title: Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody.
abstract: 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.
authors.affiliation: Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Schmidt
authors.forename: Huafeng
authors.initials: H
authors.lastname: Xu
authors.forename: Amir R
authors.initials: AR
authors.lastname: Khan
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Donnell
authors.forename: Surender
authors.initials: S
authors.lastname: Khurana
authors.forename: Lisa R
authors.initials: LR
authors.lastname: King
authors.forename: Jody
authors.initials: J
authors.lastname: Manischewitz
authors.forename: Hana
authors.initials: H
authors.lastname: Golding
authors.forename: Pirada
authors.initials: P
authors.lastname: Suphaphiphat
authors.forename: Andrea
authors.initials: A
authors.lastname: Carfi
authors.forename: Ethan C
authors.initials: EC
authors.lastname: Settembre
authors.forename: Philip R
authors.initials: PR
authors.lastname: Dormitzer
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kepler
authors.forename: Ruijun
authors.initials: R
authors.lastname: Zhang
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harrison
mesh_terms: D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000235:genetics*; D000914:Antibodies, Viral / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000235:genetics*; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007252:Influenza Vaccines / Q000276:immunology*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009975:Orthomyxoviridae / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007140:Immunoglobulin Fab Fragments; D007135:Immunoglobulin Variable Region; D007252:Influenza Vaccines