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Journal of Virology, September 2000, p. 7989-7996, Vol. 74, No. 17
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Activation of Interferon Regulatory Factor 3 Is Inhibited by the Influenza A Virus NS1 Protein

Julie Talon,1 Curt M. Horvath,2 Rosalind Polley,3 Christopher F. Basler,1 Thomas Muster,4 Peter Palese,1,* and Adolfo García-Sastre1

Department of Microbiology1 and Immunobiology Center,2 Mount Sinai School of Medicine, New York, New York 10029; Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, England3; and Department of Dermatology, University of Vienna Medical School, 1090 Vienna, Austria4

Received 1 February 2000/Accepted 8 June 2000

We present a novel mechanism by which viruses may inhibit the alpha/beta interferon (IFN-alpha /beta ) cascade. The double-stranded RNA (dsRNA) binding protein NS1 of influenza virus is shown to prevent the potent antiviral interferon response by inhibiting the activation of interferon regulatory factor 3 (IRF-3), a key regulator of IFN-alpha /beta gene expression. IRF-3 activation and, as a consequence, IFN-beta mRNA induction are inhibited in wild-type (PR8) influenza virus-infected cells but not in cells infected with an isogenic virus lacking the NS1 gene (delNS1 virus). Furthermore, NS1 is shown to be a general inhibitor of the interferon signaling pathway. Inhibition of IRF-3 activation can be achieved by the expression of wild-type NS1 in trans, not only in delNS1 virus-infected cells but also in cells infected with a heterologous RNA virus (Newcastle disease virus). We propose that inhibition of IRF-3 activation by a dsRNA binding protein significantly contributes to the virulence of influenza A viruses and possibly to that of other viruses.

* Corresponding author. Mailing address: Department of Microbiology, Mount Sinai School of Medicine, One Gustave Levy Pl., New York, NY 10029. Phone: (212) 241-7318. Fax: (212) 722-3634. E-mail: peter.palese{at}mssm.edu.

Journal of Virology, September 2000, p. 7989-7996, Vol. 74, No. 17
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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