Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody

Cell. 2016 Apr 7;165(2):449-63. doi: 10.1016/j.cell.2016.02.022. Epub 2016 Mar 3.

Abstract

Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here, we define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AIDS Vaccines / immunology*
  • Amino Acid Sequence
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • B-Lymphocytes / immunology
  • HIV Antibodies / chemistry
  • HIV Antibodies / immunology*
  • HIV Envelope Protein gp120 / immunology
  • HIV Infections / immunology*
  • HIV Infections / prevention & control
  • HIV-1 / immunology
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Sequence Alignment

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • gp120 protein, Human immunodeficiency virus 1