1887

Abstract

The continual threat posed by newly emerging influenza virus strains is demonstrated by the recent outbreak of H5N1 influenza virus in Hong Kong. Currently, immunization against influenza virus infection is fairly adequate, but it is imperative that improved vaccines are developed that can protect against a variety of strains and be generated rapidly. Since humoral immunity is ineffective against serologically distinct viruses, one strategy would be to develop vaccines that emphasize cellular immunity. Here we report the successful protection of C57BL/6 mice from a lethal A/HK/156/97 (HK156) infection by immunizing first with an H9N2 isolate, A/Quail/HK/G1/97 (QHKG1), that harbours internal genes 98% homologous to HK156. This strategy also protected mice that are deficient in antibody production, indicating that the immunity is T-cell-mediated. In the course of these studies, we generated a highly pathogenic H5N1 reassortant which implicated NP and PB2 as having an important contribution to pathogenesis when present with a highly cleavable H5. These results provide the first demonstration that protective cell-mediated immunity can be established against the highly virulent HK156 virus and have important implications for the development of novel strategies for the prevention and treatment of HK156 infection and the design of future influenza vaccines.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-81-11-2689
2000-11-01
2019-11-16
Loading full text...

Full text loading...

/deliver/fulltext/jgv/81/11/0812689a.html?itemId=/content/journal/jgv/10.1099/0022-1317-81-11-2689&mimeType=html&fmt=ahah

References

  1. Ada, G. L. & Jones, P. D. ( 1986; ). The immune response to influenza infection. Current Topics in Microbiology and Immunology 128, 1-54.
    [Google Scholar]
  2. Allan, W., Tabi, Z., Cleary, A. & Doherty, P. C. ( 1990; ). Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells. Journal of Immunology 144, 3980-3986.
    [Google Scholar]
  3. Anker, W. J., Bakker, A. K. & Masurel, N. ( 1978; ). Cross-protection in mice after immunization with H2N2, H3N2, and Heq2Neq2 influenza virus strains. Infection and Immunity 21, 96-101.
    [Google Scholar]
  4. Belshe, R. B. ( 1998; ). Influenza as a zoonosis: how likely is a pandemic? [comment]. Lancet 351, 460-461.[CrossRef]
    [Google Scholar]
  5. CDC ( 1998; ). Update: isolation of avian influenza A (H5N1) viruses from humans–Hong Kong, 1997–1998. Morbidity and Mortality Weekly Reports 46, 1245–1247.
    [Google Scholar]
  6. Claas, E. C., de Jong, J. C., van Beek, R., Rimmelzwaan, G. F. & Osterhaus, A. D. ( 1998a; ). Human influenza virus A/HongKong/156/97 (H5N1) infection. Vaccine 16, 977-978.[CrossRef]
    [Google Scholar]
  7. Claas, E. C., Osterhaus, A. D., van Beek, R., De Jong, J. C., Rimmelzwaan, G. F., Senne, D. A., Krauss, S., Shortridge, K. F. & Webster, R. G. (1998b). Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus [see comments]. Lancet 351, 472–477. [Erratum 351, 1292.].
  8. Cole, G. A., Hogg, T. L., Coppola, M. A. & Woodland, D. L. ( 1997; ). Efficient priming of CD8+ memory T cells specific for a subdominant epitope following Sendai virus infection. Journal of Immunology 158, 4301-4309.
    [Google Scholar]
  9. Couch, R. B. & Kasel, J. A. ( 1983; ). Immunity to influenza in man. Annual Review of Microbiology 37, 529-549.[CrossRef]
    [Google Scholar]
  10. Doherty, P. C., Allan, W., Eichelberger, M. & Carding, S. R. ( 1992; ). Roles of alpha beta and gamma delta T cell subsets in viral immunity. Annual Review of Immunology 10, 123-151.[CrossRef]
    [Google Scholar]
  11. Eichelberger, M., Allan, W., Zijlstra, M., Jaenisch, R. & Doherty, P. C. ( 1991; ). Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. Journal of Experimental Medicine 174, 875-880.[CrossRef]
    [Google Scholar]
  12. Epstein, S. L., Lo, C. Y., Misplon, J. A. & Bennink, J. R. ( 1998; ). Mechanism of protective immunity against influenza virus infection in mice without antibodies. Journal of Immunology 160, 322-327.
    [Google Scholar]
  13. Epstein, S. L., Stack, A., Misplon, J. A., Lo, C. Y., Mostowski, H., Bennink, J. & Subbarao, K. ( 2000; ). Vaccination with DNA encoding internal proteins of influenza virus does not require CD8+ cytotoxic T lymphocytes: either CD4+ or CD8+ T cells can promote survival and recovery after challenge. International Immunology 12, 91-101.[CrossRef]
    [Google Scholar]
  14. Flynn, K. J., Belz, G. T., Altman, J. D., Ahmed, R., Woodland, D. L. & Doherty, P. C. ( 1998; ). Virus-specific CD8+ T cells in primary and secondary influenza pneumonia. Immunity 8, 683-691.[CrossRef]
    [Google Scholar]
  15. Gao, P., Watanabe, S., Ito, T., Goto, H., Wells, K., McGregor, M., Cooley, A. J. & Kawaoka, Y. ( 1999; ). Biological heterogeneity, including systemic replication in mice, of H5N1 influenza A virus isolates from humans in Hong Kong. Journal of Virology 73, 3184-3189.
    [Google Scholar]
  16. Gorman, O. T., Bean, W. J. & Webster, R. G. ( 1992; ). Evolutionary processes in influenza viruses: divergence, rapid evolution, and stasis. Current Topics in Microbiology and Immunology 176, 75-97.
    [Google Scholar]
  17. Graham, M. B. & Braciale, T. J. ( 1997; ). Resistance to and recovery from lethal influenza virus infection in B lymphocyte-deficient mice. Journal of Experimental Medicine 186, 2063-2068.[CrossRef]
    [Google Scholar]
  18. Guan, Y., Shortridge, K. F., Krauss, S. & Webster, R. G. ( 1999; ). Molecular characterization of H9N2 influenza viruses: were they the donors of the ‘internal’ genes of H5N1 viruses in Hong Kong? Proceedings of the National Academy of Sciences, USA 96, 9363-9367.[CrossRef]
    [Google Scholar]
  19. Gubareva, L. V., McCullers, J. A., Bethell, R. C. & Webster, R. G. ( 1998; ). Characterization of influenza A/HongKong/156/97 (H5N1) virus in a mouse model and protective effect of zanamivir on H5N1 infection in mice. Journal of Infectious Diseases 178, 1592-1596.[CrossRef]
    [Google Scholar]
  20. Hou, S. & Doherty, P. C. ( 1995; ). Clearance of Sendai virus by CD8+ T cells requires direct targeting to virus-infected epithelium. European Journal of Immunology 25, 111-116.[CrossRef]
    [Google Scholar]
  21. Jameson, J., Cruz, J., Terajima, M. & Ennis, F. A. ( 1999; ). Human CD8+ and CD4+ T lymphocyte memory to influenza A viruses of swine and avian species. Journal of Immunology 162, 7578-7583.
    [Google Scholar]
  22. Kagi, D. & Hengartner, H. ( 1996; ). Different roles for cytotoxic T cells in the control of infections with cytopathic versus noncytopathic viruses. Current Opinion in Immunology 8, 472-477.[CrossRef]
    [Google Scholar]
  23. Kitamura, D., Roes, J., Kuhn, R. & Rajewsky, K. ( 1991; ). A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350, 423-426.[CrossRef]
    [Google Scholar]
  24. Kodihalli, S., Haynes, J. R., Robinson, H. L. & Webster, R. G. ( 1997; ). Cross-protection among lethal H5N2 influenza viruses induced by DNA vaccine to the hemagglutinin. Journal of Virology 71, 3391-3396.
    [Google Scholar]
  25. Kodihalli, S., Goto, H., Kobasa, D. L., Krauss, S., Kawaoka, Y. & Webster, R. G. ( 1999; ). DNA vaccine encoding hemagglutinin provides protective immunity against H5N1 influenza virus infection in mice. Journal of Virology 73, 2094-2098.
    [Google Scholar]
  26. Liang, S., Mozdzanowska, K., Palladino, G. & Gerhard, W. ( 1994; ). Heterosubtypic immunity to influenza type A virus in mice. Effector mechanisms and their longevity. Journal of Immunology 152, 1653-1661.
    [Google Scholar]
  27. Lu, X., Tumpey, T. M., Morken, T., Zaki, S. R., Cox, N. J. & Katz, J. M. ( 1999; ). A mouse model for the evaluation of pathogenesis and immunity to influenza A (H5N1) viruses isolated from humans. Journal of Virology 73, 5903-5911.
    [Google Scholar]
  28. Neumann, G., Watanabe, T., Ito, H., Watanabe, S., Goto, H., Gao, P., Hughes, M., Perez, D. R., Donis, R., Hoffmann, E., Hobom, G. & Kawaoka, Y. ( 1999; ). Generation of influenza A viruses entirely from cloned cDNAs [see comments]. Proceedings of the National Academy of Sciences, USA 96, 9345-9350.[CrossRef]
    [Google Scholar]
  29. Nguyen, H. H., Moldoveanu, Z., Novak, M. J., van Ginkel, F. W., Ban, E., Kiyono, H., McGhee, J. R. & Mestecky, J. ( 1999; ). Heterosubtypic immunity to lethal influenza A virus infection is associated with virus-specific CD8+ cytotoxic T lymphocyte responses induced in mucosa-associated tissues. Virology 254, 50-60.[CrossRef]
    [Google Scholar]
  30. Oukka, M., Manuguerra, J. C., Livaditis, N., Tourdot, S., Riche, N., Vergnon, I., Cordopatis, P. & Kosmatopoulos, K. ( 1996; ). Protection against lethal viral infection by vaccination with nonimmunodominant peptides. Journal of Immunology 157, 3039-3045.
    [Google Scholar]
  31. Palmer, D. F., Coleman, M., Dowdle, W. R. & Schild, G. G. ( 1975; ). Advanced laboratory techniques for influenza diagnosis. U.S. Department of Health, Education and Welfare, Immunology Series 6, 51-52.
    [Google Scholar]
  32. Rammensee, H. G., Friede, T. & Stevanoviic, S. ( 1995; ). MHC ligands and peptide motifs: first listing. Immunogenetics 41, 178-228.[CrossRef]
    [Google Scholar]
  33. Riberdy, J. M., Flynn, K. J., Stech, J., Webster, R. G., Altman, J. D. & Doherty, P. C. ( 1999; ). Protection against a lethal avian influenza A virus in a mammalian system. Journal of Virology 73, 1453-1459.
    [Google Scholar]
  34. Rimmelzwaan, G. F. & Osterhaus, A. D. ( 1995; ). Cytotoxic T lymphocyte memory: role in cross-protective immunity against influenza? Vaccine 13, 703-705.[CrossRef]
    [Google Scholar]
  35. Rott, R. ( 1992; ). The pathogenic determinant of influenza virus. Veterinary Microbiology 33, 303–310. [Erratum 34, 398.].[CrossRef]
    [Google Scholar]
  36. Scholtissek, C., Burger, H., Kistner, O. & Shortridge, K. F. ( 1985; ). The nucleoprotein as a possible major factor in determining host specificity of influenza H3N2 viruses. Virology 147, 287-294.[CrossRef]
    [Google Scholar]
  37. Schulman, J. L. & Kilbourne, E. D. ( 1965; ). Induction of partial specific heterotypic immunity in mice by a single infection with influenza A virus. Journal of Bacteriology 89, 170-174.
    [Google Scholar]
  38. Schulman, J. L., Petigrow, C. & Woodruff, J. ( 1977; ). Effects of cell mediated immunity in influenza virus infection in mice. Developments in Biological Standardization 39, 385-390.
    [Google Scholar]
  39. Shortridge, K. F. ( 1999; ). Poultry and the influenza H5N1 outbreak in Hong Kong, 1997: abridged chronology and virus isolation. Vaccine 17, S26-S29.[CrossRef]
    [Google Scholar]
  40. Shortridge, K. F., Zhou, N. N., Guan, Y., Gao, P., Ito, T., Kawaoka, Y., Kodihalli, S., Krauss, S., Markwell, D., Murti, K. G., Norwood, M., Senne, D., Sims, L., Takada, A. & Webster, R. G. ( 1998; ). Characterization of avian H5N1 influenza viruses from poultry in Hong Kong. Virology 252, 331-342.[CrossRef]
    [Google Scholar]
  41. Steinhauer, D. A. ( 1999; ). Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology 258, 1-20.[CrossRef]
    [Google Scholar]
  42. Subbarao, K., Klimov, A., Katz, J., Regnery, H., Lim, W., Hall, H., Perdue, M., Swayne, D., Bender, C., Huang, J., Hemphill, M., Rowe, T., Shaw, M., Xu, X., Fukuda, K. & Cox, N. ( 1998; ). Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness [see comments]. Science 279, 393-396.[CrossRef]
    [Google Scholar]
  43. Topham, D. J., Tripp, R. A. & Doherty, P. C. ( 1997; ). CD8+ T cells clear influenza virus by perforin or Fas-dependent processes. Journal of Immunology 159, 5197-5200.
    [Google Scholar]
  44. Townsend, A. R., Rothbard, J., Gotch, F. M., Bahadur, G., Wraith, D. & McMichael, A. J. ( 1986; ). The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell 44, 959-968.[CrossRef]
    [Google Scholar]
  45. Ulmer, J. B., Fu, T. M., Deck, R. R., Friedman, A., Guan, L., DeWitt, C., Liu, X., Wang, S., Liu, M. A., Donnelly, J. J. & Caulfield, M. J. ( 1998; ). Protective CD4+ and CD8+ T cells against influenza virus induced by vaccination with nucleoprotein DNA. Journal of Virology 72, 5648-5653.
    [Google Scholar]
  46. Webster, R. G. & Hay, A. J. ( 1998; ). The H5N1 influenza outbreak in Hong Kong: a test of pandemic preparedness. In Textbook of Influenza, pp. 561-565. Edited by K. G. Nicholson, R. G. Webster & A. J. Hay. Malden:Blackwell Science.
  47. Yap, K. L. & Ada, G. L. ( 1978; ). The recovery of mice from influenza virus infection: adoptive transfer of immunity with immune T lymphocytes. Scandinavian Journal of Immunology 7, 389-397.[CrossRef]
    [Google Scholar]
  48. Yewdell, J. W., Bennink, J. R., Smith, G. L. & Moss, B. ( 1985; ). Influenza A virus nucleoprotein is a major target antigen for cross-reactive anti-influenza A virus cytotoxic T lymphocytes. Proceedings of the National Academy of Sciences, USA 82, 1785-1789.[CrossRef]
    [Google Scholar]
  49. Yuen, K. Y., Chan, P. K., Peiris, M., Tsang, D. N., Que, T. L., Shortridge, K. F., Cheung, P. T., To, W. K., Ho, E. T., Sung, R. & Cheng, A. F. ( 1998; ). Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus [see comments]. Lancet 351, 467-471.[CrossRef]
    [Google Scholar]
  50. Zhong, W., Marshall, D., Coleclough, C. & Woodland, D. L. ( 2000; ). CD4+ T cell priming accelerates the clearance of Sendai virus in mice, but has a negative effect on CD8+ T cell memory. Journal of Immunology 164, 3274-3282.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-81-11-2689
Loading
/content/journal/jgv/10.1099/0022-1317-81-11-2689
Loading

Data & Media loading...

Most Cited This Month

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