Studies of the Hong Kong Influenza Hemagglutinin

  • John J. Skehel
  • Donald C. Wiley


An influenza virus consists of a transcriptase complex surrounded by a lipid membrane. Each complex contains eight RNA molecules, which make up the virus genome in association with polypeptides of five different types, members of at least three of which participate in transcriptase activity. The virus membrane is derived from the surface membrane of the infected cells, from which the assembled virus is released by a process of membrane budding. During infection, this membrane is modified to contain two types of virus-specified glycoproteins, the hemagglutinins (about 500–1000 per virus) and the neuraminidase molecules (about 100–500 per virus). The more abundant hemagglutinin is the glycoprotein that interacts with infectivity-neutralizing antibodies.1 Because of the hemagglutinin’s consequent importance in antigenic variation, its structure and antigenicity have been analyzed in detail. In this chapter, we will describe a number of the applications of antihemagglutinin monoclonal antibodies in these studies. We will concentrate on the hemagglutinins of viruses of the H3 antigenic subtype, the Hong Kong influenza viruses, primarily because detailed information on the three-dimensional structure of a hemagglutinin is at present only available for the hemagglutinin of the 1968 Hong Kong virus.


Influenza Virus Amino Acid Substitution Antigenic Variant Single Amino Acid Substitution Antibody Binding Site 
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  1. 1.
    Webster, R. G., and Laver, W. G., 1975, Antigenic variation of influenza viruses, in: Influenza Viruses and Influenza (E. D. Kilbourne, ed.), Academic Press, New York, pp. 270–314.Google Scholar
  2. 2.
    Kilbourne, E. D., 1969, Future influenza vaccines and the use of genetic recombinants, Bull. WHO 41:643–645.PubMedGoogle Scholar
  3. 3.
    Ward, C. W., 1981, Influenza haemagglutinin, Curr. Top. Microbiol. Immunol. 94:1–74.PubMedCrossRefGoogle Scholar
  4. 4.
    Wilson, I. A., Skehel, J. J., and Wiley, D. C., 1981, Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution, Nature 289:366–373.PubMedCrossRefGoogle Scholar
  5. 5.
    Skehel, J. J., Daniels, R. S., Douglas, A. R., and Wiley, D. C., 1983, Antigenic and amino acid sequence variations in the haemagglutinins of type A influenza viruses recently isolated from human subjects, Bull. WHO 61:671–676.PubMedGoogle Scholar
  6. 6.
    Webster, R. G., and Laver, W. G., 1980, Determination of the number of nonoverlapping antigenic areas on Hong Kong (H3N2) influenza virus HA with monoclonal antibodies and the selection of variants with potential epidemiological significance, Virology 104:139–148.PubMedCrossRefGoogle Scholar
  7. 7.
    Underwood, P. A., 1984, An antigenic map of the haemagglutinin of the influenza Hong Kong subtype (H3N2) constructed using mouse monoclonal antibodies, Mol. Immunol. 21:663–671.PubMedCrossRefGoogle Scholar
  8. 8.
    Breschkin, A. M., Ahern, J., and White, D. O., 1981, Antigenic determinants of influenza virus haemagglutinin. VIII. Topography of the antigenic regions of influenza virus haemagglutinin determined by competitive radioimmune assay with monoclonal antibodies, Virology 113:130–140.PubMedCrossRefGoogle Scholar
  9. 9.
    Laver, W. G., Air, G. M., Webster, R. C., Gerhard, W., Ward, C. W., and Dopheide, T. A. A., 1979, Antigenic drift in type A influenza virus: Sequence differences in the haemagglutinin of Hong Kong (H3N2) variants selected with monoclonal hybridoma antibodies, Virology 98:226–237.PubMedCrossRefGoogle Scholar
  10. 10.
    Laver, W. G., Air, G. M., and Webster, R. G., 1981, Mechanism of antigenic drift in influenza virus. Amino acid sequence changes in an antigenically active region of Hong Kong (H3N2) influenza virus haemagglutinin, J. Mol. Biol. 145:339–361.PubMedCrossRefGoogle Scholar
  11. 11.
    Newton, S. E., Air, G. M., Webster, R. G., and Laver, W. G., 1983, Sequence of the haemagglutinin gene of influenza virus A/Memphis/1/71 and previously uncharacterized monoclonal antibody-derived variants, Virology 128:495–501.PubMedCrossRefGoogle Scholar
  12. 12.
    Daniels, R. S., Douglas, A. R., Skehel, J. J., and Wiley, D. C., 1983, Analyses of the antigenicity of influenza haemagglutinin at the pH optimum for virus mediated membrane fusion, J. Gen. Virol. 64:1657–1662.PubMedCrossRefGoogle Scholar
  13. 13.
    Daniels, R. S., Douglas, A. R., Skehel, J.J., Waterfield, M. D., Wilson, I. A., and Wiley, D. C., 1983, Studies of the influenza virus haemagglutinin in the pH5 conformation, in: The Origin of Pandemic Influenza Viruses (W. G. Laver, ed.), Elsevier, New York, pp. 1–8.Google Scholar
  14. 14.
    Moss, B. A., Underwood, P. A., Bender, V. J., and Whittaker, R. G., 1980, Antigenic drift in the haemagglutinin from various strains of influenza virus A/Hong Kong/68 (H3N2), in: Structure and Variation in influenza Virus (W. G. Laver and G. M. Air, eds.), Elsevier, New York, pp. 329–338.Google Scholar
  15. 15.
    Skehel, J. J., Stevens, D. J., Daniels, R. S., Douglas, A. R., Knossow, M., Wilson, I. A., and Wiley, D. C., 1984, A carbohydrate side-chain on haemagglutinins of Hong Kong influenza viruses inhibits recognition by a monoclonal antibody, Proc. Natl. Acad. Sci. USA 81:1779–1783.PubMedCrossRefGoogle Scholar
  16. 16.
    Wiley, D. C., Wilson, I. A., and Skehel, J. J., 1981, Structural identifications of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation, Nature 289:373–378.PubMedCrossRefGoogle Scholar
  17. 17.
    Caton, A. J., Brownlee, G. G., Yewdell, J. W., and Gerhard, W., 1982, The antigenic structure of the influenza virus A/PR/8/34 haemagglutinin (H1 subtype), Cell 31:417–427.PubMedCrossRefGoogle Scholar
  18. 18.
    Knossow, M., Daniels, R. S., Douglas, A. R., Skehel, J. J., and Wiley, D. C., 1984, Three dimensional structure of an antigenic mutant of influenza virus haemagglutinin, Nature 311:678–680.PubMedCrossRefGoogle Scholar
  19. 19.
    Wrigley, N. G., Brown, E. B., Daniels, R. S., Douglas, A. R., Skehel, J. J., and Wiley, D. C., 1983, Electron microscopy of influenza haemagglutinin-monoclonal antibody complexes. Virology 131:308–314.PubMedCrossRefGoogle Scholar
  20. 20.
    Laver, W. G., Air, G. M., Dopheide, T. A., and Ward, C. W., 1980, Amino acid sequence changes in the haemagglutinin of A/Hong Kong (H3N2) influenza virus during the period 1968–1977, Nature 283:454–457.PubMedCrossRefGoogle Scholar
  21. 21.
    Both, G. W., Sleigh, M. J., Cox, N. J., and Kendal, A. P., 1983, Antigenic drift in H3 influenza haemagglutinin from 1968–1980: Multiple evolutionary pathways and sequential amino acid changes at key antigenic sites, J. Virol. 48:52–60.PubMedGoogle Scholar
  22. 22.
    Sleigh, M. J., Both, G. W., Underwood, P. A., and Bender, V. J., 1981, Antigenic drift in the haemagglutinin of the Hong Kong influenza subtype: Correlation of amino acid changes with alterations in viral antigenicity, J. Virol. 37:845–853.PubMedGoogle Scholar
  23. 23.
    Skehel, J. J., Bayley, P. M., Brown, E. B., Martin, S. R., Waterfield, M. D., White, J. M., Wilson, I. A., and Wiley, D. C., 1982, Changes in the conformation of influenza virus haemagglutinin at the pH optimum of virus-mediated membrane fusion, Proc. Natl. Acad. Sci. USA 79:968–972.PubMedCrossRefGoogle Scholar
  24. 24.
    Jensen, K. W., Minuse, E., and Francis, T., Jr., 1957, Serologic comparisons with lines of influenza virus isolated and serially transferred in different experimental hosts, J. Immunol. 787:356–364.Google Scholar
  25. 25.
    Schild, G. C., Oxford, J. S., de Jong, J. C., and Webster, R. G., 1983, Evidence for host-cell selection of influenza virus antigenic variants, Nature 303:706–709.PubMedCrossRefGoogle Scholar
  26. 26.
    Rott, R., Orlich, M., Klenk, H.-D., Wang, M. L., Skehel, J. J., and Wiley, D. C., 1984, Studies on the adaptation of influenza viruses to MDCK cells, EMBO J. 3:3329–3332.PubMedGoogle Scholar
  27. 27.
    Daniels, R. S., Douglas, A. R., Skehel, J. J., Wiley, D. C., Naeve, C. W., Webster, R. G., Rogers, G. N., and Paulson, J. C., 1984, Antigenic analyses of influenza virus haemagglutinins with different receptor-binding specificities, Virology 138:174–177.PubMedCrossRefGoogle Scholar
  28. 23.
    Rogers, G. N., Paulson, J. C., Daniels, R. S., Skehel, J. J., Wilson, I. A., and Wiley, D. C., 1983, Single amino acid substitutions in influenza haemagglutinin change receptor binding specificity, Nature 304:76–78.PubMedCrossRefGoogle Scholar
  29. 29.
    Webster, R. G., Brown, L. E., and Jackson, D. C., 1983, Changes in the antigenicity of the haemagglutinin molecule of H3 influenza virus at acidic pH, Virology 126:587–599.PubMedCrossRefGoogle Scholar
  30. 30.
    Daniels, R. S., Downie, J. C., Hay, A. J., Knossow, M., Skehel, J. J., Wang, M. L., and Wiley, D. C., 1985, Fusion mutants of the influenza virus haemagglutinin, Cell (in press).Google Scholar
  31. 31.
    Yewdell, J. W., Webster, R. G., and Gerhard, W. U., 1979, Antigenic variation in three distinct determinants of an influenza type A haemagglutinin molecule, Nature 279:246–248.PubMedCrossRefGoogle Scholar
  32. 32.
    Amit, A. G., Mariuzza, R. A., Saludjian, P., Poljak, R. J., Lamoyi, E., and Nisonoff, A., 1983, Preliminary crystallographic study of the Fab fragment of a monoclonal anti-phenylarsonate antibody possessing a major idiotypic specificity, J. Mol. Biol. 169:637–638.PubMedCrossRefGoogle Scholar
  33. 33.
    Schulman, M., Wilde, C. D., and Köhler, G., 1978, A better cell line for making hybridomas secreting specific antibodies, Nature 276:269–270.CrossRefGoogle Scholar
  34. 34.
    Köhler, G., and Milstein, C., 1975, Continuous cultures of fused cells secreting antibody of predefined specificity, Nature 256:495–497.PubMedCrossRefGoogle Scholar
  35. 35.
    Köhler, G., and Milstein, C., 1976, Derivation of specific antibody-producing tissue culture and tumor lines by cell fusion, Eur. J. Immunol. 6:511–519.PubMedCrossRefGoogle Scholar
  36. 36.
    Fazekas de St. Groth, S., and Scheidegger, D., 1980, Production of monoclonal antibodies: Strategy and tactics, J. Immunol. Meth. 35:1–21.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • John J. Skehel
    • 1
  • Donald C. Wiley
    • 2
  1. 1.National Institute for Medical ResearchLondonEngland
  2. 2.Department of Biochemistry and Molecular BiologyHarvard UniversityCambridgeUSA

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