Enhanced in vitro potency and in vivo immunogenicity of a CTL epitope from hepatitis C virus core protein following amino acid replacement at secondary HLA-A2.1 binding positions

J Clin Invest. 1998 Sep 15;102(6):1239-48. doi: 10.1172/JCI3714.


Since the natural immune response to hepatitis C virus (HCV) is often unable to clear the infection, to enhance immunogenicity we studied substituted peptides from an HCV cytotoxic T lymphocyte (CTL) epitope (C7A2) from a conserved region of the HCV core protein (DLMGYIPLV) recognized by CTL lines from HLA-A2.1(+) HCV-infected patients and HLA-A2.1 transgenic mice. HLA-A2.1 binding, human and murine CTL recognition, and in vivo immunogenicity (using mice transgenic for human HLA-A2 in lieu of immunizing humans) were analyzed to define peptides with enhanced immunogenicity. Peptides substituted at position 1 showed enhanced HLA-A2 binding affinity, but paradoxically poorer immunogenicity. A peptide with Ala substituted at position 8 (8A) showed higher HLA-A2 binding affinity and CTL recognition and was a more potent in vivo immunogen in HLA-A2-transgenic mice, inducing higher CTL responses with higher avidity against native C7A2 than induced by C7A2 itself. These results suggest that peptide 8A is a more potent in vitro antigen and in vivo immunogen than C7A2 and may be useful as a vaccine component. They provide proof of principle that the strategy of epitope enhancement can enhance immunogenicity of a CTL epitope recognized by human CTL.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alanine / genetics
  • Alanine / immunology
  • Animals
  • Antigenic Variation
  • Cytotoxicity, Immunologic
  • Epitopes
  • HLA-A2 Antigen / immunology*
  • Hepatitis C Antigens / genetics
  • Hepatitis C Antigens / immunology*
  • Humans
  • Mice
  • Mice, Transgenic
  • Oligopeptides / genetics
  • Oligopeptides / immunology*
  • Protein Binding
  • T-Lymphocytes, Cytotoxic*
  • Vaccination
  • Viral Core Proteins / genetics
  • Viral Core Proteins / immunology*
  • Viral Hepatitis Vaccines / immunology


  • Epitopes
  • HLA-A2 Antigen
  • Hepatitis C Antigens
  • Oligopeptides
  • Viral Core Proteins
  • Viral Hepatitis Vaccines
  • nucleocapsid protein, Hepatitis C virus
  • Alanine