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Multiple Anti-Interferon Actions of the Influenza A Virus NS1 Protein<sup>
</sup>
Georg Kochs,<sup>1</sup><sup>,
</sup><sup>*</sup> Adolfo García-Sastre,<sup>2</sup><sup>,3</sup> and Luis Martínez-Sobrido<sup>2</sup><sup>,3</sup><sup>,</sup><sup>*</sup> Department of Virology, University of Freiburg, D-79008 Freiburg, Germany,<sup>1</sup> Department of Microbiology,<sup>2</sup> Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York 10029<sup>3</sup>
Received 22 November 2006/ Accepted 6 April 2007
<!-- ABS --> The replication and pathogenicity of influenza A virus (FLUAV)<sup> </sup>are controlled in part by the alpha/beta interferon (IFN-
/ß
<sup> </sup>system. This virus-host interplay is dependent on the production<sup> </sup>of IFN-/ß and on the capacity of the viral nonstructural<sup> </sup>protein NS1 to counteract the IFN system. Two different mechanisms<sup> </sup>have been described for NS1, namely, blocking the activation<sup> </sup>of IFN regulatory factor 3 (IRF3) and blocking posttranscriptional<sup> </sup>processing of cellular mRNAs. Here we directly compare the abilities<sup> </sup>of NS1 gene products from three different human FLUAV (H1N1)<sup> </sup>strains to counteract the antiviral host response. We found<sup> </sup>that A/PR/8/34 NS1 has a strong capacity to inhibit IRF3 and<sup> </sup>activation of the IFN-ß promoter but is unable to<sup> </sup>suppress expression of other cellular genes. In contrast, the<sup> </sup>NS1 proteins of A/Tx/36/91 and of A/BM/1/18, the virus that<sup> </sup>caused the Spanish influenza pandemic, caused suppression of<sup> </sup>additional cellular gene expression. Thus, these NS1 proteins<sup> </sup>prevented the establishment of an IFN-induced antiviral state,<sup> </sup>allowing virus replication even in the presence of IFN. Interestingly,<sup> </sup>the block in gene expression was dependent on a newly described<sup> </sup>NS1 domain that is important for interaction with the cleavage<sup> </sup>and polyadenylation specificity factor (CPSF) component of the<sup> </sup>cellular pre-mRNA processing machinery but is not functional<sup> </sup>in A/PR/8/34 NS1. We identified the Phe-103 and Met-106 residues<sup> </sup>in NS1 as being critical for CPSF binding, together with the<sup> </sup>previously described C-terminal binding domain. Our results<sup> </sup>demonstrate the capacity of FLUAV NS1 to suppress the antiviral<sup> </sup>host defense at multiple levels and the existence of strain-specific<sup> </sup>differences that may modulate virus pathogenicity.
</sup>Georg Kochs,<sup>1</sup><sup>,
</sup><sup>*</sup> Adolfo García-Sastre,<sup>2</sup><sup>,3</sup> and Luis Martínez-Sobrido<sup>2</sup><sup>,3</sup><sup>,</sup><sup>*</sup> Department of Virology, University of Freiburg, D-79008 Freiburg, Germany,<sup>1</sup> Department of Microbiology,<sup>2</sup> Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York 10029<sup>3</sup>Received 22 November 2006/ Accepted 6 April 2007
<!-- ABS --> The replication and pathogenicity of influenza A virus (FLUAV)<sup> </sup>are controlled in part by the alpha/beta interferon (IFN-
/ß<sup> </sup>system. This virus-host interplay is dependent on the production<sup> </sup>of IFN-/ß and on the capacity of the viral nonstructural<sup> </sup>protein NS1 to counteract the IFN system. Two different mechanisms<sup> </sup>have been described for NS1, namely, blocking the activation<sup> </sup>of IFN regulatory factor 3 (IRF3) and blocking posttranscriptional<sup> </sup>processing of cellular mRNAs. Here we directly compare the abilities<sup> </sup>of NS1 gene products from three different human FLUAV (H1N1)<sup> </sup>strains to counteract the antiviral host response. We found<sup> </sup>that A/PR/8/34 NS1 has a strong capacity to inhibit IRF3 and<sup> </sup>activation of the IFN-ß promoter but is unable to<sup> </sup>suppress expression of other cellular genes. In contrast, the<sup> </sup>NS1 proteins of A/Tx/36/91 and of A/BM/1/18, the virus that<sup> </sup>caused the Spanish influenza pandemic, caused suppression of<sup> </sup>additional cellular gene expression. Thus, these NS1 proteins<sup> </sup>prevented the establishment of an IFN-induced antiviral state,<sup> </sup>allowing virus replication even in the presence of IFN. Interestingly,<sup> </sup>the block in gene expression was dependent on a newly described<sup> </sup>NS1 domain that is important for interaction with the cleavage<sup> </sup>and polyadenylation specificity factor (CPSF) component of the<sup> </sup>cellular pre-mRNA processing machinery but is not functional<sup> </sup>in A/PR/8/34 NS1. We identified the Phe-103 and Met-106 residues<sup> </sup>in NS1 as being critical for CPSF binding, together with the<sup> </sup>previously described C-terminal binding domain. Our results<sup> </sup>demonstrate the capacity of FLUAV NS1 to suppress the antiviral<sup> </sup>host defense at multiple levels and the existence of strain-specific<sup> </sup>differences that may modulate virus pathogenicity.