Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors

Proc Natl Acad Sci U S A. 2018 Jul 17;115(29):7569-7574. doi: 10.1073/pnas.1802378115. Epub 2018 Jun 28.


Elicitation of broadly neutralizing antibodies (bnAbs) is a leading strategy in rational vaccine design against antigenically diverse pathogens. Here, we studied a panel of monoclonal antibodies (mAbs) from mice immunized with the hepatitis C virus (HCV) envelope glycoproteins E1E2. Six of the mAbs recognize the conserved E2 antigenic site 412-423 (AS412) and cross-neutralize diverse HCV genotypes. Immunogenetic and structural analysis revealed that the antibodies originated from two different germline (GL) precursors and bind AS412 in a β-hairpin conformation. Intriguingly, the anti-HCV activity of one antibody lineage is associated with maturation of the light chain (LC), whereas the other lineage is dependent on heavy-chain (HC) maturation. Crystal structures of GL precursors of the LC-dependent lineage in complex with AS412 offer critical insights into the maturation process of bnAbs to HCV, providing a scientific foundation for utilizing the mouse model to study AS412-targeting vaccine candidates.

Keywords: E1E2 glycoproteins; HCV vaccine; antibody germline precursors; broadly neutralizing antibodies; hepatitis C Virus.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Neutralizing / chemistry*
  • Antibodies, Neutralizing / immunology
  • Cell Line
  • Hepacivirus / chemistry*
  • Hepacivirus / immunology
  • Hepatitis C Antibodies / chemistry*
  • Hepatitis C Antibodies / immunology
  • Humans
  • Immunoglobulin Light Chains / chemistry*
  • Immunoglobulin Light Chains / immunology
  • Mice
  • Single-Chain Antibodies / chemistry*
  • Single-Chain Antibodies / immunology
  • Viral Envelope Proteins / chemistry*
  • Viral Envelope Proteins / immunology
  • Viral Hepatitis Vaccines / chemistry
  • Viral Hepatitis Vaccines / immunology


  • Antibodies, Neutralizing
  • Hepatitis C Antibodies
  • Immunoglobulin Light Chains
  • Single-Chain Antibodies
  • Viral Envelope Proteins
  • Viral Hepatitis Vaccines

Associated data

  • PDB/6BZU
  • PDB/6BZY
  • PDB/6BZW
  • PDB/6BZV