1887

Abstract

The H5N1 influenza A viruses have circulated widely in the avian population for 10 years with only sporadic infection of humans observed and no sustained human to human transmission. Vaccination against potential pandemic strains is one strategy in planning for future influenza pandemics; however, the success of live attenuated vaccines for H5N1 has been limited, due to poor replication in the human upper respiratory tract (URT). Mutations that increase the ability of H5N1 viruses to replicate in the URT will aid immunogenicity of these vaccines and provide information about humanizing adaptations in H5N1 strains that may signal transmissibility. As well as mediating receptor interactions, the haemagglutinin (HA) protein of influenza facilitates fusion of the viral membrane and genome entry into the host cell; this process is pH dependent. We have shown in this study that the pH at which a panel of avian influenza HA proteins, including H5, mediate fusion is higher than that for human influenza HA proteins, and that mutations in the H5 HA can reduce the pH of fusion. Coupled with receptor switching mutations, increasing the pH stability of the H5 HA resulted in increased viral shedding of H5N1 from the nasal cavity of ferrets and contact transmission to a co-housed animal. Ferret serum antibodies induced by infection with any of the mutated H5 HA viruses neutralized HA pseudotyped lentiviruses bearing homologous or heterologous H5 HAs, suggesting that this strategy to increase nasal replication of a vaccine virus would not compromise vaccine efficacy.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.050526-0
2013-06-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/94/6/1220.html?itemId=/content/journal/jgv/10.1099/vir.0.050526-0&mimeType=html&fmt=ahah

References

  1. Aditama T. Y., Samaan G., Kusriastuti R., Sampurno O. D., Purba W., Misriyah, Santoso H., Bratasena A., Maruf A.other authors 2012; Avian influenza H5N1 transmission in households, Indonesia. PLoS ONE 7:e29971 [View Article][PubMed]
    [Google Scholar]
  2. Alberini I., Del Tordello E., Fasolo A., Temperton N. J., Galli G., Gentile C., Montomoli E., Hilbert A. K., Banzhoff A.other authors 2009; Pseudoparticle neutralization is a reliable assay to measure immunity and cross-reactivity to H5N1 influenza viruses. Vaccine 27:5998–6003 [View Article][PubMed]
    [Google Scholar]
  3. Auewarakul P., Suptawiwat O., Kongchanagul A., Sangma C., Suzuki Y., Ungchusak K., Louisirirotchanakul S., Lerdsamran H., Pooruk P.other authors 2007; An avian influenza H5N1 virus that binds to a human-type receptor. J Virol 81:9950–9955 [View Article][PubMed]
    [Google Scholar]
  4. Ayora-Talavera G., Shelton H., Scull M. A., Ren J., Jones I. M., Pickles R. J., Barclay W. S. 2009; Mutations in H5N1 influenza virus hemagglutinin that confer binding to human tracheal airway epithelium. PLoS ONE 4:e7836 [View Article][PubMed]
    [Google Scholar]
  5. Bender C., Hall H., Huang J., Klimov A., Cox N., Hay A., Gregory V., Cameron K., Lim W., Subbarao K. 1999; Characterization of the surface proteins of influenza A (H5N1) viruses isolated from humans in 1997-1998. Virology 254:115–123 [View Article][PubMed]
    [Google Scholar]
  6. Beyer W. E. P., Ruigrok R. W. H., van Driel H., Masurel N. 1986; Influenza virus strains with a fusion threshold of pH 5.5 or lower are inhibited by amantadine. Arch Virol 90:173–181 [View Article][PubMed]
    [Google Scholar]
  7. Carrat F., Luong J., Lao H., Sallé A. V., Lajaunie C., Wackernagel H. 2006; A ‘small-world-like’ model for comparing interventions aimed at preventing and controlling influenza pandemics. BMC Med 4:26 [View Article][PubMed]
    [Google Scholar]
  8. Cauchemez S., Bhattarai A., Marchbanks T. L., Fagan R. P., Ostroff S., Ferguson N. M., Swerdlow D., Sodha S. V., Moll M. E.other authors 2011; Role of social networks in shaping disease transmission during a community outbreak of 2009 H1N1 pandemic influenza. Proc Natl Acad Sci U S A 108:2825–2830 [View Article][PubMed]
    [Google Scholar]
  9. Chen L. M., Blixt O., Stevens J., Lipatov A. S., Davis C. T., Collins B. E., Cox N. J., Paulson J. C., Donis R. O. 2012a; In vitro evolution of H5N1 avian influenza virus toward human-type receptor specificity. Virology 422:105–113 [View Article][PubMed]
    [Google Scholar]
  10. Chen Z., Zhou H., Kim L., Jin H. 2012b; The receptor binding specificity of the live attenuated influenza H2 and H6 vaccine viruses contributes to vaccine immunogenicity and protection in ferrets. J Virol 86:2780–2786 [View Article][PubMed]
    [Google Scholar]
  11. Chutinimitkul S., van Riel D., Munster V. J., van den Brand J. M., Rimmelzwaan G. F., Kuiken T., Osterhaus A. D., Fouchier R. A., de Wit E. 2010; In vitro assessment of attachment pattern and replication efficiency of H5N1 influenza A viruses with altered receptor specificity. J Virol 84:6825–6833 [View Article][PubMed]
    [Google Scholar]
  12. Couch R. B., Keitel W. A., Cate T. R. 1997; Improvement of inactivated influenza virus vaccines. J Infect Dis 176:Suppl. 1S38–S44 [View Article][PubMed]
    [Google Scholar]
  13. DuBois R. M., Zaraket H., Reddivari M., Heath R. J., White S. W., Russell C. J. 2011; Acid stability of the hemagglutinin protein regulates H5N1 influenza virus pathogenicity. PLoS Pathog 7:e1002398 [View Article][PubMed]
    [Google Scholar]
  14. Elleman C. J., Barclay W. S. 2004; The M1 matrix protein controls the filamentous phenotype of influenza A virus. Virology 321:144–153 [View Article][PubMed]
    [Google Scholar]
  15. England R. J., Homer J. J., Knight L. C., Ell S. R. 1999; Nasal pH measurement: a reliable and repeatable parameter. Clin Otolaryngol Allied Sci 24:67–68 [View Article][PubMed]
    [Google Scholar]
  16. Gambaryan A., Tuzikov A., Pazynina G., Bovin N., Balish A., Klimov A. 2006; Evolution of the receptor binding phenotype of influenza A (H5) viruses. Virology 344:432–438 [View Article][PubMed]
    [Google Scholar]
  17. 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]
  18. Giannecchini S., Campitelli L., Calzoletti L., De Marco M. A., Azzi A., Donatelli I. 2006; Comparison of in vitro replication features of H7N3 influenza viruses from wild ducks and turkeys: potential implications for interspecies transmission. J Gen Virol 87:171–175 [View Article][PubMed]
    [Google Scholar]
  19. Harvey R., Martin A. C., Zambon M., Barclay W. S. 2004; Restrictions to the adaptation of influenza A virus H5 hemagglutinin to the human host. J Virol 78:502–507 [View Article][PubMed]
    [Google Scholar]
  20. 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]
  21. 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]
  22. Horimoto T., Kawaoka Y. 2009; Designing vaccines for pandemic influenza. Curr Top Microbiol Immunol 333:165–176 [View Article][PubMed]
    [Google Scholar]
  23. 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]
  24. Karron R. A., Talaat K., Luke C., Callahan K., Thumar B., Dilorenzo S., McAuliffe J., Schappell E., Suguitan A.other authors 2009; Evaluation of two live attenuated cold-adapted H5N1 influenza virus vaccines in healthy adults. Vaccine 27:4953–4960 [View Article][PubMed]
    [Google Scholar]
  25. Krenn B. M., Egorov A., Romanovskaya-Romanko E., Wolschek M., Nakowitsch S., Ruthsatz T., Kiefmann B., Morokutti A., Humer J.other authors 2011; Single HA2 mutation increases the infectivity and immunogenicity of a live attenuated H5N1 intranasal influenza vaccine candidate lacking NS1. PLoS ONE 6:e18577 [View Article][PubMed]
    [Google Scholar]
  26. Lakdawala S. S., Subbarao K. 2012; The ongoing battle against influenza: the challenge of flu transmission. Nat Med 18:1468–1470 [View Article][PubMed]
    [Google Scholar]
  27. 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]
  28. Lin Y. P., Wharton S. A., Martín J., Skehel J. J., Wiley D. C., Steinhauer D. A. 1997; Adaptation of egg-grown and transfectant influenza viruses for growth in mammalian cells: selection of hemagglutinin mutants with elevated pH of membrane fusion. Virology 233:402–410 [View Article][PubMed]
    [Google Scholar]
  29. Loeb M., Russell M. L., Moss L., Fonseca K., Fox J., Earn D. J., Aoki F., Horsman G., Van Caeseele P.other authors 2010; Effect of influenza vaccination of children on infection rates in Hutterite communities: a randomized trial. JAMA (J Am Med Assoc) 303:943–950 [View Article][PubMed]
    [Google Scholar]
  30. 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]
  31. Mok K. P., Wong C. H., Cheung C. Y., Chan M. C., Lee S. M., Nicholls J. M., Guan Y., Peiris J. S. 2009; Viral genetic determinants of H5N1 influenza viruses that contribute to cytokine dysregulation. J Infect Dis 200:1104–1112 [View Article][PubMed]
    [Google Scholar]
  32. Neumann G., Kawaoka Y. 1999; Genetic engineering of influenza and other negative-strand RNA viruses containing segmented genomes. Adv Virus Res 53:265–300 [View Article][PubMed]
    [Google Scholar]
  33. Reed M. L., Yen H. L., DuBois R. M., Bridges O. A., Salomon R., Webster R. G., Russell C. J. 2009; Amino acid residues in the fusion peptide pocket regulate the pH of activation of the H5N1 influenza virus hemagglutinin protein. J Virol 83:3568–3580 [View Article][PubMed]
    [Google Scholar]
  34. Reed M. L., Bridges O. A., Seiler P., Kim J. K., Yen H. L., Salomon R., Govorkova E. A., Webster R. G., Russell C. J. 2010; The pH of activation of the hemagglutinin protein regulates H5N1 influenza virus pathogenicity and transmissibility in ducks. J Virol 84:1527–1535 [View Article][PubMed]
    [Google Scholar]
  35. 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]
  36. Skehel J. J., Wiley D. C. 2000; Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69:531–569 [View Article][PubMed]
    [Google Scholar]
  37. Stevens J., Corper A. L., Basler C. F., Taubenberger J. K., Palese P., Wilson I. A. 2004; Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science 303:1866–1870 [View Article][PubMed]
    [Google Scholar]
  38. Stevens J., Blixt O., Tumpey T. M., Taubenberger J. K., Paulson J. C., Wilson I. A. 2006; Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312:404–410 [View Article][PubMed]
    [Google Scholar]
  39. Su Y., Yang H. Y., Zhang B. J., Jia H. L., Tien P. 2008; Analysis of a point mutation in H5N1 avian influenza virus hemagglutinin in relation to virus entry into live mammalian cells. Arch Virol 153:2253–2261 [View Article][PubMed]
    [Google Scholar]
  40. Subbarao K., Murphy B. R., Fauci A. S. 2006; Development of effective vaccines against pandemic influenza. Immunity 24:5–9 [View Article][PubMed]
    [Google Scholar]
  41. Temperton N. J., Hoschler K., Major D., Nicolson C., Manvell R., Hien V. M., Ha D. Q., de Jong M., Zambon M.other authors 2007; A sensitive retroviral pseudotype assay for influenza H5N1-neutralizing antibodies. Influenza Other Respi Viruses 1:105–112 [View Article][PubMed]
    [Google Scholar]
  42. Ungchusak K., Auewarakul P., Dowell S. F., Kitphati R., Auwanit W., Puthavathana P., Uiprasertkul M., Boonnak K., Pittayawonganon C.other authors 2005; Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med 352:333–340 [View Article][PubMed]
    [Google Scholar]
  43. Wang H., Feng Z., Shu Y., Yu H., Zhou L., Zu R., Huai Y., Dong J., Bao C.other authors 2008; Probable limited person-to-person transmission of highly pathogenic avian influenza A (H5N1) virus in China. Lancet 371:1427–1434 [View Article][PubMed]
    [Google Scholar]
  44. Wang W., Lu B., Zhou H., Suguitan A. L. Jr, Cheng X., Subbarao K., Kemble G., Jin H. 2010; Glycosylation at 158N of the hemagglutinin protein and receptor binding specificity synergistically affect the antigenicity and immunogenicity of a live attenuated H5N1 A/Vietnam/1203/2004 vaccine virus in ferrets. J Virol 84:6570–6577 [View Article][PubMed]
    [Google Scholar]
  45. Washington N., Steele R. J., Jackson S. J., Bush D., Mason J., Gill D. A., Pitt K., Rawlins D. A. 2000; Determination of baseline human nasal pH and the effect of intranasally administered buffers. Int J Pharm 198:139–146 [View Article][PubMed]
    [Google Scholar]
  46. Watanabe Y., Ibrahim M. S., Ellakany H. F., Kawashita N., Mizuike R., Hiramatsu H., Sriwilaijaroen N., Takagi T., Suzuki Y., Ikuta K. 2011; Acquisition of human-type receptor binding specificity by new H5N1 influenza virus sublineages during their emergence in birds in Egypt. PLoS Pathog 7:e1002068 [View Article][PubMed]
    [Google Scholar]
  47. WHO (2012a Antigenic and Genetic Characteristics of Zoonotic Influenza Viruses and the Development of Candidate Vaccines for Pandemic Prepardness. Geneva: World Health Organization
  48. WHO (2012b Cumulative Number of Confirmed Human Cases for Avian Influenza A (H5N1) Reported to WHO, 2003–2012. Geneva: World Health Organization
  49. 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]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.050526-0
Loading
/content/journal/jgv/10.1099/vir.0.050526-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error