Multiple Anti-Interferon Actions of the Influenza A Virus NS1 Protein

[sharon sanders]

Multiple Anti-Interferon Actions of the Influenza A Virus NS1 Protein<sup>

</sup>

Georg Kochs,¹<sup>,

</sup>^* Adolfo García-Sastre,²^,3 and Luis Martínez-Sobrido²^,3<sup>,

</sup>^* Department of Virology, University of Freiburg, D-79008 Freiburg, Germany,¹ Department of Microbiology,² Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York 10029³
Received 22 November 2006/ Accepted 6 April 2007

<!-- ABS --> The replication and pathogenicity of influenza A virus (FLUAV)are controlled in part by the alpha/beta interferon (IFN-

/ß)system. This virus-host interplay is dependent on the productionof IFN-

/ß and on the capacity of the viral nonstructuralprotein NS1 to counteract the IFN system. Two different mechanismshave been described for NS1, namely, blocking the activationof IFN regulatory factor 3 (IRF3) and blocking posttranscriptionalprocessing of cellular mRNAs. Here we directly compare the abilitiesof NS1 gene products from three different human FLUAV (H1N1)strains to counteract the antiviral host response. We foundthat A/PR/8/34 NS1 has a strong capacity to inhibit IRF3 andactivation of the IFN-ß promoter but is unable tosuppress expression of other cellular genes. In contrast, theNS1 proteins of A/Tx/36/91 and of A/BM/1/18, the virus thatcaused the Spanish influenza pandemic, caused suppression ofadditional cellular gene expression. Thus, these NS1 proteinsprevented the establishment of an IFN-induced antiviral state,allowing virus replication even in the presence of IFN. Interestingly,the block in gene expression was dependent on a newly describedNS1 domain that is important for interaction with the cleavageand polyadenylation specificity factor (CPSF) component of thecellular pre-mRNA processing machinery but is not functionalin A/PR/8/34 NS1. We identified the Phe-103 and Met-106 residuesin NS1 as being critical for CPSF binding, together with thepreviously described C-terminal binding domain. Our resultsdemonstrate the capacity of FLUAV NS1 to suppress the antiviralhost defense at multiple levels and the existence of strain-specificdifferences that may modulate virus pathogenicity.


http://jvi.asm.org/cgi/content/abstract/81/13/7011