Cross-neutralization of influenza A viruses mediated by a single antibody loop.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE

Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.

Antibodies, Neutralizing/*chemistry ; Antibodies, Neutralizing/*immunology ; Antibodies, Viral/*chemistry ; Antibodies, Viral/*immunology ; Antibody Specificity/*immunology ; Influenza A virus/*classification ; Influenza A virus/*immunology; Animals ; Antibodies, Neutralizing/genetics ; Antibodies, Viral/genetics ; Antibody Specificity/genetics ; 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 Vaccines/immunology ; Mice ; Models, Molecular ; Molecular Sequence Data ; Mutation/genetics ; Orthomyxoviridae Infections/immunology ; Orthomyxoviridae Infections/prevention & control ; Orthomyxoviridae Infections/virology ; Protein Conformation

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.

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Y1-GM-1104 United States GM NIGMS NIH HHS; U54-AI057158 United States AI NIAID NIH HHS; U01 AI070373 United States AI NIAID NIH HHS; P01AI058113 United States AI NIAID NIH HHS; P41 RR017573 United States RR NCRR NIH HHS; U54 GM094586 United States GM NIGMS NIH HHS; Y1-CO-1020 United States CO NCI NIH HHS; GM080209 United States GM NIGMS NIH HHS; U01AI070373 United States AI NIAID NIH HHS; T32 GM080209 United States GM NIGMS NIH HHS; U54 AI057158 United States AI NIAID NIH HHS; HHSN266200700010C United States AI NIAID NIH HHS; P01 AI058113 United States AI NIAID NIH HHS

GENBANK JX206996; JX206997
PDB 4FNK; 4FNL; 4FP8; 4FQR

0 (Antibodies, Neutralizing)
0 (Antibodies, Viral)
0 (Antigens, Viral)
0 (Complementarity Determining Regions)
0 (Epitopes)
0 (Hemagglutinin Glycoproteins, Influenza Virus)
0 (Influenza Vaccines)

Date Created: 20120918 Date Completed: 20121112 Latest Revision: 20211021

20221213

PMC3538848

10.1038/nature11414

22982990