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.
Alonso-CaplenF. V., KrugR. M.1991; Regulation of the extent of splicing of influenza virus NS1 mRNA: role of the rates of splicing and of the nucleocytoplasmic transport of NS1 mRNA. Mol Cell Biol 11:1092–1098
Alonso-CaplenF. V., NemeroffM. E., QiuY., KrugR. M.1992; Nucleocytoplasmic transport: the influenza virus NS1 protein regulates the transport of spliced NS2 mRNA and its precursor NS1 mRNA. Genes Dev 6:255–267[CrossRef]
AragonT., de la LunaS., NovoaI., CarrascoL., OrtinJ., NietoA.2000; Eukaryotic translation initiation factor 4GI is a cellular target for NS1 protein, a translational activator of influenza virus. Mol Cell Biol 20:6259–6268[CrossRef]
BaskinC. R., Bielefeldt-OhmannH., Garcia-SastreA., TumpeyT. M., Van HoevenN., CarterV. S., ThomasM. J., ProllS., SolorzanoA.other authors2007; Functional genomic and serological analysis of the protective immune response resulting from vaccination of macaques with an NS1-truncated influenza virus. J Virol 81:11817–11827[CrossRef]
BaslerC. F., ReidA. H., DybingJ. K., JanczewskiT. A., FanningT. G., ZhengH., SalvatoreM., PerdueM. L., SwayneD. E.other authors2001; Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. Proc Natl Acad Sci U S A 98:2746–2751[CrossRef]
BergmannM., RomirerI., SachetM., FleischhackerR., Garcia-SastreA., PaleseP., WolffK., PehambergerH., JakeszR., MusterT.2001; A genetically engineered influenza A virus with ras -dependent oncolytic properties. Cancer Res 61:8188–8193
BucherE., HemmesH., de HaanP., GoldbachR., PrinsM.2004; The influenza A virus NS1 protein binds small interfering RNAs and suppresses RNA silencing in plants. J Gen Virol 85:983–991[CrossRef]
BurguiI., AragonT., OrtinJ., NietoA.2003; PABP1 and eIF4GI associate with influenza virus NS1 protein in viral mRNA translation initiation complexes. J Gen Virol 84:3263–3274[CrossRef]
CastiglioniP., HallD. S., JacovettyE. L., IngulliE., ZanettiM.2008; Protection against influenza A virus by memory CD8 T cells requires reactivation by bone marrow-derived dendritic cells. J Immunol 180:4956–4964[CrossRef]
CauthenA. N., SwayneD. E., SekellickM. J., MarcusP. I., SuarezD. L.2007; Amelioration of influenza virus pathogenesis in chickens attributed to the enhanced interferon-inducing capacity of a virus with a truncated NS1 gene. J Virol 81:1838–1847[CrossRef]
ChenZ., LiY., KrugR. M.1999; Influenza A virus NS1 protein targets poly(A)-binding protein II of the cellular 3′-end processing machinery. EMBO J 18:2273–2283[CrossRef]
CheungC. Y., PoonL. L., LauA. S., LukW., LauY. L., ShortridgeK. F., GordonS., GuanY., PeirisJ. S.2002; Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?. Lancet 360:1831–1837[CrossRef]
ChienC. Y., TejeroR., HuangY., ZimmermanD. E., RiosC. B., KrugR. M., MontelioneG. T.1997; A novel RNA-binding motif in influenza A virus non-structural protein 1. Nat Struct Biol 4:891–895[CrossRef]
ChienC. Y., XuY., XiaoR., AraminiJ. M., SahasrabudheP. V., KrugR. M., MontelioneG. T.2004; Biophysical characterization of the complex between double-stranded RNA and the N-terminal domain of the NS1 protein from influenza A virus: evidence for a novel RNA-binding mode. Biochemistry 43:1950–1962[CrossRef]
de la LunaS., FortesP., BelosoA., OrtinJ.1995; Influenza virus NS1 protein enhances the rate of translation initiation of viral mRNAs. J Virol 69:2427–2433
DelgadilloM. O., SaenzP., SalvadorB., GarciaJ. A., Simon-MateoC.2004; Human influenza virus NS1 protein enhances viral pathogenicity and acts as an RNA silencing suppressor in plants. J Gen Virol 85:993–999[CrossRef]
DittmannJ., StertzS., GrimmD., SteelJ., Garcia-SastreA., HallerO., KochsG.2008; Influenza A virus strains differ in sensitivity to the antiviral action of Mx-GTPase. J Virol 82:3624–3631[CrossRef]
DonelanN. R., BaslerC. F., Garcia-SastreA.2003; A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of beta interferon and is attenuated in mice. J Virol 77:13257–13266[CrossRef]
EgorovA., BrandtS., SereinigS., RomanovaJ., FerkoB., KatingerD., GrassauerA., AlexandrovaG., KatingerH., MusterT.1998; Transfectant influenza A viruses with long deletions in the NS1 protein grow efficiently in Vero cells. J Virol 72:6437–6441
EhrhardtC., MarjukiH., WolffT., NurnbergB., PlanzO., PleschkaS., LudwigS.2006; Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence. Cell Microbiol 8:1336–1348[CrossRef]
EnamiM., EnamiK.2000; Characterization of influenza virus NS1 protein by using a novel helper-virus-free reverse genetic system. J Virol 74:5556–5561[CrossRef]
FalconA. M., FortesP., MarionR. M., BelosoA., OrtinJ.1999; Interaction of influenza virus NS1 protein and the human homologue of Staufen in vivo and in vitro . Nucleic Acids Res 27:2241–2247[CrossRef]
FalconA. M., MarionR. M., ZurcherT., GomezP., PortelaA., NietoA., OrtinJ.2004; Defective RNA replication and late gene expression in temperature-sensitive influenza viruses expressing deleted forms of the NS1 protein. J Virol 78:3880–3888[CrossRef]
FalconA. M., Fernandez-SesmaA., NakayaY., MoranT. M., OrtinJ., Garcia-SastreA.2005; Attenuation and immunogenicity in mice of temperature-sensitive influenza viruses expressing truncated NS1 proteins. J Gen Virol 86:2817–2821[CrossRef]
FortesP., LamondA. I., OrtinJ.1995; Influenza virus NS1 protein alters the subnuclear localization of cellular splicing components. J Gen Virol 76:1001–1007[CrossRef]
GaraigortaU., OrtinJ.2007; Mutation analysis of a recombinant NS replicon shows that influenza virus NS1 protein blocks the splicing and nucleo-cytoplasmic transport of its own viral mRNA. Nucleic Acids Res 35:4573–4582[CrossRef]
GarciaM. A., GilJ., VentosoI., GuerraS., DomingoE., RivasC., EstebanM.2006; Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev 70:1032–1060[CrossRef]
Garcia-SastreA., EgorovA., MatassovD., BrandtS., LevyD. E., DurbinJ. E., PaleseP., MusterT.1998; Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252:324–330[CrossRef]
GarfinkelM. S., KatzeM. G.1993; Translational control by influenza virus. Selective translation is mediated by sequences within the viral mRNA 5′-untranslated region. J Biol Chem 268:22223–22226
GeissG. K., SalvatoreM., TumpeyT. M., CarterV. S., WangX., BaslerC. F., TaubenbergerJ. K., BumgarnerR. E., PaleseP.other authors2002; Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza. Proc Natl Acad Sci U S A 99:10736–10741[CrossRef]
GharbiS. I., ZvelebilM. J., ShuttleworthS. J., HancoxT., SaghirN., TimmsJ. F., WaterfieldM. D.2007; Exploring the specificity of the PI3K family inhibitor LY294002. Biochem J 404:15–21[CrossRef]
GrimmD., StaeheliP., HufbauerM., KoernerI., Martinez-SobridoL., SolorzanoA., Garcia-SastreA., HallerO., KochsG.2007; Replication fitness determines high virulence of influenza A virus in mice carrying functional Mx1 resistance gene. Proc Natl Acad Sci U S A 104:6806–6811[CrossRef]
GuoZ., ChenL. M., ZengH., GomezJ. A., PlowdenJ., FujitaT., KatzJ. M., DonisR. O., SambharaS.2007; NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I. Am J Respir Cell Mol Biol 36:263–269[CrossRef]
HaleB. G., JacksonD., ChenY. H., LambR. A., RandallR. E.2006; Influenza A virus NS1 protein binds p85 β and activates phosphatidylinositol-3-kinase signaling. Proc Natl Acad Sci U S A 103:14194–14199[CrossRef]
HaleB. G., BarclayW. S., RandallR. E., RussellR. J.2008a; Structure of an avian influenza A virus NS1 protein effector domain. Virology 378:1–5[CrossRef]
HaleB. G., BattyI. H., DownesC. P., RandallR. E.2008b; Binding of influenza A virus NS1 protein to the inter-SH2 domain of p85 suggests a novel mechanism for phosphoinositide 3-kinase activation. J Biol Chem 283:1372–1380[CrossRef]
HatadaE., HasegawaM., ShimizuK., HatanakaM., FukudaR.1990; Analysis of influenza A virus temperature-sensitive mutants with mutations in RNA segment 8. J Gen Virol 71:1283–1292[CrossRef]
HatadaE., SaitoS., FukudaR.1999; Mutant influenza viruses with a defective NS1 protein cannot block the activation of PKR in infected cells. J Virol 73:2425–2433
HawkinsP. T., AndersonK. E., DavidsonK., StephensL. R.2006; Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans 34:647–662[CrossRef]
HaymanA., ComelyS., LackenbyA., MurphyS., McCauleyJ., GoodbournS., BarclayW.2006; Variation in the ability of human influenza A viruses to induce and inhibit the IFN- β pathway. Virology 347:52–64[CrossRef]
HaymanA., ComelyS., LackenbyA., HartgrovesL. C., GoodbournS., McCauleyJ. W., BarclayW. S.2007; NS1 proteins of avian influenza A viruses can act as antagonists of the human alpha/beta interferon response. J Virol 81:2318–2327[CrossRef]
HylandL., WebbyR., SandbulteM. R., ClarkeB., HouS.2006; Influenza virus NS1 protein protects against lymphohematopoietic pathogenesis in an in vivo mouse model. Virology 349:156–163[CrossRef]
InglisS. C., BarrettT., BrownC. M., AlmondJ. W.1979; The smallest genome RNA segment of influenza virus contains two genes that may overlap. Proc Natl Acad Sci U S A 76:3790–3794[CrossRef]
JacksonD., HossainM. J., HickmanD., PerezD. R., LambR. A.2008; A new influenza virus virulence determinant: the NS1 protein four C-terminal residues modulate pathogenicity. Proc Natl Acad Sci U S A 105:4381–4386[CrossRef]
JiaoP., TianG., LiY., DengG., JiangY., LiuC., LiuW., BuZ., KawaokaY., ChenH.2008; A single-amino-acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice. J Virol 82:1146–1154[CrossRef]
LambR. A., ChoppinP. W.1979; Segment 8 of the influenza virus genome is unique in coding for two polypeptides. Proc Natl Acad Sci U S A 76:4908–4912[CrossRef]
LambR. A., LaiC. J.1980; Sequence of interrupted and uninterrupted mRNAs and cloned DNA coding for the two overlapping nonstructural proteins of influenza virus. Cell 21:475–485[CrossRef]
LambR. A., ChoppinP. W., ChanockR. M., LaiC. J.1980; Mapping of the two overlapping genes for polypeptides NS1 and NS2 on RNA segment 8 of influenza virus genome. Proc Natl Acad Sci U S A 77:1857–1861[CrossRef]
LiY., YamakitaY., KrugR. M.1998; Regulation of a nuclear export signal by an adjacent inhibitory sequence: the effector domain of the influenza virus NS1 protein. Proc Natl Acad Sci U S A 95:4864–4869[CrossRef]
LiY., ChenZ. Y., WangW., BakerC. C., KrugR. M.2001; The 3′-end-processing factor CPSF is required for the splicing of single-intron pre-mRNAs in vivo. RNA 7:920–931[CrossRef]
LiW. X., LiH., LuR., LiF., DusM., AtkinsonP., BrydonE. W., JohnsonK. L., Garcia-SastreA.other authors2004; Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing. Proc Natl Acad Sci U S A 101:1350–1355[CrossRef]
LiS., MinJ. Y., KrugR. M., SenG. C.2006a; Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA. Virology 349:13–21[CrossRef]
LiY., AndersonD. H., LiuQ., ZhouY.2008; Mechanism of influenza A virus NS1 protein interaction with the p85 β , but not the p85 α , subunit of PI3K and upregulation of PI3K activity. J Biol Chem in press
LipatovA. S., AndreanskyS., WebbyR. J., HulseD. J., RehgJ. E., KraussS., PerezD. R., DohertyP. C., WebsterR. G., SangsterM. Y.2005; Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses. J Gen Virol 86:1121–1130[CrossRef]
LiuJ., LynchP. A., ChienC. Y., MontelioneG. T., KrugR. M., BermanH. M.1997; Crystal structure of the unique RNA-binding domain of the influenza virus NS1 protein. Nat Struct Biol 4:896–899[CrossRef]
LuY., WambachM., KatzeM. G., KrugR. M.1995; Binding of the influenza virus NS1 protein to double-stranded RNA inhibits the activation of the protein kinase that phosphorylates the elF-2 translation initiation factor. Virology 214:222–228[CrossRef]
LudwigS., SchultzU., MandlerJ., FitchW. M., ScholtissekC.1991; Phylogenetic relationship of the nonstructural (NS) genes of influenza A viruses. Virology 183:566–577[CrossRef]
LudwigS., WangX., EhrhardtC., ZhengH., DonelanN., PlanzO., PleschkaS., Garcia-SastreA., HeinsG., WolffT.2002; The influenza A virus NS1 protein inhibits activation of Jun N-terminal kinase and AP-1 transcription factors. J Virol 76:11166–11171[CrossRef]
MarionR. M., AragonT., BelosoA., NietoA., OrtinJ.1997a; The N-terminal half of the influenza virus NS1 protein is sufficient for nuclear retention of mRNA and enhancement of viral mRNA translation. Nucleic Acids Res 25:4271–4277[CrossRef]
MarionR. M., ZurcherT., de la LunaS., OrtinJ.1997b; Influenza virus NS1 protein interacts with viral transcription-replication complexes in vivo . J Gen Virol 78:2447–2451
MelenK., KinnunenL., FagerlundR., IkonenN., TwuK. Y., KrugR. M., JulkunenI.2007; Nuclear and nucleolar targeting of influenza A virus NS1 protein: striking differences between different virus subtypes. J Virol 81:5995–6006[CrossRef]
MibayashiM., Martinez-SobridoL., LooY. M., CardenasW. B., GaleM.Jr, Garcia-SastreA.2007; Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol 81:514–524[CrossRef]
MinJ. Y., KrugR. M.2006; The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: inhibiting the 2′-5′ oligo (A) synthetase/RNase L pathway. Proc Natl Acad Sci U S A 103:7100–7105[CrossRef]
MinJ. Y., LiS., SenG. C., KrugR. M.2007; A site on the influenza A virus NS1 protein mediates both inhibition of PKR activation and temporal regulation of viral RNA synthesis. Virology 363:236–243[CrossRef]
MurayamaR., HaradaY., ShibataT., KurodaK., HayakawaS., ShimizuK., TanakaT.2007; Influenza A virus non-structural protein 1 (NS1) interacts with cellular multifunctional protein nucleolin during infection. Biochem Biophys Res Commun 362:880–885[CrossRef]
NemeroffM. E., BarabinoS. M., LiY., KellerW., KrugR. M.1998; Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3′ end formation of cellular pre-mRNAs. Mol Cell 1:991–1000[CrossRef]
NewbyC. M., SabinL., PekoszA.2007; The RNA binding domain of influenza A virus NS1 protein affects secretion of tumor necrosis factor alpha, interleukin-6, and interferon in primary murine tracheal epithelial cells. J Virol 81:9469–9480[CrossRef]
NoahD. L., TwuK. Y., KrugR. M.2003; Cellular antiviral responses against influenza A virus are countered at the posttranscriptional level by the viral NS1A protein via its binding to a cellular protein required for the 3′ end processing of cellular pre-mRNAS. Virology 307:386–395[CrossRef]
OpitzB., RejaibiA., DauberB., EckhardJ., VinzingM., SchmeckB., HippenstielS., SuttorpN., WolffT.2007; IFN β induction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein. Cell Microbiol 9:930–938[CrossRef]
PaleseP., ShawM. L.2007; Orthomyxoviridae : the viruses and their replication. In Fields Virology , 5th edn. pp 1647–1689Edited byKnipe HowleyD. M. Philadelphia: Lippincott Williams & Wilkins;
ParkY. W., KatzeM. G.1995; Translational control by influenza virus. Identification of cis-acting sequences and trans-acting factors which may regulate selective viral mRNA translation. J Biol Chem 270:28433–28439[CrossRef]
QianX. Y., ChienC. Y., LuY., MontelioneG. T., KrugR. M.1995; An amino-terminal polypeptide fragment of the influenza virus NS1 protein possesses specific RNA-binding activity and largely helical backbone structure. RNA 1:948–956
QiuY., KrugR. M.1994; The influenza virus NS1 protein is a poly(A)-binding protein that inhibits nuclear export of mRNAs containing poly(A. J Virol 68:2425–2432
QiuY., NemeroffM., KrugR. M.1995; The influenza virus NS1 protein binds to a specific region in human U6 snRNA and inhibits U6–U2 and U6–U4 snRNA interactions during splicing. RNA 1:304–316
QuinlivanM., ZamarinD., Garcia-SastreA., CullinaneA., ChambersT., PaleseP.2005; Attenuation of equine influenza viruses through truncations of the NS1 protein. J Virol 79:8431–8439[CrossRef]
RandallR. E., GoodbournS.2008; Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 89:1–47[CrossRef]
RichtJ. A., LekcharoensukP., LagerK. M., VincentA. L., LoiaconoC. M., JankeB. H., WuW. H., YoonK. J., WebbyR. J.other authors2006; Vaccination of pigs against swine influenza viruses by using an NS1-truncated modified live-virus vaccine. J Virol 80:11009–11018[CrossRef]
SalvatoreM., BaslerC. F., ParisienJ. P., HorvathC. M., BourmakinaS., ZhengH., MusterT., PaleseP., Garcia-SastreA.2002; Effects of influenza A virus NS1 protein on protein expression: the NS1 protein enhances translation and is not required for shutoff of host protein synthesis. J Virol 76:1206–1212[CrossRef]
SatterlyN., TsaiP. L., van DeursenJ., NussenzveigD. R., WangY., FariaP. A., LevayA., LevyD. E., FontouraB. M.2007; Influenza virus targets the mRNA export machinery and the nuclear pore complex. Proc Natl Acad Sci U S A 104:1853–1858[CrossRef]
ShimizuK., IguchiA., GomyouR., OnoY.1999; Influenza virus inhibits cleavage of the HSP70 pre-mRNAs at the polyadenylation site. Virology 254:213–219[CrossRef]
ShinY.-K., LiuQ., TikooS. K., BabiukL. A., ZhouY.2007a; Influenza A virus NS1 protein activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by direct interaction with the p85 subunit of PI3K. J Gen Virol 88:13–18[CrossRef]
ShinY. K., LiY., LiuQ., AndersonD. H., BabiukL. A., ZhouY.2007b; SH3 binding motif 1 in influenza A virus NS1 protein is essential for PI3K/Akt signalling pathway activation. J Virol 81:12730–12739[CrossRef]
SilvermanR. H.2007; Viral encounters with 2′,5′-oligoadenylate synthetase and RNase L during the interferon antiviral response. J Virol 81:12720–12729[CrossRef]
SimonsenL., ClarkeM. J., WilliamsonG. D., StroupD. F., ArdenN. H., SchonbergerL. B.1997; The impact of influenza epidemics on mortality: introducing a severity index. Am J Public Health 87:1944–1950[CrossRef]
SolorzanoA., WebbyR. J., LagerK. M., JankeB. H., Garcia-SastreA., RichtJ. A.2005; Mutations in the NS1 protein of swine influenza virus impair anti-interferon activity and confer attenuation in pigs. J Virol 79:7535–7543[CrossRef]
StasakovaJ., FerkoB., KittelC., SereinigS., RomanovaJ., KatingerH., EgorovA.2005; Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1 β and 18. J Gen Virol 86:185–195[CrossRef]
SubbaraoK., KlimovA., KatzJ., RegneryH., LimW., HallH., PerdueM., SwayneD., BenderC.other authors1998; Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279:393–396[CrossRef]
TakizawaT., OhashiK., NakanishiY.1996; Possible involvement of double-stranded RNA-activated protein kinase in cell death by influenza virus infection. J Virol 70:8128–8132
TalonJ., HorvathC. M., PolleyR., BaslerC. F., MusterT., PaleseP., Garcia-SastreA.2000a; Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J Virol 74:7989–7996[CrossRef]
TalonJ., SalvatoreM., O'NeillR. E., NakayaY., ZhengH., MusterT., Garcia-SastreA., PaleseP.2000b; Influenza A and B viruses expressing altered NS1 proteins: a vaccine approach. Proc Natl Acad Sci U S A 97:4309–4314[CrossRef]
TanS. L., KatzeM. G.1998; Biochemical and genetic evidence for complex formation between the influenza A virus NS1 protein and the interferon-induced PKR protein kinase. J Interferon Cytokine Res 18:757–766[CrossRef]
ToK. F., ChanP. K., ChanK. F., LeeW. K., LamW. Y., WongK. F., TangN. L., TsangD. N., SungR. Y.other authors2001; Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol 63:242–246[CrossRef]
TreanorJ. J., SnyderM. H., LondonW. T., MurphyB. R.1989; The B allele of the NS gene of avian influenza viruses, but not the A allele, attenuates a human influenza A virus for squirrel monkeys. Virology 171:1–9[CrossRef]
TwuK. Y., NoahD. L., RaoP., KuoR. L., KrugR. M.2006; The CPSF30 binding site on the NS1A protein of influenza A virus s a potential antiviral target. J Virol 80:3957–3965[CrossRef]
VincentA. L., MaW., LagerK. M., JankeB. H., WebbyR. J., Garcia-SastreA., RichtJ. A.2007; Efficacy of intranasal administration of a truncated NS1 modified live influenza virus vaccine in swine. Vaccine 25:7999–8009[CrossRef]
WangW., KrugR. M.1998; U6atac snRNA, the highly divergent counterpart of U6 snRNA, is the specific target that mediates inhibition of AT-AC splicing by the influenza virus NS1 protein. RNA 4:55–64
WangW., RiedelK., LynchP., ChienC. Y., MontelioneG. T., KrugR. M.1999; RNA binding by the novel helical domain of the influenza virus NS1 protein requires its dimer structure and a small number of specific basic amino acids. RNA 5:195–205[CrossRef]
WangX., LiM., ZhengH., MusterT., PaleseP., BegA. A., Garcia-SastreA.2000; Influenza A virus NS1 protein prevents activation of NF- κ B and induction of alpha/beta interferon. J Virol 74:11566–11573[CrossRef]
WangX., BaslerC. F., WilliamsB. R., SilvermanR. H., PaleseP., Garcia-SastreA.2002; Functional replacement of the carboxy-terminal two-thirds of the influenza A virus NS1 protein with short heterologous dimerization domains. J Virol 76:12951–12962[CrossRef]
WeberF., WagnerV., RasmussenS. B., HartmannR., PaludanS. R.2006; Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses. J Virol 80:5059–5064[CrossRef]
WolffT., O'NeillR. E., PaleseP.1996; Interaction cloning of NS1-I, a human protein that binds to the nonstructural NS1 proteins of influenza A and B viruses. J Virol 70:5363–5372
WolffT., O'NeillR. E., PaleseP.1998; NS1-Binding protein (NS1-BP): a novel human protein that interacts with the influenza A virus nonstructural NS1 protein is relocalized in the nuclei of infected cells. J Virol 72:7170–7180
WolstenholmeA. J., BarrettT., NicholS. T., MahyB. W.1980; Influenza virus-specific RNA and protein syntheses in cells infected with temperature-sensitive mutants defective in the genome segment encoding nonstructural proteins. J Virol 35:1–7
YinC., KhanJ. A., SwapnaG. V., ErtekinA., KrugR. M., TongL., MontelioneG. T.2007; Conserved surface features form the double-stranded RNA binding site of non-structural protein 1 (NS1) from influenza A and B viruses. J Biol Chem 282:20584–20592[CrossRef]
YoungD. F., AndrejevaL., LivingstoneA., GoodbournS., LambR. A., CollinsP. L., ElliottR. M., RandallR. E.2003; Virus replication in engineered human cells that do not respond to interferons. J Virol 77:2174–2181[CrossRef]
ZhirnovO. P., KlenkH. D.2007; Control of apoptosis in influenza virus-infected cells by up-regulation of Akt and p53 signaling. Apoptosis 12:1419–1432[CrossRef]
ZhuQ., YangH., ChenW., CaoW., ZhongG., JiaoP., DengG., YuK., YangC.other authors2008; A naturally occurring deletion in its NS gene contributes to the attenuation of an H5N1 swine influenza virus in chickens. J Virol 82:220–228[CrossRef]
ZohariS., GyarmatiP., ThorenP., CzifraG., BrojerC., BelakS., BergM.2008; Genetic characterization of the NS gene indicates co-circulation of two sub-lineages of highly pathogenic avian influenza virus of H5N1 subtype in Northern Europe in 2006. Virus Genes 36:117–125[CrossRef]