HCV Glycoprotein Structure and Implications for B-Cell Vaccine Development

Int J Mol Sci. 2020 Sep 16;21(18):6781. doi: 10.3390/ijms21186781.


Despite the approval of highly efficient direct-acting antivirals in the last decade Hepatitis C virus (HCV) remains a global health burden and the development of a vaccine would constitute an important step towards the control of HCV. The high genetic variability of the viral glycoproteins E1 and E2, which carry the main neutralizing determinants, together with their intrinsic structural flexibility, the high level of glycosylation that shields conserved neutralization epitopes and immune evasion using decoy epitopes renders the design of an efficient vaccine challenging. Recent structural and functional analyses have highlighted the role of the CD81 receptor binding site on E2, which overlaps with those neutralization epitopes within E2 that have been structurally characterized to date. This CD81 binding site consists of three distinct segments including "epitope I", "epitope II" and the "CD81 binding loop". In this review we summarize the structural features of the HCV glycoproteins that have been derived from X-ray structures of neutralizing and non-neutralizing antibody fragments complexed with either recombinant E2 or epitope-derived linear peptides. We focus on the current understanding how neutralizing antibodies interact with their cognate antigen, the structural features of the respective neutralization epitopes targeted by nAbs and discuss the implications for informed vaccine design.

Keywords: Hepatitis C virus; glycoprotein; nAbs; neutralization epitope; neutralizing antibodies; vaccine.

Publication types

  • Review

MeSH terms

  • Antibodies, Neutralizing / immunology
  • Antigen-Antibody Reactions
  • Antigens, Viral / chemistry*
  • Antigens, Viral / immunology
  • B-Lymphocytes / immunology*
  • Dimerization
  • Epitopes / chemistry
  • Epitopes / immunology
  • Glycosylation
  • Hepacivirus / chemistry
  • Hepacivirus / immunology*
  • Hepatitis C Antibodies / immunology
  • Humans
  • Immunoglobulin Fab Fragments / immunology
  • Models, Molecular
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology
  • Protein Conformation
  • Protein Domains
  • Protein Processing, Post-Translational
  • Single-Chain Antibodies / immunology
  • Viral Envelope Proteins / chemistry*
  • Viral Envelope Proteins / immunology
  • Viral Hepatitis Vaccines


  • Antibodies, Neutralizing
  • Antigens, Viral
  • E1 protein, Hepatitis C virus
  • Epitopes
  • Hepatitis C Antibodies
  • Immunoglobulin Fab Fragments
  • Peptide Fragments
  • Single-Chain Antibodies
  • Viral Envelope Proteins
  • Viral Hepatitis Vaccines
  • glycoprotein E2, Hepatitis C virus