Although IFNα/β was first described as a factor with antiviral activity secreted by cells treated with partially heat-inactivated influenza A viruses (12
), it was also recognized early on that influenza viruses are poor IFNα/β inducers (13
). This is because influenza viruses, like many other viruses, encode mechanisms to evade and antagonize the IFNα/β response (14
). In the case of influenza A virus, this IFNα/β antagonistic function is encoded by the nonstructural protein 1 (NS1) gene.
NS1 of influenza A viruses is encoded by the unspliced mRNA derived from the shortest RNA segment of the 8 viral RNA segments. The protein is the most abundant nonstructural viral protein expressed in influenza A virus–infected cells. The development of reverse genetics techniques to manipulate the influenza virus genome made it possible to generate NS1 mutant viruses, including a recombinant influenza A virus lacking the NS1 gene (15
). The NS1 knockout influenza A virus, delNS1, was replication defective in most cells and hosts, except for those lacking a functional IFNα/β system. Most remarkable, delNS1 virus was highly attenuated in mice but replicated and caused disease in STAT1 knockout mice, which lack one of the key transactivator molecules needed for the IFNα/β response (15
). These results indicate that NS1 is required to overcome the IFNα/β response during influenza A virus infection.
The basis of the IFNα/β antagonistic properties of the NS1 of influenza A virus relies on its ability to prevent IFNβ synthesis; this explains the poor IFNβ–inducing properties of influenza A viruses (16,17
). In the absence of NS1, influenza A virus becomes a high IFNα/β–inducing virus, and induction of high levels of IFNα/β results in inhibition of replication of delNS1 virus. NS1, by virtue of its dsRNA binding properties, is likely to sequester viral dsRNA produced during viral infection, which prevents recognition of this dangerous molecule by cellular sensors. This model of action is consistent with the ability of NS1 expression to prevent activation of transcription factors involved in the induction of IFNα/β synthesis, including IRF3 (16
). Moreover, dsRNA binding is required for optimal inhibition of IFNβ production by NS1 (18
). Similar results were obtained with the NS1 of influenza B virus (19,20
). However, interactions of NS1 with cellular proteins also likely contribute to its IFNα/β antagonistic functions (21
). NS1 of influenza A virus, but not of influenza B virus, inhibits cellular factors involved in mRNA processing (22,23
); this function might also play a role in inhibiting IFNα/β production by influenza A virus (24
). Finally, NS1 has also been shown to have IFNα/β inhibitory properties at a post-IFNα/β synthesis level. The NS1 of both influenza A and B viruses prevents the activation of the translation inhibitory and IFN inducible protein PKR (25,26
); the NS1 of influenza B virus inhibits the activity of ISG15 (27
), an IFN-inducible protein that enhances the IFN-mediated antiviral response.