The non-structural (NS1) protein of influenza A viruses is a non-essential virulence factor that has multiple accessory functions during viral infection. In recent years, the major role ascribed to NS1 has been its inhibition of host immune responses, especially the limitation of both interferon (IFN) production and the antiviral effects of IFN-induced proteins, such as dsRNA-dependent protein kinase R (PKR) and 2'5'-oligoadenylate synthetase (OAS)/RNase L. However, it is clear that NS1 also acts directly to modulate other important aspects of the virus replication cycle, including viral RNA replication, viral protein synthesis, and general host-cell physiology. Here, we review the current literature on this remarkably multifunctional viral protein. In the first part of this article, we summarize the basic biochemistry of NS1, in particular its synthesis, structure, and intracellular localization. We then discuss the various roles NS1 has in regulating viral replication mechanisms, host innate/adaptive immune responses, and cellular signalling pathways. We focus on the NS1–RNA and NS1–protein interactions that are fundamental to these processes, and highlight apparent strain-specific ways in which different NS1 proteins may act. In this regard, the contributions of certain NS1 functions to the pathogenicity of human and animal influenza A viruses are also discussed. Finally, we outline practical applications that future studies on NS1 may lead to, including the rational design and manufacture of influenza vaccines, the development of novel antiviral drugs, and the use of oncolytic influenza A viruses as potential anti-cancer agents.

Members of the Paramyxovirinae subfamily include viruses such as measles, mumps, parainfluenza viruses (PIV) of humans, Newcastle Disease virus of birds, Sendai virus (SeV) of rodents, and simian virus 5 (SV5), which has been isolated from monkeys, dogs, pigs, and humans. Paramyxoviruses also have zoonotic potential, as has been observed with the newly emergent Hendra (HeV) and Nipah viruses, which naturally infect fruit bats but can cause serious, often fatal infections when transmitted to farm and domestic animals and to humans (reviewed in ref.2). Like all viruses, upon infection of cells, paramyxoviruses are subjected to a variety of intracellular antiviral responses, including the IFN response (reviewed in refs. 3-5). Over the last few years, it has become clear that protein products of the P͞V͞C gene of viruses within the Paramyxovirinae subfamily (for review of the molecular biology of paramyxoviruses, see ref. 1) specifically reduce the effectiveness of the IFN response. For example, the V protein of SV5 targets signal transducer and activator of transcription 1 (STAT1) for degradation, thereby blocking both IFN-␣͞␤ and IFN-␥ signaling within infected cells (6), whereas the C proteins of SeV block IFN signaling by interfering with STAT phosphorylation or stability (reviewed in refs. 7-9). As well as blocking IFN signaling, these viruses also specifically limit the production of IFN by virus-infected cells (10-12). The block on IFN-␤ production is at the level of transcription, because very little IFN-␤ mRNA is induced in cells infected with SV5. In contrast, large amounts of IFN-␤ mRNA (and thus IFN-␤) are produced by cells infected with a recombinant of SV5 (SV5V⌬C) that produces a truncated V protein lacking the cysteine-rich C terminus (which is dispensable for virus replication), suggesting that the V protein is responsible for the block on IFN production. This conclusion is supported by the observation that in gene reporter assays, the V proteins of SV5, PIV2, and SeV inhibit the activation of the IFN-␤ promoter in response to intracellular dsRNA (11).Initial transcription from the IFN-␤ promoter requires the activation of a number of cellular transcription factors, including IFN regulatory factor (IRF)-3 and NF-B, leading to the formation of an enhanceosome complex that associates with the basal transcriptional machinery to recruit RNA polymerase II to the IFN-␤ promoter (reviewed in refs. 3 and 13). The molecular details of how the V proteins of paramyxoviruses block IFN production are not known, but the block affects the signal transduction pathway that activates both NF-B and IRF-3 in response to dsRNA. Thus, these transcription factors are not activated in cells infected with wild-type SV5 but are activated in cells infected with SV5V⌬C. Furthermore, ectopic expression of SV5 V inhibits the activation of IRF-3 and NF-B by both dsRNA and infection with SV5V⌬C (10, 11). Unlike the targeted degradation of signal transducer and activator of transcription 1 (STAT1), which requires both the N-and C-t...

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