 982-1071. E-mail: dae2s{at}virginia.edu

Published ahead of print on 3 December 2008.

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

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Journal of Virology, February 2009, p. 1881-1891, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01805-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.