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Structure, Function, and Antigenicity of the Hemagglutinin of Influenza Virus

  • S. A. Wharton
  • W. Weis
  • J. J. Skehel
  • D. C. Wiley
Chapter
Part of the The Viruses book series (VIRS)

Abstract

The major surface glycoprotein of influenza virus is hemagglutinin (HA). This chapter reviews the two major functions of HA: (1) its involvement in binding to receptors on cells before their infection, and (2) its role in the fusion of viral and endosomal membranes, necessary for the release of the viral genome into the cell. In addition, HA is the viral antigen that interacts with infectivity-neutralizing antibodies; alterations in the molecule enable the virus to escape immune surveillance and cause epidemics of disease. The nature of these changes in antigenicity is discussed.

Keywords

Influenza Virus Amino Acid Substitution Membrane Fusion Human Influenza Viral Membrane 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Amit, A. G., Marizza, R. A., Phillips, S. E. V., and Poljak, R. J., 1986, Three-dimensional structure of an antigen-antibody complex at 2.8 A resolution, Science 233: 747–753.PubMedCrossRefGoogle Scholar
  2. Anders, E. M., Scalzo, A. A., Rogers, G. N., and White, D. O., 1986, Relationship between mitogenic activity of influenza viruses and the receptor-binding specificity of their haemagglutinin molecules, J. Virol. 60: 476–482.PubMedGoogle Scholar
  3. Both, G. W., Sleigh, M. J., Cox, N. J., and Kendal, A. P., 1983, Antigenic drift in influenza virus H3 haemagglutinin from 1968 to 1980. Multiple evolutionary pathways and sequential amino acid changes at key antigenic sites, J. Virol. 48: 52–60.PubMedGoogle Scholar
  4. Brand, C. M., and Skehel, J. J., 1972, Crystalline antigen from the influenza virus envelope, Nature New Biol. 238: 145–147.PubMedCrossRefGoogle Scholar
  5. 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 (Hl subtype), Cell 31: 417–427.PubMedCrossRefGoogle Scholar
  6. Coleman, M. T., Dowdle, W. R., Pereira, H. G., Schild, G. C., and Chang, W. K., 1968, The Hong Kong/68 influenza A2 variant, Lancet 2: 1384–1413.PubMedCrossRefGoogle Scholar
  7. Daniels, R. S., Douglas, A. R., Skehel, J. J., and Wiley, D. C., 1983a, Analyses of the antigenicity of influenza haemagglutinin at the pH optimum for virus-mediated membrane fusion, J. Gen. Virol. 64: 1657–1661.PubMedCrossRefGoogle Scholar
  8. Daniels, R. S., Douglas, A. R., Skehel, J. J., Waterfield, M. D., Wilson, I. A., and Wiley, D. C., 1983b, Studies of the influenza virus haemagglutinin in the pH5 conformation, in: The Origin of Pandemic Influenza Viruses ( W. G. Laver, ed.), pp. 1–7, Elsevier, New York.Google Scholar
  9. 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
  10. Daniels, R. S., Skehel, J. J., and Wiley, D. C., 1985a, Amino acid sequences of haemagglutinins of influenza viruses of the H3 subtype isolated from horses, J. Gen. Virol. 66: 457–464.PubMedCrossRefGoogle Scholar
  11. Daniels, R. S., Douglas, A. R., Skehel, J. J., and Wiley, D. C., 1985b, Antigenic and amino acid sequence analyses of influenza viruses of the H1N1 subtype isolated between 1982 and 1984, Bull. WHO 63: 273–277.PubMedGoogle Scholar
  12. Daniels, R. S., Downie, J. C., Knossow, M., Skehel, J. J., Wang, M.-L., and Wiley, D. C., 1985c, Fusion mutants of influenza virus haemagglutinin glycoprotein, Cell 40: 431–439.CrossRefGoogle Scholar
  13. Daniels, R. S., Jeffries, S., Yates, P., Schild, G. C., Rogers, G. N., Paulson, J. C., Wharton, S. A., Douglas, A. R., Skehel, J. J., and Wiley, D. C., 1987, The receptor binding and membrane fusion properties of influenza virus variants selected using anti-haemagglutinin monoclonal antibodies, EMBO J. 6: 1459–1465.PubMedGoogle Scholar
  14. Doms, R. W., Helenius, A. H., and White, J., 1985, Membrane fusion activity of the influenza virus haemagglutinin, J. Biol. Chem. 260: 2973–2981.PubMedGoogle Scholar
  15. Doms, R. W., Gething, M.-J., Henneberry, J., White, J., and Helenius, A., 1986, Variant influenza virus haemagglutinin that induces fusion at elevated pH, J. Virol. 57: 603–613.PubMedGoogle Scholar
  16. Duzgunes, N., and Gambale, F., 1988, Membrane action of synthetic N-terminal peptides of influenza virus haemagglutinin and its mutants, FEBS Lett. 227: 110–114.PubMedCrossRefGoogle Scholar
  17. Ellens, H., Bentz, J., and Szoka, F. C., 1986, Fusion of phosphatidylethanolamine-containing liposomes and the mechanism of the L,,-H11 phase transition, Biochemistry 25: 4141–4147.PubMedCrossRefGoogle Scholar
  18. Fang, R., Min Jou, W., Huylebroeck, D., Devos, R., and Fiers, W., 1981, Complete structure of A/duck/Ukraine/63 influenza haemagglutinin gene- Animal virus as progenitor of human H3 Hong Kong 1968 influenza haemagglutinin, Cell 25: 315–323.PubMedCrossRefGoogle Scholar
  19. Fazekas, de St. Groth, S., 1977, Antigenic, adaptive and adsorptive variants of the influenza A haemagglutinin, in: Topics in Infectious Diseases, Vol. 3 ( R. G. Laver, H. Bachmayer, and R. Weil, eds.), pp. 25–48, Springer-Verlag, Vienna.Google Scholar
  20. Gerhard, W., Yewdell, J., Frankel, M. E., and Webster, R. G., 1981, Antigenic structure of influenza virus haemagglutinin defined by hybridoma antibodies, Nature (Land.) 290: 713–717.CrossRefGoogle Scholar
  21. Gething, M.-J., Doms, R. W., York, D., and White, J., 1986, Studies on the mechanism of membrane fusion: Site-specific mutagenesis of the haemagglutinin of influenza virus, J. Cell Biol. 102: 11–23.PubMedCrossRefGoogle Scholar
  22. Graves, P. N., Schulman, J. F., Young, J. F., and Palese, P., 1983, Preparation of influenza virus subviral particles lacking the HAI subunit of haemagglutinin: Unmasking of cross reactive HA2 determinants, Virology 126: 106–116.PubMedCrossRefGoogle Scholar
  23. Gruner, S. M., Cullis, P. R., Hope, M. J., and Tilcock, C. P. S., 1985, Lipid polymorphism: The molecule basis of nonbilayer phases, Annu. Rev. Biophys. Biophys. Chem. 14: 211–238.PubMedCrossRefGoogle Scholar
  24. Huang, R. T. C., Rott, R., and Klenk, H.-D., 1981, Influenza viruses cause haemolysis and fusion of cells, Virology 110: 243–247.PubMedCrossRefGoogle Scholar
  25. Huddleston, J. A., and Brownlee, G. G., 1982, The sequence of the nucleoprotein gene of human influenza A virus, strain A/NT/60/68, Nucl. Acid. Res. 10: 1029–1038.CrossRefGoogle Scholar
  26. Klenk, H.-D., Rott, R., Orlich, M., and Blodom, J., 1975, Activation of influenza A viruses by trypsin treatment, Virology 68: 426–439.PubMedCrossRefGoogle Scholar
  27. Knossow, M., Daniels, R. S., Douglas, A. R., Skehel, J. J., and Wiley, D. C., 1984, Three-dimensional structure of an antigenic mutant of the influenza virus haemagglutinin, Nature (Lond.) 311: 678–680.CrossRefGoogle Scholar
  28. Lambrecht, B., and Schmidt, M. F. G., 1986, Membrane fusion induced by influenza virus haemagglutinin requires protein bound fatty acids, FEBS Lett. 202: 127–132.PubMedCrossRefGoogle Scholar
  29. Laver, W. G., and Webster, R. G., 1973, Studies on the origin of pandemic influenza. III. Evidence implicating duck and equine influenza viruses as possible progenitors of the Hong Kong strain of human influenza, Virology 51: 383–391.PubMedCrossRefGoogle Scholar
  30. Laver, W. G., Air, G. M., Webster, R. G., Gerhard, W., Ward, C. W., and Dopheide, T. 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
  31. Laver, W. G., Air, G. M., and Webster, R. G., 1981, Mechanism of antigenic drift in influenza virus. Amino and sequence changes in an antigenically active region of Hong Kong (H3N2) influenza virus haemagglutinin, J. Mol. Biol. 145: 339–361.PubMedCrossRefGoogle Scholar
  32. Lear, J. D., and de Grado, W. F., 1987, Membrane binding and conformational properties of a peptide representing the amino terminus of influenza virus HA2, j. Biol. Chem. 262: 6500–6505.PubMedGoogle Scholar
  33. Lesk, A. M., and Hardman, K. D., 1982, Computer-generated schematic diagrams of protein structures, Science 216: 539–540.PubMedCrossRefGoogle Scholar
  34. Maeda, T., and Ohnishi, S., 1980, Activation-of influenza virus by acidic media causes haemolysis and fusion of erythrocytes, FEBS Lett. 122: 283–287.PubMedCrossRefGoogle Scholar
  35. Matlin, K. S., 1986, The sorting of proteins to the plasma membrane in epithelial cells, J. Cell Biol. 103: 2565–2568.PubMedCrossRefGoogle Scholar
  36. Mulder, J., and Masurel, N., 1958, Pre-epidemic antibody against the 1957 strain of Asiatic influenza in the serum of older persons living in the Netherlands, Lancet 1: 810.PubMedCrossRefGoogle Scholar
  37. Murata, M., Sugahara, Y., Takahashi, S., and Ohnishi, S.-I., 1987, pH-dependent membrane fusion activity of a synthetic twenty amino acid peptide with the same sequence as that of the hydrophobic segment of influenza virus haemagglutinin, J. Biochem. 102:957–962.Google Scholar
  38. Natali, A., Oxford, J. A., and Schild, G. C., 1981, Frequency of naturally occurring antibody to influenza virus antigenic variants selected with monoclonal antibody, J. Hyg. Cam b. 87: 185–190.CrossRefGoogle Scholar
  39. Neville, D. M., and Hudson, T. H., 1986, Transmembrane transport of diphtheria toxin, related toxins, and colicins, Annu. Rev. Biochem. 55: 195–224.PubMedCrossRefGoogle Scholar
  40. 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
  41. Pereira, M. S., 1982, Persistence of influenza in a population, in: Virus Persistence, Thirty-third Symposium of the Society for General Microbiology ( B. W. J. Mahy, A. C. Minson, and G. K. Darby, eds.), pp. 15–37, Cambridge University Press, Cambridge.Google Scholar
  42. Pritchett, T. J., Brossmer, R., Rose, R., and Paulson, J. C., 1987, Recognition of monovalent sialosides by influenza virus H3 haemagglutinin, Virology 160: 502–506.PubMedCrossRefGoogle Scholar
  43. Rand, R. P., 1981, Interacting phospholipid bilayers: Measured forces and induced structural changes, Annu. Rev. Biophys. Bioeng. 10: 277–314.PubMedCrossRefGoogle Scholar
  44. Raymond, F. L., Caton, A. J., Cox, N. J., Kendal, A. P., and Brownlee, G. G., 1983, Antigenicity and evolution amongst recent influenza viruses of the H1N1 subtypes, Nucl. Acid Res. 11: 7191–7203.CrossRefGoogle Scholar
  45. Raymond, F. L., Caton, A. J., Cox, N. J., Kendal, A. P., and Brownlee, G. G., 1986, The antigenicity and evolution of influenza H1 haemagglutinin from 1950–1957 and 1977–1983: Two pathways from one gene. Virology 148: 275–287.PubMedCrossRefGoogle Scholar
  46. 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 (Loud.) 304: 76–79.CrossRefGoogle Scholar
  47. Rogers, G. N., Daniels, R. S., Skehel, J. J., Wiley, D. C., Wang, X.-F., Higa, H. H., and Paulson, J. C., 1985, Host-mediated selection of influenza virus receptor variants, J. Biol. Chem. 260: 7362–7367.PubMedGoogle Scholar
  48. Ruigrok, R. W. H., Wrigley, N. G., Calder, L. J., Cusack, S., Wharton, S. A., Brown, E. B., and Skehel, J. J., 1986a, Electron microscopy of the low pH structure of influenza virus haemagglutinin, EMBO J. 5: 41–49.PubMedGoogle Scholar
  49. Ruigrok, R. W. H., Martin, S. R., Wharton, S. A., Skehel, J. J., Bayley, P. M., and Wiley, D. C., 1986b, Conformational changes in the haemagglutinin of influenza virus which accompany heat-induced fusion with liposomes, Virology 155: 484–497.PubMedCrossRefGoogle Scholar
  50. Ruigrok, R. W. H., Aitken, A., Calder, L. J., Martin, S. R., Skehel, J. J., Wharton, S. A., Weis, W., and Wiley, D. C., 1988, Studies on the structure of the influenza virus haemagglutinin at the pH of membrane fusion, J. Gen. Virol. 69: 2785–2795.PubMedCrossRefGoogle Scholar
  51. Sato, S. B., Kawasaki, K., and Ohnishi, S.-I., 1983, Haemolytic activity of influenza virus haemagglutinin glycoproteins activated in mildly acidic environments, Proc. Natl. Acad. Sci. USA 80: 3153–3157.PubMedCrossRefGoogle Scholar
  52. 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 (Lond.) 303: 706–709.Google Scholar
  53. Scholtissek, C., Rohde, W., Van Hoyningen, V., and Rott, R., 1978a, On the origin of the human influenza virus subtypes H2N2 and H3N2, Virology 87: 13–20.PubMedCrossRefGoogle Scholar
  54. Scholtissek, C., Van Hoyningen, V., and Rott, R., 1978b, Genetic relatedness between the new 1977 epidemic strains (H1N1) of influenza and human influenza strains isolated between 1947 and 1957, Virology 89: 613–617.PubMedCrossRefGoogle Scholar
  55. Scholtissek, C., Burger, H., Kistner, O., and Shortridge, K. F., 1985, The nucleoprotein as a possible major factor in determining host specificity of influenza H3N2 viruses, Virology 147: 287–294.PubMedCrossRefGoogle Scholar
  56. Skehel, J. J., Bayley, P. M., Brown, E. M., 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
  57. 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
  58. Smith, W. C., Andrewes, C. H., and Laidlaw, P. P., 1933, A virus obtained from influenza patients, Lancet 2: 66–68.CrossRefGoogle Scholar
  59. Stegmann, T., Hoekstra, D., Scherphof, G., and Wilschut, J., 1985, Kinetics of pH-dependent fusion between influenza virus and liposomes, Biochemistry 24: 3107–3113.PubMedCrossRefGoogle Scholar
  60. Stegmann, T., Hoekstra, D., and Wilschut, J., 1986, Fusion activity of influenza virus: A comparison between biological and artificial target membrane vesicles, J. Biol. Chem. 261: 10966–10969.PubMedGoogle Scholar
  61. Stevens, D. J., Douglas, A. R., Skehel, J. J., and Wiley, D. C., 1987, Antigenic and amino acid sequence analysis of the variants of H1N1 influenza virus in 1986, Bull. WHO 65: 177–180.Google Scholar
  62. Tumova, B., and Pereira, H. G., 1965, Genetic interaction between influenza A viruses of human and animal origin, Virology 27: 253–261.PubMedCrossRefGoogle Scholar
  63. Underwood, P. A., Skehel, J. J., and Wiley, D. C., 1987, Receptor binding characteristics of monoclonal antibody-selected antigenic variants of influenza virus, J. Virol. 61: 206–208.PubMedGoogle Scholar
  64. Waddell, G. H., Tiegland, M. B., and Sigel, M. M., 1963, A new influenza virus associated with equine respiratory disease, J. Am. Vet. Med. Assoc. 143: 587–590.PubMedGoogle Scholar
  65. Wang, M.-L., Skehel, J. J., and Wiley, D. C., 1986, Comparative analyses of the specificities of anti-influenza haemagglutinin antibodies in human sera, J. Virol. 57: 124–128.PubMedGoogle Scholar
  66. Ward, C. W., and Dopheide, T. A., 1981, Evolution of the Hong Kong influenza A subtype. Structural relationship between the haemagglutinin from A/duck/Ukraine/63 (Hav7) and the Hong Kong (H3) haemagglutinins, Biochem. J. 195: 337–340.PubMedGoogle Scholar
  67. Webster, R. G., Campbell, C. H., and Granoff, A., 1971, The in vivo production of “new” influenza A viruses. 1. Genetic recombination between avian and mammalian influenza viruses, Virology 44: 317–328.PubMedCrossRefGoogle Scholar
  68. 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
  69. Weis, W., 1987, Receptor binding to the influenza virus hemagglutinin, Doctoral thesis, Harvard University, Cambridge, Massachusetts.Google Scholar
  70. Weis, W., Brown, J. H., Cusack, S., Paulson, J. C., Skehel, J. J., and Wiley, D. C., 1988, Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid, Nature (Lond.) 333: 426–431.CrossRefGoogle Scholar
  71. Wharton, S. A., 1987, The role of influenza virus haemagglutinin in membrane fusion, Microbiol. Sci. 4: 119–124.PubMedGoogle Scholar
  72. Wharton, S. A., Skehel, J. J., and Wiley, D. C., 1986, Studies of influenza virus haemagglutinin-mediated membrane fusion, Virology 149: 27–35.PubMedCrossRefGoogle Scholar
  73. Wharton, S. A., Martin, S. R., Ruigrok, R. W. H., Skehel, J. J., and Wiley, D. C., 1988a, Membrane fusion by peptide analogues of influenza virus haemagglutinin, J. Gen. Virol. 69: 1847–1857.PubMedCrossRefGoogle Scholar
  74. Wharton, S. A., Ruigrok, R. W. H., Martin, S. R., Skehel, J. J., Bayley, P. M., Weis, W., and Wiley, D. C., 1988b, Conformational aspects of the acid-induced fusion mechanism of influenza virus haemagglutinin: Circular dichroism and fluorescence studies, J. Biol. Chem. 263: 4474–4480.PubMedGoogle Scholar
  75. White, J., Matlin, K., and Helenius, A., 1981, Cell fusion by Semliki forest, influenza and vesicular stomatitis virus, J. Cell Biol. 89: 674–679.PubMedCrossRefGoogle Scholar
  76. White, J., Helenius, A., and Gething, M.-J., 1982, Haemagglutinin of influenza virus expressed from a cloned gene promotes membrane fusion, Nature (Lond.) 300: 658–659.CrossRefGoogle Scholar
  77. White, J., Kielian, M., and Helenius, A., 1983, Membrane fusion proteins of enveloped animal viruses, Q. Rev. Biophys. 16: 151–195.PubMedCrossRefGoogle Scholar
  78. WHO Memorandum, 1980, A revision of the system of nomenclature for influenza viruses: A WHO memorandum, Bull. WHO 58: 585–591.Google Scholar
  79. Wiley, D. C., and Skehel, J. J., 1987, The structure and function of the haemagglutinin membrane glycoprotein of influenza virus, Annu. Rev. Biochem. 56: 365–394.PubMedCrossRefGoogle Scholar
  80. Wiley, D. C., Wilson, I. A., and Skehel, J. J., 1981, Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation, Nature (Lond.) 289: 373–378.CrossRefGoogle Scholar
  81. Wilson, I. A., Skehel, J. J., and Wiley, D. C., 1981, Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution, Nature (Lond.) 289: 366–373.CrossRefGoogle Scholar
  82. Winter, G., and Fields, S., 1981, The structure of the gene encoding the nucleoprotein of human influenza virus A/PR/8/34, Virology 114: 423–428.PubMedCrossRefGoogle Scholar
  83. Yewdell, J. W., Webster, R. G., and Gerhard, W., 1979, Antigenic variation in three distinct determinants of an influenza type A haemagglutinin molecule, Nature (Lond.) 279: 246–248.CrossRefGoogle Scholar
  84. Yewdell, J. W., Caton, A. J., and Gerhard, W., 1986, Selection of influenza A virus adsorptive mutants by growth in the presence of a mixture of monoclonal antihaemagglutinin antibodies, J. Virol. 57: 623–628.PubMedGoogle Scholar
  85. Young, J. F., Desselberger, U., and Palese, P., 1979, Evolution of human influenza A viruses in nature: Sequential mutations in the genomes of new H1N1 isolates, Cell 18: 73–83.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • S. A. Wharton
    • 1
  • W. Weis
    • 2
  • J. J. Skehel
    • 1
  • D. C. Wiley
    • 2
  1. 1.Division of VirologyNational Institute for Medical ResearchLondonEngland
  2. 2.Department of Biochemistry and Molecular BiologyHarvard UniversityCambridgeUSA

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