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Journal of Virology, April 2006, p. 3957-3965, Vol. 80, No. 8
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.8.3957-3965.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The CPSF30 Binding Site on the NS1A Protein of Influenza A Virus Is a Potential Antiviral Target

Karen Y. Twu, Diana L. Noah,{dagger} Ping Rao,{ddagger} Rei-Lin Kuo, and Robert M. Krug*

Institute for Cellular and Molecular Biology, Section of Molecular Genetics and Microbiology, University of Texas at Austin, Austin, Texas 78712

Received 9 November 2005/ Accepted 22 January 2006

The emergence of influenza A viruses resistant to the two existing classes of antiviral drugs highlights the need for additional antiviral drugs, particularly considering the potential threat of a pandemic of H5N1 influenza A viruses. Here, we determine whether influenza A virus replication can be selectively inhibited by blocking the ability of its NS1A protein to inhibit the 3'-end processing of cellular pre-mRNAs, including beta interferon (IFN-ß) pre-mRNA. Pre-mRNA processing is inhibited via the binding of the NS1A protein to the cellular CPSF30 protein, and mutational inactivation of this NS1A binding site causes severe attenuation of the virus. We demonstrate that binding of CPSF30 is mediated by two of its zinc fingers, F2F3, and that the CPSF30/F2F3 binding site on the NS1A protein extends from amino acid 144 to amino acid 186. We generated MDCK cells that constitutively express epitope-tagged F2F3 in the nucleus, although at only approximately one-eighth the level of the NS1A protein produced during virus infection. Influenza A virus replication was inhibited in this cell line, whereas no inhibition was observed with influenza B virus, whose NS1B protein lacks a binding site for CPSF30. Influenza A virus, but not influenza B virus, induced increased production of IFN-ß mRNA in the F2F3-expressing cells. These results, which indicate that F2F3 inhibits influenza A virus replication by blocking the binding of endogenous CPSF30 to the NS1A protein, point to this NS1A binding site as a potential target for the development of antivirals directed against influenza A virus.

* Corresponding author. Mailing address: Institute for Cellular and Molecular Biology, University of Texas at Austin, 2500 Speedway, Austin, TX 78712. Phone: (512) 232-5563. Fax: (512) 232-5564. E-mail: rkrug{at}mail.utexas.edu.

{dagger} Present address: Emerging Pathogens Division, Southern Research Institute, Birmingham, Alabama 35205.

{ddagger} Present address: Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520.

Journal of Virology, April 2006, p. 3957-3965, Vol. 80, No. 8
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.8.3957-3965.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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