Influenza virus non-structural protein NS1: interferon antagonism and beyond

Abstract

Most viruses express one or several proteins that counter the antiviral defences of the host cell. This is the task of non-structural protein NS1 in influenza viruses. Absent in the viral particle, but highly expressed in the infected cell, NS1 dramatically inhibits cellular gene expression and prevents the activation of key players in the IFN system. In addition, NS1 selectively enhances the translation of viral mRNAs and may regulate the synthesis of viral RNAs. Our knowledge of the virus and of NS1 has increased dramatically during the last 15 years. The atomic structure of NS1 has been determined, many cellular partners have been identified and its multiple activities have been studied in depth. This review presents our current knowledge, and attempts to establish relationships between the RNA sequence, the structure of the protein, its ligands, its activities and the pathogenicity of the virus. A better understanding of NS1 could help in elaborating novel antiviral strategies, based on either live vaccines with altered NS1 or on small-compound inhibitors of NS1. IntroductionInfluenza viruses are enveloped viruses whose genome, 13 kb in size, is made up of eight ssRNAs of negative polarity. Transcription and replication of viral RNAs take place in the nucleus of the infected cell, generating at least 18 different species of positive-strand viral RNAs. These include (i) the eight complementary RNAs that act as templates for the synthesis of new genomic RNAs, (ii) eight unspliced mRNAs and (iii) at least two spliced mRNAs. The viral mRNas collectively encode up to 15 proteins, which schematically fall in three classes: (i) the four membraneassociated proteins comprise the two major surface glycoproteins haemagglutinin (HA) and neuraminidase (NA), the ion channel M2, and the matrix protein M1, which coats the inner face of the viral envelope; (ii) the three subunits of the viral polymerase (PA, PB1 and PB2) are tightly associated with the viral ribonucleoproteins (RNPs), in which the viral RNAs are bound to the nucleoprotein (NP); and, finally, (iii) nuclear export protein (NEP, formerly known as NS2) is also present in the virion, whilst NS1, PB1-F2, PA-X, PA-N155, PA-N182 and N40 are expressed in the infected cells, but absent from the viral particle. The unspliced viral mRNAs encode eight full-length products, and three PB1-and PArelated N-terminally truncated products that are not uniformly expressed among different strains (PB1-N40, PA-N155 and PA-N182) (Muramoto et al., 2013;Wise et al., 2009). In addition, PB1-F2 is encoded in the (+1) reading frame of PB1 and PA-X is produced from the PA mRNA through a ribosomal frameshift (Jagger et al., 2012). Finally,~10-15 % of the M-and NS-specific mRNAs are spliced , thus encoding M2 and NEP, respectively.Amongst the viral proteins, non-structural protein NS1 is probably that which is most involved in the interactions between the virus and the host cell, notably in antagonizing the antiviral response. It is therefore a key player in the viral cycle (Hale et al., 2...

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