Structural determinants for naturally evolving H5N1 hemagglutinin to switch its receptor specificity

Cell. 2013 Jun 20;153(7):1475-85. doi: 10.1016/j.cell.2013.05.035. Epub 2013 Jun 6.


Of the factors governing human-to-human transmission of the highly pathogenic avian-adapted H5N1 virus, the most critical is the acquisition of mutations on the viral hemagglutinin (HA) to "quantitatively switch" its binding from avian to human glycan receptors. Here, we describe a structural framework that outlines a necessary set of H5 HA receptor-binding site (RBS) features required for the H5 HA to quantitatively switch its preference to human receptors. We show here that the same RBS HA mutations that lead to aerosol transmission of A/Vietnam/1203/04 and A/Indonesia/5/05 viruses, when introduced in currently circulating H5N1, do not lead to a quantitative switch in receptor preference. We demonstrate that HAs from circulating clades require as few as a single base pair mutation to quantitatively switch their binding to human receptors. The mutations identified by this study can be used to monitor the emergence of strains having human-to-human transmission potential.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Birds
  • Evolution, Molecular
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry*
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics*
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism
  • Host Specificity
  • Humans
  • Influenza A Virus, H5N1 Subtype / chemistry*
  • Influenza A Virus, H5N1 Subtype / pathogenicity
  • Influenza A Virus, H5N1 Subtype / physiology
  • Influenza in Birds / virology*
  • Influenza, Human / epidemiology
  • Influenza, Human / transmission*
  • Influenza, Human / virology*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • N-Acetylneuraminic Acid / metabolism
  • Phylogeny
  • Receptors, Virus / chemistry
  • Receptors, Virus / metabolism
  • Sequence Alignment


  • Hemagglutinin Glycoproteins, Influenza Virus
  • Receptors, Virus
  • hemagglutinin, avian influenza A virus
  • N-Acetylneuraminic Acid