1887

Abstract

Typical avian influenza A viruses are restricted from replicating efficiently and causing disease in humans. However, an avian virus can become adapted to humans by mutating or recombining with currently circulating human viruses. These viruses have the potential to cause pandemics in an immunologically naïve human population. It is critical that we understand the molecular basis of host-range restriction and how this can be overcome. Here, we review our current understanding of the mechanisms by which influenza viruses adapt to replicate efficiently in a new host. We predominantly focus on the influenza polymerase, which remains one of the least understood host-range barriers.

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2014-06-01
2024-12-12
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References

  1. Aggarwal S., Dewhurst S., Takimoto T., Kim B. 2011; Biochemical impact of the host adaptation-associated PB2 E627K mutation on the temperature-dependent RNA synthesis kinetics of influenza A virus polymerase complex. J Biol Chem 286:34504–34513 [View Article][PubMed]
    [Google Scholar]
  2. Almond J. W. 1977; A single gene determines the host range of influenza virus. Nature 270:617–618 [View Article][PubMed]
    [Google Scholar]
  3. Baigent S. J., McCauley J. W. 2001; Glycosylation of haemagglutinin and stalk-length of neuraminidase combine to regulate the growth of avian influenza viruses in tissue culture. Virus Res 79:177–185 [View Article][PubMed]
    [Google Scholar]
  4. Banks J., Speidel E. S., Moore E., Plowright L., Piccirillo A., Capua I., Cordioli P., Fioretti A., Alexander D. J. 2001; Changes in the haemagglutinin and the neuraminidase genes prior to the emergence of highly pathogenic H7N1 avian influenza viruses in Italy. Arch Virol 146:963–973 [View Article][PubMed]
    [Google Scholar]
  5. Barber M. R., Aldridge J. R. Jr, Webster R. G., Magor K. E. 2010; Association of RIG-I with innate immunity of ducks to influenza. Proc Natl Acad Sci U S A 107:5913–5918 [View Article][PubMed]
    [Google Scholar]
  6. Baum L. G., Paulson J. C. 1990; Sialyloligosaccharides of the respiratory epithelium in the selection of human influenza virus receptor specificity. Acta Histochem Suppl 40:35–38[PubMed]
    [Google Scholar]
  7. Baum L. G., Paulson J. C. 1991; The N2 neuraminidase of human influenza virus has acquired a substrate specificity complementary to the hemagglutinin receptor specificity. Virology 180:10–15 [View Article][PubMed]
    [Google Scholar]
  8. Beaton A. R., Krug R. M. 1986; Transcription antitermination during influenza viral template RNA synthesis requires the nucleocapsid protein and the absence of a 5′ capped end. Proc Natl Acad Sci U S A 83:6282–6286 [View Article][PubMed]
    [Google Scholar]
  9. Benfield C. T., Lyall J. W., Kochs G., Tiley L. S. 2008; Asparagine 631 variants of the chicken Mx protein do not inhibit influenza virus replication in primary chicken embryo fibroblasts or in vitro surrogate assays. J Virol 82:7533–7539 [View Article][PubMed]
    [Google Scholar]
  10. Blumenkrantz D., Roberts K. L., Shelton H., Lycett S., Barclay W. S. 2013; The short stalk length of highly pathogenic avian influenza H5N1 virus neuraminidase limits transmission of pandemic H1N1 virus in ferrets. J Virol 87:10539–10551 [View Article][PubMed]
    [Google Scholar]
  11. Bogs J., Kalthoff D., Veits J., Pavlova S., Schwemmle M., Mänz B., Mettenleiter T. C., Stech J. 2011; Reversion of PB2-627E to -627K during replication of an H5N1 Clade 2.2 virus in mammalian hosts depends on the origin of the nucleoprotein. J Virol 85:10691–10698 [View Article][PubMed]
    [Google Scholar]
  12. Bortz E., Westera L., Maamary J., Steel J., Albrecht R. A., Manicassamy B., Chase G., Martínez-Sobrido L., Schwemmle M., García-Sastre A. 2011; Host- and strain-specific regulation of influenza virus polymerase activity by interacting cellular proteins. MBio 2:e00151-11 [View Article][PubMed]
    [Google Scholar]
  13. Bradel-Tretheway B. G., Mattiacio J. L., Krasnoselsky A., Stevenson C., Purdy D., Dewhurst S., Katze M. G. 2011; Comprehensive proteomic analysis of influenza virus polymerase complex reveals a novel association with mitochondrial proteins and RNA polymerase accessory factors. J Virol 85:8569–8581 [View Article][PubMed]
    [Google Scholar]
  14. Brown I. H. 2008; The role of pigs in interspecies transmission. In Avian Influenza (Monographs in Virology, vol. 27) pp. 88–100 Edited by Klenk H.-D., Matrosovich M. N., Stech J. Basel: Karger; [View Article]
    [Google Scholar]
  15. Brown I. H. 2013; History and epidemiology of Swine influenza in Europe. Curr Top Microbiol Immunol 370:133–146[PubMed]
    [Google Scholar]
  16. Bullido R., Gómez-Puertas P., Saiz M. J., Portela A. 2001; Influenza A virus NEP (NS2 protein) downregulates RNA synthesis of model template RNAs. J Virol 75:4912–4917 [View Article][PubMed]
    [Google Scholar]
  17. Bussey K. A., Bousse T. L., Desmet E. A., Kim B., Takimoto T. 2010; PB2 residue 271 plays a key role in enhanced polymerase activity of influenza A viruses in mammalian host cells. J Virol 84:4395–4406 [View Article][PubMed]
    [Google Scholar]
  18. Bussey K. A., Desmet E. A., Mattiacio J. L., Hamilton A., Bradel-Tretheway B., Bussey H. E., Kim B., Dewhurst S., Takimoto T. 2011; PA residues in the 2009 H1N1 pandemic influenza virus enhance avian influenza virus polymerase activity in mammalian cells. J Virol 85:7020–7028 [View Article][PubMed]
    [Google Scholar]
  19. Carr S. M., Carnero E., García-Sastre A., Brownlee G. G., Fodor E. 2006; Characterization of a mitochondrial-targeting signal in the PB2 protein of influenza viruses. Virology 344:492–508 [View Article][PubMed]
    [Google Scholar]
  20. Castrucci M. R., Kawaoka Y. 1993; Biologic importance of neuraminidase stalk length in influenza A virus. J Virol 67:759–764[PubMed]
    [Google Scholar]
  21. Cauldwell A. V., Moncorgé O., Barclay W. S. 2013; Unstable polymerase–nucleoprotein interaction is not responsible for avian influenza virus polymerase restriction in human cells. J Virol 87:1278–1284 [View Article][PubMed]
    [Google Scholar]
  22. Chen G. W., Chang S. C., Mok C. K., Lo Y. L., Kung Y. N., Huang J. H., Shih Y. H., Wang J. Y., Chiang C.other authors 2006; Genomic signatures of human versus avian influenza A viruses. Emerg Infect Dis 12:1353–1360 [View Article][PubMed]
    [Google Scholar]
  23. Chen H., Bright R. A., Subbarao K., Smith C., Cox N. J., Katz J. M., Matsuoka Y. 2007; Polygenic virulence factors involved in pathogenesis of 1997 Hong Kong H5N1 influenza viruses in mice. Virus Res 128:159–163 [View Article][PubMed]
    [Google Scholar]
  24. Chua M. A., Schmid S., Perez J. T., Langlois R. A., Tenoever B. R. 2013; Influenza A virus utilizes suboptimal splicing to coordinate the timing of infection. Cell Reports 3:23–29 [View Article][PubMed]
    [Google Scholar]
  25. Clements M. L., Subbarao E. K., Fries L. F., Karron R. A., London W. T., Murphy B. R. 1992; Use of single-gene reassortant viruses to study the role of avian influenza A virus genes in attenuation of wild-type human influenza A virus for squirrel monkeys and adult human volunteers. J Clin Microbiol 30:655–662[PubMed]
    [Google Scholar]
  26. Conenello G. M., Tisoncik J. R., Rosenzweig E., Varga Z. T., Palese P., Katze M. G. 2011; A single N66S mutation in the PB1-F2 protein of influenza A virus increases virulence by inhibiting the early interferon response in vivo . J Virol 85:652–662 [View Article][PubMed]
    [Google Scholar]
  27. Crescenzo-Chaigne B., van der Werf S., Naffakh N. 2002; Differential effect of nucleotide substitutions in the 3′ arm of the influenza A virus vRNA promoter on transcription/replication by avian and human polymerase complexes is related to the nature of PB2 amino acid 627. Virology 303:240–252 [View Article][PubMed]
    [Google Scholar]
  28. de Jong M. D., Simmons C. P., Thanh T. T., Hien V. M., Smith G. J., Chau T. N., Hoang D. M., Chau N. V., Khanh T. H.other authors 2006; Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 12:1203–1207 [View Article][PubMed]
    [Google Scholar]
  29. Desmet E. A., Bussey K. A., Stone R., Takimoto T. 2013; Identification of the N-terminal domain of the influenza virus PA responsible for the suppression of host protein synthesis. J Virol 87:3108–3118 [View Article][PubMed]
    [Google Scholar]
  30. Dittmann J., Stertz S., Grimm D., Steel J., García-Sastre A., Haller O., Kochs G. 2008; Influenza A virus strains differ in sensitivity to the antiviral action of Mx-GTPase. J Virol 82:3624–3631 [View Article][PubMed]
    [Google Scholar]
  31. Finkelstein D. B., Mukatira S., Mehta P. K., Obenauer J. C., Su X., Webster R. G., Naeve C. W. 2007; Persistent host markers in pandemic and H5N1 influenza viruses. J Virol 81:10292–10299 [View Article][PubMed]
    [Google Scholar]
  32. Flick R., Hobom G. 1999; Interaction of influenza virus polymerase with viral RNA in the ‘corkscrew’ conformation. J Gen Virol 80:2565–2572[PubMed]
    [Google Scholar]
  33. Flick R., Neumann G., Hoffmann E., Neumeier E., Hobom G. 1996; Promoter elements in the influenza vRNA terminal structure. RNA 2:1046–1057[PubMed]
    [Google Scholar]
  34. Fodor E., Pritlove D. C., Brownlee G. G. 1994; The influenza virus panhandle is involved in the initiation of transcription. J Virol 68:4092–4096[PubMed]
    [Google Scholar]
  35. Foeglein Á., Loucaides E. M., Mura M., Wise H. M., Barclay W. S., Digard P. 2011; Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase. J Gen Virol 92:1650–1661 [View Article][PubMed]
    [Google Scholar]
  36. Fouchier R. A., Munster V., Wallensten A., Bestebroer T. M., Herfst S., Smith D., Rimmelzwaan G. F., Olsen B., Osterhaus A. D. 2005; Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls. J Virol 79:2814–2822 [View Article][PubMed]
    [Google Scholar]
  37. Gabriel G., Dauber B., Wolff T., Planz O., Klenk H. D., Stech J. 2005; The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A 102:18590–18595 [View Article][PubMed]
    [Google Scholar]
  38. Gabriel G., Abram M., Keiner B., Wagner R., Klenk H. D., Stech J. 2007; Differential polymerase activity in avian and mammalian cells determines host range of influenza virus. J Virol 81:9601–9604 [View Article][PubMed]
    [Google Scholar]
  39. Gabriel G., Herwig A., Klenk H. D. 2008; Interaction of polymerase subunit PB2 and NP with importin α1 is a determinant of host range of influenza A virus. PLoS Pathog 4:e11 [View Article][PubMed]
    [Google Scholar]
  40. Gabriel G., Klingel K., Otte A., Thiele S., Hudjetz B., Arman-Kalcek G., Sauter M., Shmidt T., Rother F.other authors 2011; Differential use of importin-α isoforms governs cell tropism and host adaptation of influenza virus. Nat Commun 2:156 [View Article][PubMed]
    [Google Scholar]
  41. Gack M. U., Shin Y. C., Joo C.-H., Urano T., Liang C., Sun L., Takeuchi O., Akira S., Chen Z.other authors 2007; TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446:916–920 [View Article][PubMed]
    [Google Scholar]
  42. Gack M. U., Albrecht R. A., Urano T., Inn K. S., Huang I. C., Carnero E., Farzan M., Inoue S., Jung J. U., García-Sastre A. 2009; Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe 5:439–449 [View Article][PubMed]
    [Google Scholar]
  43. Gamblin S. J., Haire L. F., Russell R. J., Stevens D. J., Xiao B., Ha Y., Vasisht N., Steinhauer D. A., Daniels R. S.other authors 2004; The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303:1838–1842 [View Article][PubMed]
    [Google Scholar]
  44. Gao Y., Zhang Y., Shinya K., Deng G., Jiang Y., Li Z., Guan Y., Tian G., Li Y.other authors 2009; Identification of amino acids in HA and PB2 critical for the transmission of H5N1 avian influenza viruses in a mammalian host. PLoS Pathog 5:e1000709 [View Article][PubMed]
    [Google Scholar]
  45. Gao R., Cao B., Hu Y., Feng Z., Wang D., Hu W., Chen J., Jie Z., Qiu H.other authors 2013; Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med 368:1888–1897 [View Article][PubMed]
    [Google Scholar]
  46. Garten R. J., Davis C. T., Russell C. A., Shu B., Lindstrom S., Balish A., Sessions W. M., Xu X., Skepner E.other authors 2009; Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 325:197–201 [View Article][PubMed]
    [Google Scholar]
  47. Glaser L., Stevens J., Zamarin D., Wilson I. A., García-Sastre A., Tumpey T. M., Basler C. F., Taubenberger J. K., Palese P. 2005; A single amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding specificity. J Virol 79:11533–11536 [View Article][PubMed]
    [Google Scholar]
  48. Graef K. M., Vreede F. T., Lau Y. F., McCall A. W., Carr S. M., Subbarao K., Fodor E. 2010; The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon. J Virol 84:8433–8445 [View Article][PubMed]
    [Google Scholar]
  49. Hale B. G., Randall R. E., Ortín J., Jackson D. 2008; The multifunctional NS1 protein of influenza A viruses. J Gen Virol 89:2359–2376 [View Article][PubMed]
    [Google Scholar]
  50. Hale B. G., Albrecht R. A., García-Sastre A. 2010; Innate immune evasion strategies of influenza viruses. Future Microbiol 5:23–41 [View Article][PubMed]
    [Google Scholar]
  51. Haller O., Kochs G. 2011; Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J Interferon Cytokine Res 31:79–87 [View Article][PubMed]
    [Google Scholar]
  52. Hatta M., Gao P., Halfmann P., Kawaoka Y. 2001; Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293:1840–1842 [View Article][PubMed]
    [Google Scholar]
  53. Hatta M., Hatta Y., Kim J. H., Watanabe S., Shinya K., Nguyen T., Lien P. S., Le Q. M., Kawaoka Y. 2007; Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathog 3:1374–1379 [View Article][PubMed]
    [Google Scholar]
  54. Hayman A., Comely S., Lackenby A., Hartgroves L. C. S., Goodbourn S., McCauley J. W., Barclay W. 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 [View Article][PubMed]
    [Google Scholar]
  55. Heaton N. S., Sachs D., Chen C. J., Hai R., Palese P. 2013; Genome-wide mutagenesis of influenza virus reveals unique plasticity of the hemagglutinin and NS1 proteins. Proc Natl Acad Sci U S A 110:20248–20253 [View Article][PubMed]
    [Google Scholar]
  56. Herfst S., Chutinimitkul S., Ye J., de Wit E., Munster V. J., Schrauwen E. J., Bestebroer T. M., Jonges M., Meijer A.other authors 2010; Introduction of virulence markers in PB2 of pandemic swine-origin influenza virus does not result in enhanced virulence or transmission. J Virol 84:3752–3758 [View Article][PubMed]
    [Google Scholar]
  57. Herfst S., Schrauwen E. J., Linster M., Chutinimitkul S., de Wit E., Munster V. J., Sorrell E. M., Bestebroer T. M., Burke D. F.other authors 2012; Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336:1534–1541 [View Article][PubMed]
    [Google Scholar]
  58. Hoffmann T. W., Munier S., Larcher T., Soubieux D., Ledevin M., Esnault E., Tourdes A., Croville G., Guérin J. L.other authors 2012; Length variations in the NA stalk of an H7N1 influenza virus have opposite effects on viral excretion in chickens and ducks. J Virol 86:584–588 [View Article][PubMed]
    [Google Scholar]
  59. Hossain M. J., Hickman D., Perez D. R. 2008; Evidence of expanded host range and mammalian-associated genetic changes in a duck H9N2 influenza virus following adaptation in quail and chickens. PLoS ONE 3:e3170 [View Article][PubMed]
    [Google Scholar]
  60. Huang T. S., Palese P., Krystal M. 1990; Determination of influenza virus proteins required for genome replication. J Virol 64:5669–5673[PubMed]
    [Google Scholar]
  61. Hudjetz B., Gabriel G. 2012; Human-like PB2 627K influenza virus polymerase activity is regulated by importin-α1 and -α7. PLoS Pathog 8:e1002488 [View Article][PubMed]
    [Google Scholar]
  62. Ilyushina N. A., Khalenkov A. M., Seiler J. P., Forrest H. L., Bovin N. V., Marjuki H., Barman S., Webster R. G., Webby R. J. 2010; Adaptation of pandemic H1N1 influenza viruses in mice. J Virol 84:8607–8616 [View Article][PubMed]
    [Google Scholar]
  63. Imai M., Watanabe T., Hatta M., Das S. C., Ozawa M., Shinya K., Zhong G., Hanson A., Katsura H.other authors 2012; Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486:420–428[PubMed]
    [Google Scholar]
  64. Iwai A., Shiozaki T., Kawai T., Akira S., Kawaoka Y., Takada A., Kida H., Miyazaki T. 2010; Influenza A virus polymerase inhibits type I interferon induction by binding to interferon β promoter stimulator 1. J Biol Chem 285:32064–32074 [View Article][PubMed]
    [Google Scholar]
  65. Jagger B. W., Memoli M. J., Sheng Z. M., Qi L., Hrabal R. J., Allen G. L., Dugan V. G., Wang R., Digard P.other authors 2010; The PB2-E627K mutation attenuates viruses containing the 2009 H1N1 influenza pandemic polymerase. MBio 1:e00067-10 [View Article][PubMed]
    [Google Scholar]
  66. Jagger B. W., Wise H. M., Kash J. C., Walters K. A., Wills N. M., Xiao Y. L., Dunfee R. L., Schwartzman L. M., Ozinsky A.other authors 2012; An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science 337:199–204 [View Article][PubMed]
    [Google Scholar]
  67. Jorba N., Coloma R., Ortín J. 2009; Genetic trans-complementation establishes a new model for influenza virus RNA transcription and replication. PLoS Pathog 5:e1000462 [View Article][PubMed]
    [Google Scholar]
  68. Karpala A. J., Stewart C., McKay J., Lowenthal J. W., Bean A. G. 2011; Characterization of chicken Mda5 activity: regulation of IFN-β in the absence of RIG-I functionality. J Immunol 186:5397–5405 [View Article][PubMed]
    [Google Scholar]
  69. Kesimer M., Scull M., Brighton B., DeMaria G., Burns K., O’Neal W., Pickles R. J., Sheehan J. K. 2009; Characterization of exosome-like vesicles released from human tracheobronchial ciliated epithelium: a possible role in innate defense. FASEB J 23:1858–1868 [View Article][PubMed]
    [Google Scholar]
  70. Knepper J., Schierhorn K. L., Becher A., Budt M., Tönnies M., Bauer T. T., Schneider P., Neudecker J., Rückert J. C.other authors 2013; The novel human influenza A(H7N9) virus is naturally adapted to efficient growth in human lung tissue. MBio 4:e00601-13 [View Article][PubMed]
    [Google Scholar]
  71. Ko J. H., Jin H. K., Asano A., Takada A., Ninomiya A., Kida H., Hokiyama H., Ohara M., Tsuzuki M.other authors 2002; Polymorphisms and the differential antiviral activity of the chicken Mx gene. Genome Res 12:595–601 [View Article][PubMed]
    [Google Scholar]
  72. Kobasa D., Kodihalli S., Luo M., Castrucci M. R., Donatelli I., Suzuki Y., Suzuki T., Kawaoka Y. 1999; Amino acid residues contributing to the substrate specificity of the influenza A virus neuraminidase. J Virol 73:6743–6751[PubMed]
    [Google Scholar]
  73. Kuzuhara T., Kise D., Yoshida H., Horita T., Murazaki Y., Nishimura A., Echigo N., Utsunomiya H., Tsuge H. 2009; Structural basis of the influenza A virus RNA polymerase PB2 RNA-binding domain containing the pathogenicity-determinant lysine 627 residue. J Biol Chem 284:6855–6860 [View Article][PubMed]
    [Google Scholar]
  74. Labadie K., Dos Santos Afonso E., Rameix-Welti M. A., van der Werf S., Naffakh N. 2007; Host-range determinants on the PB2 protein of influenza A viruses control the interaction between the viral polymerase and nucleoprotein in human cells. Virology 362:271–282 [View Article][PubMed]
    [Google Scholar]
  75. Lakdawala S. S., Lamirande E. W., Suguitan A. L. Jr, Wang W., Santos C. P., Vogel L., Matsuoka Y., Lindsley W. G., Jin H., Subbarao K. 2011; Eurasian-origin gene segments contribute to the transmissibility, aerosol release, and morphology of the 2009 pandemic H1N1 influenza virus. PLoS Pathog 7:e1002443 [View Article][PubMed]
    [Google Scholar]
  76. Li Z., Chen H., Jiao P., Deng G., Tian G., Li Y., Hoffmann E., Webster R. G., Matsuoka Y., Yu K. 2005; Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J Virol 79:12058–12064 [View Article][PubMed]
    [Google Scholar]
  77. Li J., Zu Dohna H., Cardona C. J., Miller J., Carpenter T. E. 2011; Emergence and genetic variation of neuraminidase stalk deletions in avian influenza viruses. PLoS ONE 6:e14722 [View Article][PubMed]
    [Google Scholar]
  78. Liniger M., Summerfield A., Zimmer G., McCullough K. C., Ruggli N. 2012; Chicken cells sense influenza A virus infection through MDA5 and CARDIF signaling involving LGP2. J Virol 86:705–717 [View Article][PubMed]
    [Google Scholar]
  79. Liu Q., Lu L., Sun Z., Chen G. W., Wen Y., Jiang S. 2013; Genomic signature and protein sequence analysis of a novel influenza A (H7N9) virus that causes an outbreak in humans in China. Microbes Infect 15:432–439 [View Article][PubMed]
    [Google Scholar]
  80. Long J. S., Howard W. A., Núñez A., Moncorgé O., Lycett S., Banks J., Barclay W. S. 2013; The effect of the PB2 mutation 627K on highly pathogenic H5N1 avian influenza virus is dependent on the virus lineage. J Virol 87:9983–9996 [View Article][PubMed]
    [Google Scholar]
  81. Maines T. R., Chen L. M., Van Hoeven N., Tumpey T. M., Blixt O., Belser J. A., Gustin K. M., Pearce M. B., Pappas C.other authors 2011; Effect of receptor binding domain mutations on receptor binding and transmissibility of avian influenza H5N1 viruses. Virology 413:139–147 [View Article][PubMed]
    [Google Scholar]
  82. Mänz B., Brunotte L., Reuther P., Schwemmle M. 2012; Adaptive mutations in NEP compensate for defective H5N1 RNA replication in cultured human cells. Nat Commun 3:802 [View Article][PubMed]
    [Google Scholar]
  83. Mänz B., Dornfeld D., Götz V., Zell R., Zimmermann P., Haller O., Kochs G., Schwemmle M. 2013; Pandemic influenza A viruses escape from restriction by human MxA through adaptive mutations in the nucleoprotein. PLoS Pathog 9:e1003279 [View Article][PubMed]
    [Google Scholar]
  84. Marazzi I., Ho J. S., Kim J., Manicassamy B., Dewell S., Albrecht R. A., Seibert C. W., Schaefer U., Jeffrey K. L.other authors 2012; Suppression of the antiviral response by an influenza histone mimic. Nature 483:428–433 [View Article][PubMed]
    [Google Scholar]
  85. Massin P., van der Werf S., Naffakh N. 2001; Residue 627 of PB2 is a determinant of cold sensitivity in RNA replication of avian influenza viruses. J Virol 75:5398–5404 [View Article][PubMed]
    [Google Scholar]
  86. Matrosovich M. N., Gambaryan A. S., Teneberg S., Piskarev V. E., Yamnikova S. S., Lvov D. K., Robertson J. S., Karlsson K. A. 1997; Avian influenza A viruses differ from human viruses by recognition of sialyloligosaccharides and gangliosides and by a higher conservation of the HA receptor-binding site. Virology 233:224–234 [View Article][PubMed]
    [Google Scholar]
  87. Matrosovich M., Zhou N., Kawaoka Y., Webster R. 1999; The surface glycoproteins of H5 influenza viruses isolated from humans, chickens, and wild aquatic birds have distinguishable properties. J Virol 73:1146–1155[PubMed]
    [Google Scholar]
  88. Mayer D., Molawi K., Martínez-Sobrido L., Ghanem A., Thomas S., Baginsky S., Grossmann J., García-Sastre A., Schwemmle M. 2007; Identification of cellular interaction partners of the influenza virus ribonucleoprotein complex and polymerase complex using proteomic-based approaches. J Proteome Res 6:672–682 [View Article][PubMed]
    [Google Scholar]
  89. Mehle A., Doudna J. A. 2008; An inhibitory activity in human cells restricts the function of an avian-like influenza virus polymerase. Cell Host Microbe 4:111–122 [View Article][PubMed]
    [Google Scholar]
  90. Mehle A., Doudna J. A. 2009; Adaptive strategies of the influenza virus polymerase for replication in humans. Proc Natl Acad Sci U S A 106:21312–21316 [View Article][PubMed]
    [Google Scholar]
  91. Mehle A., Dugan V. G., Taubenberger J. K., Doudna J. A. 2012; Reassortment and mutation of the avian influenza virus polymerase PA subunit overcome species barriers. J Virol 86:1750–1757 [View Article][PubMed]
    [Google Scholar]
  92. Mitnaul L. J., Matrosovich M. N., Castrucci M. R., Tuzikov A. B., Bovin N. V., Kobasa D., Kawaoka Y. 2000; Balanced hemagglutinin and neuraminidase activities are critical for efficient replication of influenza A virus. J Virol 74:6015–6020 [View Article][PubMed]
    [Google Scholar]
  93. Moeller A., Kirchdoerfer R. N., Potter C. S., Carragher B., Wilson I. A. 2012; Organization of the influenza virus replication machinery. Science 338:1631–1634 [View Article][PubMed]
    [Google Scholar]
  94. Moncorgé O., Mura M., Barclay W. S. 2010; Evidence for avian and human host cell factors that affect the activity of influenza virus polymerase. J Virol 84:9978–9986 [View Article][PubMed]
    [Google Scholar]
  95. Moncorgé O., Long J. S., Cauldwell A. V., Zhou H., Lycett S. J., Barclay W. S. 2013; Investigation of influenza virus polymerase activity in pig cells. J Virol 87:384–394 [View Article][PubMed]
    [Google Scholar]
  96. Mukherjee S., Majumdar S., Vipat V. C., Mishra A. C., Chakrabarti A. K. 2012; Non structural protein of avian influenza A (H11N1) virus is a weaker suppressor of immune responses but capable of inducing apoptosis in host cells. Virol J 9:149 [View Article][PubMed]
    [Google Scholar]
  97. Munier S., Larcher T., Cormier-Aline F., Soubieux D., Su B., Guigand L., Labrosse B., Cherel Y., Quéré P.other authors 2010; A genetically engineered waterfowl influenza virus with a deletion in the stalk of the neuraminidase has increased virulence for chickens. J Virol 84:940–952 [View Article][PubMed]
    [Google Scholar]
  98. Munir M., Zohari S., Metreveli G., Baule C., Belák S., Berg M. 2011; Alleles A and B of non-structural protein 1 of avian influenza A viruses differentially inhibit beta interferon production in human and mink lung cells. J Gen Virol 92:2111–2121 [View Article][PubMed]
    [Google Scholar]
  99. Naffakh N., Tomoiu A., Rameix-Welti M. A., van der Werf S. 2008; Host restriction of avian influenza viruses at the level of the ribonucleoproteins. Annu Rev Microbiol 62:403–424 [View Article][PubMed]
    [Google Scholar]
  100. Nakazono Y., Hara K., Kashiwagi T., Hamada N., Watanabe H. 2012; The RNA polymerase PB2 subunit of influenza A/HongKong/156/1997 (H5N1) restricts the replication of reassortant ribonucleoprotein complexes [corrected]. PLoS ONE 7:e32634 [View Article][PubMed]
    [Google Scholar]
  101. Nemeroff M. E., Barabino S. M., Li Y., Keller W., Krug R. 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 [View Article][PubMed]
    [Google Scholar]
  102. Neumann G., Hobom G. 1995; Mutational analysis of influenza virus promoter elements in vivo . J Gen Virol 76:1709–1717 [View Article][PubMed]
    [Google Scholar]
  103. Ng A. K., Chan W. H., Choi S. T., Lam M. K., Lau K. F., Chan P. K., Au S. W., Fodor E., Shaw P. C. 2012; Influenza polymerase activity correlates with the strength of interaction between nucleoprotein and PB2 through the host-specific residue K/E627. PLoS ONE 7:e36415 [View Article][PubMed]
    [Google Scholar]
  104. Noronha J. M., Liu M., Squires R. B., Pickett B. E., Hale B. G., Air G. M., Galloway S. E., Takimoto T., Schmolke M.other authors 2012; Influenza virus sequence feature variant type analysis: evidence of a role for NS1 in influenza virus host range restriction. J Virol 86:5857–5866 [View Article][PubMed]
    [Google Scholar]
  105. O’Neill R. E., Jaskunas R., Blobel G., Palese P., Moroianu J. 1995; Nuclear import of influenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import. J Biol Chem 270:22701–22704 [View Article][PubMed]
    [Google Scholar]
  106. Obenauer J. C., Denson J., Mehta P. K., Su X., Mukatira S., Finkelstein D. B., Xu X., Wang J., Ma J.other authors 2006; Large-scale sequence analysis of avian influenza isolates. Science 311:1576–1580 [View Article][PubMed]
    [Google Scholar]
  107. Paterson D., Te Velthuis A. J., Vreede F. T., Fodor E. 2013; Host-restriction of influenza virus polymerase activity by PB2 627E is diminished on short viral templates in an NP-independent manner. J Virol 88:339–344 [View Article][PubMed]
    [Google Scholar]
  108. Perez J. T., Varble A., Sachidanandam R., Zlatev I., Manoharan M., García-Sastre A., tenOever B. R. 2010; Influenza A virus-generated small RNAs regulate the switch from transcription to replication. Proc Natl Acad Sci U S A 107:11525–11530 [View Article][PubMed]
    [Google Scholar]
  109. Perez J. T., Zlatev I., Aggarwal S., Subramanian S., Sachidanandam R., Kim B., Manoharan M., tenOever B. R. 2012; A small-RNA enhancer of viral polymerase activity. J Virol 86:13475–13485 [View Article][PubMed]
    [Google Scholar]
  110. Pleschka S., Jaskunas R., Engelhardt O. G., Zürcher T., Palese P., García-Sastre A. 1996; A plasmid-based reverse genetics system for influenza A virus. J Virol 70:4188–4192[PubMed]
    [Google Scholar]
  111. Qi X., Pan Y., Qin Y., Zu R., Tang F., Zhou M., Wang H., Song Y. 2012; Molecular characterization of avian-like H1N1 swine influenza A viruses isolated in Eastern China, 2011. Virol Sin 27:292–298 [View Article][PubMed]
    [Google Scholar]
  112. Rajsbaum R., Albrecht R. A., Wang M. K., Maharaj N. P., Versteeg G. A., Nistal-Villán E., García-Sastre A., Gack M. U. 2012; Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein. PLoS Pathog 8:e1003059 [View Article][PubMed]
    [Google Scholar]
  113. Rameix-Welti M. A., Tomoiu A., Dos Santos Afonso E., van der Werf S., Naffakh N. 2009; Avian influenza A virus polymerase association with nucleoprotein, but not polymerase assembly, is impaired in human cells during the course of infection. J Virol 83:1320–1331 [View Article][PubMed]
    [Google Scholar]
  114. Resa-Infante P., Jorba N., Zamarreño N., Fernández Y., Juárez S., Ortín J. 2008; The host-dependent interaction of α-importins with influenza PB2 polymerase subunit is required for virus RNA replication. PLoS ONE 3:e3904 [View Article][PubMed]
    [Google Scholar]
  115. Robb N. C., Smith M., Vreede F. T., Fodor E. 2009; NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome. J Gen Virol 90:1398–1407 [View Article][PubMed]
    [Google Scholar]
  116. Roberts K. L., Shelton H., Scull M., Pickles R., Barclay W. S. 2011; Lack of transmission of a human influenza virus with avian receptor specificity between ferrets is not due to decreased virus shedding but rather a lower infectivity in vivo . J Gen Virol 92:1822–1831 [View Article][PubMed]
    [Google Scholar]
  117. Rogers G. N., Paulson J. C. 1983; Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin. Virology 127:361–373 [View Article][PubMed]
    [Google Scholar]
  118. Sakabe S., Ozawa M., Takano R., Iwastuki-Horimoto K., Kawaoka Y. 2011; Mutations in PA, NP, and HA of a pandemic (H1N1) 2009 influenza virus contribute to its adaptation to mice. Virus Res 158:124–129 [View Article][PubMed]
    [Google Scholar]
  119. Schmolke M., Manicassamy B., Pena L., Sutton T., Hai R., Varga Z. T., Hale B. G., Steel J., Pérez D. R., García-Sastre A. 2011; Differential contribution of PB1-F2 to the virulence of highly pathogenic H5N1 influenza A virus in mammalian and avian species. PLoS Pathog 7:e1002186 [View Article][PubMed]
    [Google Scholar]
  120. Scholtissek C., Koennecke I., Rott R. 1978a; Host range recombinants of fowl plague (influenza A) virus. Virology 91:79–85 [View Article][PubMed]
    [Google Scholar]
  121. Scholtissek C., Rohde W., Von Hoyningen V., Rott R. 1978b; On the origin of the human influenza virus subtypes H2N2 and H3N2. Virology 87:13–20 [View Article][PubMed]
    [Google Scholar]
  122. Scull M. A., Gillim-Ross L., Santos C., Roberts K. L., Bordonali E., Subbarao K., Barclay W. S., Pickles R. J. 2009; Avian influenza virus glycoproteins restrict virus replication and spread through human airway epithelium at temperatures of the proximal airways. PLoS Pathog 5:e1000424 [View Article][PubMed]
    [Google Scholar]
  123. Shelton H., Roberts K. L., Molesti E., Temperton N., Barclay W. S. 2013; Mutations in haemagglutinin that affect receptor binding and pH stability increase replication of a PR8 influenza virus with H5 HA in the upper respiratory tract of ferrets and may contribute to transmissibility. J Gen Virol 94:1220–1229 [View Article][PubMed]
    [Google Scholar]
  124. Shi M., Jagger B. W., Wise H. M., Digard P., Holmes E. C., Taubenberger J. K. 2012; Evolutionary conservation of the PA-X open reading frame in segment 3 of influenza A virus. J Virol 86:12411–12413 [View Article][PubMed]
    [Google Scholar]
  125. Shinya K., Hamm S., Hatta M., Ito H., Ito T., Kawaoka Y. 2004; PB2 amino acid at position 627 affects replicative efficiency, but not cell tropism, of Hong Kong H5N1 influenza A viruses in mice. Virology 320:258–266 [View Article][PubMed]
    [Google Scholar]
  126. Shinya K., Ebina M., Yamada S., Ono M., Kasai N., Kawaoka Y. 2006; Avian flu: influenza virus receptors in the human airway. Nature 440:435–436 [View Article][PubMed]
    [Google Scholar]
  127. Sironi L., Williams J. L., Moreno-Martin A. M., Ramelli P., Stella A., Jianlin H., Weigend S., Lombardi G., Cordioli P., Mariani P. 2008; Susceptibility of different chicken lines to H7N1 highly pathogenic avian influenza virus and the role of Mx gene polymorphism coding amino acid position 631. Virology 380:152–156 [View Article][PubMed]
    [Google Scholar]
  128. Song M. S., Pascua P. N., Lee J. H., Baek Y. H., Lee O. J., Kim C. J., Kim H., Webby R. J., Webster R. G., Choi Y. K. 2009; The polymerase acidic protein gene of influenza A virus contributes to pathogenicity in a mouse model. J Virol 83:12325–12335 [View Article][PubMed]
    [Google Scholar]
  129. Sorrell E. M., Perez D. R. 2007; Adaptation of influenza A/Mallard/Potsdam/178-4/83 H2N2 virus in Japanese quail leads to infection and transmission in chickens. Avian Dis 51:Suppl264–268 [View Article][PubMed]
    [Google Scholar]
  130. Sorrell E. M., Wan H., Araya Y., Song H., Perez D. R. 2009; Minimal molecular constraints for respiratory droplet transmission of an avian–human H9N2 influenza A virus. Proc Natl Acad Sci U S A 106:7565–7570 [View Article][PubMed]
    [Google Scholar]
  131. Soundararajan V., Tharakaraman K., Raman R., Raguram S., Shriver Z., Sasisekharan V., Sasisekharan R. 2009; Extrapolating from sequence – the 2009 H1N1 ‘swine’ influenza virus. Nat Biotechnol 27:510–513 [View Article][PubMed]
    [Google Scholar]
  132. Steel J., Lowen A. C., Mubareka S., Palese P. 2009; Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog 5:e1000252 [View Article][PubMed]
    [Google Scholar]
  133. Steensels M., Van Borm S., Lambrecht B., De Vriese J., Le Gros F. X., Bublot M., van den Berg T. 2007; Efficacy of an inactivated and a fowlpox-vectored vaccine in Muscovy ducks against an Asian H5N1 highly pathogenic avian influenza viral challenge. Avian Dis 51:Suppl325–331 [View Article][PubMed]
    [Google Scholar]
  134. Subbarao E. K., London W., Murphy B. R. 1993; A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol 67:1761–1764[PubMed]
    [Google Scholar]
  135. Suzuki Y. 1994; Gangliosides as influenza virus receptors. Variation of influenza viruses and their recognition of the receptor sialo-sugar chains. Prog Lipid Res 33:429–457 [View Article][PubMed]
    [Google Scholar]
  136. Tamuri A. U., Dos Reis M., Hay A. J., Goldstein R. A. 2009; Identifying changes in selective constraints: host shifts in influenza. PLOS Comput Biol 5:e1000564 [View Article][PubMed]
    [Google Scholar]
  137. Tarendeau F., Boudet J., Guilligay D., Mas P. J., Bougault C. M., Boulo S., Baudin F., Ruigrok R. W., Daigle N.other authors 2007; Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit. Nat Struct Mol Biol 14:229–233 [View Article][PubMed]
    [Google Scholar]
  138. Tarendeau F., Crepin T., Guilligay D., Ruigrok R. W., Cusack S., Hart D. J. 2008; Host determinant residue lysine 627 lies on the surface of a discrete, folded domain of influenza virus polymerase PB2 subunit. PLoS Pathog 4:e1000136 [View Article][PubMed]
    [Google Scholar]
  139. Taubenberger J. K., Reid A. H., Lourens R. M., Wang R., Jin G., Fanning T. G. 2005; Characterization of the 1918 influenza virus polymerase genes. Nature 437:889–893 [View Article][PubMed]
    [Google Scholar]
  140. Tharakaraman K., Raman R., Viswanathan K., Stebbins N. W., Jayaraman A., Krishnan A., Sasisekharan V., Sasisekharan R. 2013; Structural determinants for naturally evolving H5N1 hemagglutinin to switch its receptor specificity. Cell 153:1475–1485 [View Article][PubMed]
    [Google Scholar]
  141. Thompson C. I., Barclay W. S., Zambon M. C., Pickles R. J. 2006; Infection of human airway epithelium by human and avian strains of influenza a virus. J Virol 80:8060–8068 [View Article][PubMed]
    [Google Scholar]
  142. Tian S. F., Buckler-White A. J., London W. T., Reck L. J., Chanock R. M., Murphy B. R. 1985; Nucleoprotein and membrane protein genes are associated with restriction of replication of influenza A/Mallard/NY/78 virus and its reassortants in squirrel monkey respiratory tract. J Virol 53:771–775[PubMed]
    [Google Scholar]
  143. Tiley L. S., Hagen M., Matthews J. T., Krystal M. 1994; Sequence-specific binding of the influenza virus RNA polymerase to sequences located at the 5′ ends of the viral RNAs. J Virol 68:5108–5116[PubMed]
    [Google Scholar]
  144. Tong S., Li Y., Rivailler P., Conrardy C., Castillo D. A., Chen L. M., Recuenco S., Ellison J. A., Davis C. T.other authors 2012; A distinct lineage of influenza A virus from bats. Proc Natl Acad Sci U S A 109:4269–4274 [View Article][PubMed]
    [Google Scholar]
  145. Tong S., Zhu X., Li Y., Shi M., Zhang J., Bourgeois M., Yang H., Chen X., Recuenco S.other authors 2013; New World bats harbor diverse influenza A viruses. PLoS Pathog 9:e1003657 [View Article][PubMed]
    [Google Scholar]
  146. Twu K. Y., Kuo R. L., Marklund J., Krug R. M. 2007; The H5N1 influenza virus NS genes selected after 1998 enhance virus replication in mammalian cells. J Virol 81:8112–8121 [View Article][PubMed]
    [Google Scholar]
  147. Umbach J. L., Yen H. L., Poon L. L., Cullen B. R. 2010; Influenza A virus expresses high levels of an unusual class of small viral leader RNAs in infected cells. MBio 1:e00204-10 [View Article][PubMed]
    [Google Scholar]
  148. Van Reeth K. 2007; Avian and swine influenza viruses: our current understanding of the zoonotic risk. Vet Res 38:243–260 [View Article][PubMed]
    [Google Scholar]
  149. van Riel D., Munster V. J., de Wit E., Rimmelzwaan G. F., Fouchier R. A., Osterhaus A. D., Kuiken T. 2006; H5N1 virus attachment to lower respiratory tract. Science 312:399 [View Article][PubMed]
    [Google Scholar]
  150. van Riel D., den Bakker M. A., Leijten L. M., Chutinimitkul S., Munster V. J., de Wit E., Rimmelzwaan G. F., Fouchier R. A., Osterhaus A. D., Kuiken T. 2010; Seasonal and pandemic human influenza viruses attach better to human upper respiratory tract epithelium than avian influenza viruses. Am J Pathol 176:1614–1618 [View Article][PubMed]
    [Google Scholar]
  151. Varga Z. T., Ramos I., Hai R., Schmolke M., García-Sastre A., Fernandez-Sesma A., Palese P. 2011; The influenza virus protein PB1-F2 inhibits the induction of type I interferon at the level of the MAVS adaptor protein. PLoS Pathog 7:e1002067 [View Article][PubMed]
    [Google Scholar]
  152. Varga Z. T., Grant A., Manicassamy B., Palese P. 2012; Influenza virus protein PB1-F2 inhibits the induction of type I interferon by binding to MAVS and decreasing mitochondrial membrane potential. J Virol 86:8359–8366 [View Article][PubMed]
    [Google Scholar]
  153. Viswanathan K., Koh X., Chandrasekaran A., Pappas C., Raman R., Srinivasan A., Shriver Z., Tumpey T. M., Sasisekharan R. 2010; Determinants of glycan receptor specificity of H2N2 influenza A virus hemagglutinin. PLoS ONE 5:e13768 [View Article][PubMed]
    [Google Scholar]
  154. Vreede F. T., Jung T. E., Brownlee G. G. 2004; Model suggesting that replication of influenza virus is regulated by stabilization of replicative intermediates. J Virol 78:9568–9572 [View Article][PubMed]
    [Google Scholar]
  155. Wagner R., Matrosovich M., Klenk H. D. 2002; Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev Med Virol 12:159–166 [View Article][PubMed]
    [Google Scholar]
  156. Xiao H., Killip M. J., Staeheli P., Randall R. E., Jackson D. 2013; The human interferon-induced MxA protein inhibits early stages of influenza A virus infection by retaining the incoming viral genome in the cytoplasm. J Virol 87:13053–13058 [View Article][PubMed]
    [Google Scholar]
  157. Xiong X., Coombs P. J., Martin S. R., Liu J., Xiao H., McCauley J. W., Locher K., Walker P. A., Collins P. J.other authors 2013; Receptor binding by a ferret-transmissible H5 avian influenza virus. Nature 497:392–396 [View Article][PubMed]
    [Google Scholar]
  158. Xu R., Zhu X., McBride R., Nycholat C. M., Yu W., Paulson J. C., Wilson I. A. 2012; Functional balance of the hemagglutinin and neuraminidase activities accompanies the emergence of the 2009 H1N1 influenza pandemic. J Virol 86:9221–9232 [View Article][PubMed]
    [Google Scholar]
  159. Yamada S., Suzuki Y., Suzuki T., Le M. Q., Nidom C. A., Sakai-Tagawa Y., Muramoto Y., Ito M., Kiso M.other authors 2006; Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature 444:378–382 [View Article][PubMed]
    [Google Scholar]
  160. Yamada S., Hatta M., Staker B. L., Watanabe S., Imai M., Shinya K., Sakai-Tagawa Y., Ito M., Ozawa M.other authors 2010; Biological and structural characterization of a host-adapting amino acid in influenza virus. PLoS Pathog 6:e1001034 [View Article][PubMed]
    [Google Scholar]
  161. Yen H. L., Liang C. H., Wu C. Y., Forrest H. L., Ferguson A., Choy K. T., Jones J., Wong D. D., Cheung P. P.other authors 2011; Hemagglutinin-neuraminidase balance confers respiratory-droplet transmissibility of the pandemic H1N1 influenza virus in ferrets. Proc Natl Acad Sci U S A 108:14264–14269 [View Article][PubMed]
    [Google Scholar]
  162. York A., Hengrung N., Vreede F. T., Huiskonen J. T., Fodor E. 2013; Isolation and characterization of the positive-sense replicative intermediate of a negative-strand RNA virus. Proc Natl Acad Sci U S A 110:E4238–E4245 [View Article][PubMed]
    [Google Scholar]
  163. Zell R., Krumbholz A., Eitner A., Krieg R., Halbhuber K. J., Wutzler P. 2007; Prevalence of PB1-F2 of influenza A viruses. J Gen Virol 88:536–546 [View Article][PubMed]
    [Google Scholar]
  164. Zhang Y., Zhang Q., Gao Y., He X., Kong H., Jiang Y., Guan Y., Xia X., Shu Y.other authors 2012; Key molecular factors in hemagglutinin and PB2 contribute to efficient transmission of the 2009 H1N1 pandemic influenza virus. J Virol 86:9666–9674 [View Article][PubMed]
    [Google Scholar]
  165. Zhou B., Li Y., Halpin R., Hine E., Spiro D. J., Wentworth D. E. 2011; PB2 residue 158 is a pathogenic determinant of pandemic H1N1 and H5 influenza A viruses in mice. J Virol 85:357–365 [View Article][PubMed]
    [Google Scholar]
  166. Zhou B., Pearce M. B., Li Y., Wang J., Mason R. J., Tumpey T. M., Wentworth D. E. 2013; Asparagine substitution at PB2 residue 701 enhances the replication, pathogenicity, and transmission of the 2009 pandemic H1N1 influenza A virus. PLoS ONE 8:e67616 [View Article][PubMed]
    [Google Scholar]
  167. Zhu H., Wang J., Wang P., Song W., Zheng Z., Chen R., Guo K., Zhang T., Peiris J. S.other authors 2010; Substitution of lysine at 627 position in PB2 protein does not change virulence of the 2009 pandemic H1N1 virus in mice. Virology 401:1–5 [View Article][PubMed]
    [Google Scholar]
  168. Zhu W., Zhu Y., Qin K., Yu Z., Gao R., Yu H., Zhou J., Shu Y. 2012; Mutations in polymerase genes enhanced the virulence of 2009 pandemic H1N1 influenza virus in mice. PLoS ONE 7:e33383 [View Article][PubMed]
    [Google Scholar]
  169. Zimmermann P., Mänz B., Haller O., Schwemmle M., Kochs G. 2011; The viral nucleoprotein determines Mx sensitivity of influenza A viruses. J Virol 85:8133–8140 [View Article][PubMed]
    [Google Scholar]
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