Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody.

Published

Journal Article

Affinity maturation refines a naive B-cell response by selecting mutations in antibody variable domains that enhance antigen binding. We describe a B-cell lineage expressing broadly neutralizing influenza virus antibodies derived from a subject immunized with the 2007 trivalent vaccine. The lineage comprises three mature antibodies, the unmutated common ancestor, and a common intermediate. Their heavy-chain complementarity determining region inserts into the conserved receptor-binding pocket of influenza HA. We show by analysis of structures, binding kinetics and long time-scale molecular dynamics simulations that antibody evolution in this lineage has rigidified the initially flexible heavy-chain complementarity determining region by two nearly independent pathways and that this preconfiguration accounts for most of the affinity gain. The results advance our understanding of strategies for developing more broadly effective influenza vaccines.

Full Text

Duke Authors

Cited Authors

  • Schmidt, AG; Xu, H; Khan, AR; O'Donnell, T; Khurana, S; King, LR; Manischewitz, J; Golding, H; Suphaphiphat, P; Carfi, A; Settembre, EC; Dormitzer, PR; Kepler, TB; Zhang, R; Moody, MA; Haynes, BF; Liao, H-X; Shaw, DE; Harrison, SC

Published Date

  • January 2, 2013

Published In

Volume / Issue

  • 110 / 1

Start / End Page

  • 264 - 269

PubMed ID

  • 23175789

Pubmed Central ID

  • 23175789

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1218256109

Language

  • eng

Conference Location

  • United States