V2-Directed Vaccine-like Antibodies from HIV-1 Infection Identify an Additional K169-Binding Light Chain Motif with Broad ADCC Activity

Cell Rep. 2018 Dec 11;25(11):3123-3135.e6. doi: 10.1016/j.celrep.2018.11.058.


Antibodies that bind residue K169 in the V2 region of the HIV-1 envelope correlated with reduced risk of infection in the RV144 vaccine trial but were restricted to two ED-motif-encoding light chain genes. Here, we identify an HIV-infected donor with high-titer V2 peptide-binding antibodies and isolate two antibody lineages (CAP228-16H/19F and CAP228-3D) that mediate potent antibody-dependent cell-mediated cytotoxicity (ADCC). Both lineages use the IGHV5-51 heavy chain germline gene, similar to the RV144 antibody CH58, but one lineage (CAP228-16H/19F) uses a light chain without the ED motif. A cocrystal structure of CAP228-16H bound to a V2 peptide identified a IGLV3-21 gene-encoded DDxD motif that is used to bind K169, with a mechanism that allows CAP228-16H to recognize more globally relevant V2 immunotypes. Overall, these data further our understanding of the development of cross-reactive, V2-binding, antiviral antibodies and effectively expand the human light chain repertoire able to respond to RV144-like immunogens.

Keywords: ADCC; CAP228; CH58; ED motif; HIV; K169; RV144 vaccine response; V2 antibodies; V2 structure; antibody evolution.

Publication types

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

MeSH terms

  • AIDS Vaccines / immunology*
  • Alleles
  • Amino Acid Sequence
  • Antibody-Dependent Cell Cytotoxicity / immunology*
  • HIV Antibodies / immunology*
  • HIV Antibodies / isolation & purification
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / metabolism
  • HIV Infections / immunology*
  • HIV Infections / virology*
  • Humans
  • Immunoglobulin Light Chains / chemistry
  • Immunoglobulin Light Chains / metabolism*
  • Lysine / metabolism*
  • Models, Molecular
  • Peptides / metabolism
  • Protein Binding
  • Tissue Donors


  • AIDS Vaccines
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Immunoglobulin Light Chains
  • Peptides
  • Lysine