Conserved neutralizing epitope at globular head of hemagglutinin in H3N2 influenza viruses

Yoshitaka Iba, Yoshifumi Fujii, Nobuko Ohshima, Tomomi Sumida, Ritsuko Kubota-Koketsu, Mariko Ikeda, Motoaki Wakiyama, Mikako Shirouzu, Jun Okada, Yoshinobu Okuno, Yoshikazu Kurosawa, Shigeyuki Yokoyama

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Abstract

Neutralizing antibodies that target the hemagglutinin of influenza virus either inhibit binding of hemagglutinin to cellular receptors or prevent the low-pH-induced conformational change in hemagglutinin required for membrane fusion. In general, the former type of antibody binds to the globular head formed by HA1 and has narrow strain specificity, while the latter type binds to the stem mainly formed by HA2 and has broad strain specificity. In the present study, we analyzed the epitope and function of a broadly neutralizing human antibody against H3N2 viruses, F005-126. The crystal structure of F005-126 Fab in complex with hemagglutinin revealed that the antibody binds to the globular head, spans a cleft formed by two hemagglutinin monomers in a hemagglutinin trimer, and cross-links them. It recognizes two peptide portions (sites L and R) and a glycan linked to asparagine at residue 285 using three complementarity-determining regions and framework 3 in the heavy chain. Binding of the antibody to sites L (residues 171 to 173, 239, and 240) and R (residues 91, 92, 270 to 273, 284, and 285) is mediated mainly by van der Waals contacts with the main chains of the peptides in these sites and secondarily by hydrogen bonds with a few side chains of conserved sequences in HA1. Furthermore, the glycan recognized by F005-126 is conserved among H3N2 viruses. F005-126 has the ability to prevent low-pH-induced conformational changes in hemagglutinin. The newly identified conserved epitope, including the glycan, should be immunogenic in humans and may induce production of broadly neutralizing antibodies against H3 viruses.

Original languageEnglish
Pages (from-to)7130-7144
Number of pages15
JournalJournal of Virology
Volume88
Issue number13
DOIs
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Iba, Y., Fujii, Y., Ohshima, N., Sumida, T., Kubota-Koketsu, R., Ikeda, M., Wakiyama, M., Shirouzu, M., Okada, J., Okuno, Y., Kurosawa, Y., & Yokoyama, S. (2014). Conserved neutralizing epitope at globular head of hemagglutinin in H3N2 influenza viruses. Journal of Virology, 88(13), 7130-7144. https://doi.org/10.1128/JVI.00420-14