Rapid development of broadly influenza neutralizing antibodies through redundant mutations
- 5 October 2014
- journal article
- letter
- Published by Springer Science and Business Media LLC in Nature
- Vol. 516 (7531), 418-422
- https://doi.org/10.1038/nature13764
Abstract
The neutralizing antibody response to influenza virus is dominated by antibodies that bind to the globular head of haemagglutinin, which undergoes a continuous antigenic drift, necessitating the re-formulation of influenza vaccines on an annual basis. Recently, several laboratories have described a new class of rare influenza-neutralizing antibodies that target a conserved site in the haemagglutinin stem1,2,3,4,5,6. Most of these antibodies use the heavy-chain variable region VH1-69 gene, and structural data demonstrate that they bind to the haemagglutinin stem through conserved heavy-chain complementarity determining region (HCDR) residues. However, the VH1-69 antibodies are highly mutated and are produced by some but not all individuals6,7, suggesting that several somatic mutations may be required for their development8,9. To address this, here we characterize 197 anti-stem antibodies from a single donor, reconstruct the developmental pathways of several VH1-69 clones and identify two key elements that are required for the initial development of most VH1-69 antibodies: a polymorphic germline-encoded phenylalanine at position 54 and a conserved tyrosine at position 98 in HCDR3. Strikingly, in most cases a single proline to alanine mutation at position 52a in HCDR2 is sufficient to confer high affinity binding to the selecting H1 antigen, consistent with rapid affinity maturation. Surprisingly, additional favourable mutations continue to accumulate, increasing the breadth of reactivity and making both the initial mutations and phenylalanine at position 54 functionally redundant. These results define VH1-69 allele polymorphism, rearrangement of the VDJ gene segments and single somatic mutations as the three requirements for generating broadly neutralizing VH1-69 antibodies and reveal an unexpected redundancy in the affinity maturation process.This publication has 39 references indexed in Scilit:
- Identification of TRIM22 single nucleotide polymorphisms associated with loss of inhibition of HIV-1 transcription and advanced HIV-1 diseaseAIDS, 2013
- Cross-neutralization of four paramyxoviruses by a human monoclonal antibodyNature, 2013
- Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 NeutralizationCell, 2013
- Somatic hypermutation maintains antibody thermodynamic stability during affinity maturationProceedings of the National Academy of Sciences of the United States of America, 2013
- Germinal CentersAnnual Review of Immunology, 2012
- A Neutralizing Antibody Selected from Plasma Cells That Binds to Group 1 and Group 2 Influenza A HemagglutininsScience, 2011
- A new bioinformatics analysis tools framework at EMBL-EBINucleic Acids Research, 2010
- Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccineJCI Insight, 2010
- A practical influenza neutralization assay to simultaneously quantify hemagglutinin and neuraminidase-inhibiting antibody responsesVaccine, 2010
- Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B CellsPLOS ONE, 2008