title: Affinity maturation in an HIV broadly neutralizing B-cell lineage through reorientation of variable domains.
abstract: Rapidly evolving pathogens, such as human immunodeficiency and influenza viruses, escape immune defenses provided by most vaccine-induced antibodies. Proposed strategies to elicit broadly neutralizing antibodies require a deeper understanding of antibody affinity maturation and evolution of the immune response to vaccination or infection. In HIV-infected individuals, viruses and B cells evolve together, creating a virus-antibody "arms race." Analysis of samples from an individual designated CH505 has illustrated the interplay between an antibody lineage, CH103, and autologous viruses at various time points. The CH103 antibodies, relatively broad in their neutralization spectrum, interact with the CD4 binding site of gp120, with a contact dominated by CDRH3. We show by analyzing structures of progenitor and intermediate antibodies and by correlating them with measurements of binding to various gp120s that there was a shift in the relative orientation of the light- and heavy-chain variable domains during evolution of the CH103 lineage. We further show that mutations leading to this conformational shift probably occurred in response to insertions in variable loop 5 (V5) of the HIV envelope. The shift displaced the tips of the light chain away from contact with V5, making room for the inserted residues, which had allowed escape from neutralization by the progenitor antibody. These results, which document the selective mechanism underlying this example of a virus-antibody arms race, illustrate the functional significance of affinity maturation by mutation outside the complementarity determining region surface of the antibody molecule.
authors: Laboratory of Molecular Medicine and.
authors: Daniela
authors: D
authors: Fera
authors: Laboratory of Molecular Medicine and.
authors: Aaron G
authors: AG
authors: Schmidt
authors: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710; and.
authors: Barton F
authors: BF
authors: Haynes
authors: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710; and.
authors: Feng
authors: F
authors: Gao
authors: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710; and.
authors: Hua-Xin
authors: HX
authors: Liao
authors: Department of Microbiology and Immunology, Boston University, Boston, MA 02118.
authors: Thomas B
authors: TB
authors: Kepler
authors: Laboratory of Molecular Medicine andHoward Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115; harrison@crystal.harvard.edu.
authors: Stephen C
authors: SC
authors: Harrison
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology; D001402:B-Lymphocytes; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology; D006801:Humans; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: HIV gp120; antibody structure; protein evolution; somatic hypermutation