An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein

Elife. 2020 Mar 3:9:e53169. doi: 10.7554/eLife.53169.

Abstract

A vaccine protective against diverse HCV variants is needed to control the HCV epidemic. Structures of E2 complexes with front layer-specific broadly neutralizing antibodies (bNAbs) isolated from HCV-infected individuals, revealed a disulfide bond-containing CDRH3 that adopts straight (individuals who clear infection) or bent (individuals with chronic infection) conformation. To investigate whether a straight versus bent disulfide bond-containing CDRH3 is specific to particular HCV-infected individuals, we solved a crystal structure of the HCV E2 ectodomain in complex with AR3X, a bNAb with an unusually long CDRH2 that was isolated from the chronically-infected individual from whom the bent CDRH3 bNAbs were derived. The structure revealed that AR3X utilizes both its ultralong CDRH2 and a disulfide motif-containing straight CDRH3 to recognize the E2 front layer. These results demonstrate that both the straight and bent CDRH3 classes of HCV bNAb can be elicited in a single individual, revealing a structural plasticity of VH1-69-derived bNAbs.

Keywords: Hepatitis C virus; broadly neutralizing antibodies; human; immunogen design; immunology; infectious disease; inflammation; microbiology.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / immunology*
  • Antibody Affinity
  • Cell Line
  • Gene Expression Regulation
  • Hepacivirus / genetics*
  • Humans
  • Immunoglobulin Variable Region
  • Models, Molecular
  • Protein Conformation
  • Protein Domains

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Immunoglobulin Variable Region

Associated data

  • PDB/6URH