Cross-neutralization of Influenza A Viruses Mediated by a Single Antibody Loop

Nature. 2012 Sep 27;489(7417):526-32. doi: 10.1038/nature11414. Epub 2012 Sep 16.

Abstract

Immune recognition of protein antigens relies on the combined interaction of multiple antibody loops, which provide a fairly large footprint and constrain the size and shape of protein surfaces that can be targeted. Single protein loops can mediate extremely high-affinity binding, but it is unclear whether such a mechanism is available to antibodies. Here we report the isolation and characterization of an antibody called C05, which neutralizes strains from multiple subtypes of influenza A virus, including H1, H2 and H3. X-ray and electron microscopy structures show that C05 recognizes conserved elements of the receptor-binding site on the haemagglutinin surface glycoprotein. Recognition of the haemagglutinin receptor-binding site is dominated by a single heavy-chain complementarity-determining region 3 loop, with minor contacts from heavy-chain complementarity-determining region 1, and is sufficient to achieve nanomolar binding with a minimal footprint. Thus, binding predominantly with a single loop can allow antibodies to target small, conserved functional sites on otherwise hypervariable antigens.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Neutralizing / chemistry*
  • Antibodies, Neutralizing / genetics
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / chemistry*
  • Antibodies, Viral / genetics
  • Antibodies, Viral / immunology*
  • Antibody Specificity / genetics
  • Antibody Specificity / immunology*
  • Antigens, Viral / chemistry
  • Antigens, Viral / immunology
  • Binding Sites
  • Complementarity Determining Regions / chemistry
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology
  • Conserved Sequence
  • Cross Reactions / genetics
  • Cross Reactions / immunology
  • Crystallography, X-Ray
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / chemistry
  • Epitopes / immunology
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology
  • Influenza A Virus, H1N1 Subtype / chemistry
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza A Virus, H3N2 Subtype / chemistry
  • Influenza A Virus, H3N2 Subtype / immunology
  • Influenza A virus / chemistry
  • Influenza A virus / classification*
  • Influenza A virus / immunology*
  • Influenza Vaccines / immunology
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / prevention & control
  • Orthomyxoviridae Infections / virology
  • Protein Conformation

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Antigens, Viral
  • Complementarity Determining Regions
  • Epitopes
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Influenza Vaccines

Associated data

  • GENBANK/JX206996
  • GENBANK/JX206997
  • PDB/4FNK
  • PDB/4FNL
  • PDB/4FP8
  • PDB/4FQR