Genetic and structural insights into broad neutralization of hepatitis C virus by human V H 1-69 antibodies

Sci Adv. 2019 Jan 2;5(1):eaav1882. doi: 10.1126/sciadv.aav1882. eCollection 2019 Jan.

Abstract

An effective vaccine to the antigenically diverse hepatitis C virus (HCV) must target conserved immune epitopes. Here, we investigate cross-neutralization of HCV genotypes by broadly neutralizing antibodies (bNAbs) encoded by the relatively abundant human gene family V H 1-69. We have deciphered the molecular requirements for cross-neutralization by this unique class of human antibodies from crystal structures of HCV E2 in complex with bNAbs. An unusually high binding affinity is found for germ line-reverted versions of VH1-69 precursor antibodies, and neutralization breadth is acquired during affinity maturation. Deep sequencing analysis of an HCV-immune B cell repertoire further demonstrates the importance of the V H 1-69 gene family in the generation of HCV bNAbs. This study therefore provides critical insights into immune recognition of HCV with important implications for rational vaccine design.

Publication types

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

MeSH terms

  • Antibodies, Monoclonal / immunology*
  • Antibodies, Neutralizing / immunology*
  • Antibody Affinity / immunology
  • Binding Sites
  • Blood Donors
  • Cell Line, Tumor
  • Cross Reactions / immunology
  • Dual-Specificity Phosphatases / genetics*
  • Dual-Specificity Phosphatases / immunology*
  • Epitopes / chemistry
  • Hepacivirus / immunology*
  • Hepatitis C / immunology*
  • Hepatitis C / virology
  • Hepatitis C Antibodies / immunology*
  • Humans
  • Viral Envelope Proteins / immunology
  • Viral Envelope Proteins / metabolism
  • Viral Hepatitis Vaccines / genetics
  • Viral Hepatitis Vaccines / immunology

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Epitopes
  • Hepatitis C Antibodies
  • Viral Envelope Proteins
  • Viral Hepatitis Vaccines
  • glycoprotein E2, Hepatitis C virus
  • dual specificity phosphatase 12
  • Dual-Specificity Phosphatases