title: Reconstructing a B-Cell Clonal Lineage. II. Mutation, Selection, and Affinity Maturation.
abstract: Affinity maturation of the antibody response is a fundamental process in adaptive immunity during which B-cells activated by infection or vaccination undergo rapid proliferation accompanied by the acquisition of point mutations in their rearranged immunoglobulin (Ig) genes and selection for increased affinity for the eliciting antigen. The rate of somatic hypermutation at any position within an Ig gene is known to depend strongly on the local DNA sequence, and Ig genes have region-specific codon biases that influence the local mutation rate within the gene resulting in increased differential mutability in the regions that encode the antigen-binding domains. We have isolated a set of clonally related natural Ig heavy chain-light chain pairs from an experimentally infected influenza patient, inferred the unmutated ancestral rearrangements and the maturation intermediates, and synthesized all the antibodies using recombinant methods. The lineage exhibits a remarkably uniform rate of improvement of the effective affinity to influenza hemagglutinin (HA) over evolutionary time, increasing 1000-fold overall from the unmutated ancestor to the best of the observed antibodies. Furthermore, analysis of selection reveals that selection and mutation bias were concordant even at the level of maturation to a single antigen. Substantial improvement in affinity to HA occurred along mutationally preferred paths in sequence space and was thus strongly facilitated by the underlying local codon biases.
authors.affiliation: Department of Microbiology, Boston University School of Medicine , Boston, MA , USA ; Department of Mathematics and Statistics, Boston University , Boston, MA , USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kepler
authors.affiliation: Center for Viral Hepatitis Research, Johns Hopkins University , Baltimore, MD , USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Munshaw
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center , Durham, NC , USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wiehe
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center , Durham, NC , USA.
authors.forename: Ruijun
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center , Durham, NC , USA ; Department of Medicine, Duke University Medical Center , Durham, NC , USA.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Yu
authors.affiliation: Department of Medicine, Duke University Medical Center , Durham, NC , USA ; Department of Pathology, Duke University Medical Center , Durham, NC , USA ; Hubert-Yeargan Center for Global Health, Duke University Medical Center , Durham, NC , USA ; Department of Pediatrics, Duke University Medical Center , Durham, NC , USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Woods
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center , Durham, NC , USA ; Department of Medicine, Duke University Medical Center , Durham, NC , USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Denny
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center , Durham, NC , USA ; Department of Medicine, Duke University Medical Center , Durham, NC , USA ; Department of Immunology, Duke University Medical Center , Durham, NC , USA.
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center , Durham, NC , USA ; Department of Medicine, Duke University Medical Center , Durham, NC , USA.
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.affiliation: Center for Viral Hepatitis Research, Johns Hopkins University , Baltimore, MD , USA ; Duke Human Vaccine Institute, Duke University Medical Center , Durham, NC , USA.
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center , Durham, NC , USA ; Department of Immunology, Duke University Medical Center , Durham, NC , USA.
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center , Durham, NC , USA ; Department of Medicine, Duke University Medical Center , Durham, NC , USA.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center , Durham, NC , USA ; Department of Medicine, Duke University Medical Center , Durham, NC , USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
keywords: antibody affinity maturation; antibody selection; experimental influenza infection; phylogenetics; somatic hypermutation