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.
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.
Sarobe
P
P
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Pendleton
C D
CD
Akatsuka
T
T
Lau
D
D
Engelhard
V H
VH
Feinstone
S M
SM
Berzofsky
J A
JA
D000409:Alanine / Q000235:genetics / Q000276:immunology; D000818:Animals; D000940:Antigenic Variation; D003602:Cytotoxicity, Immunologic; D000939:Epitopes; D015789:HLA-A2 Antigen / Q000276:immunology*; D018936:Hepatitis C Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic; D014611:Vaccination; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology*; D014761:Viral Hepatitis Vaccines / Q000276:immunology
D000939:Epitopes; D015789:HLA-A2 Antigen; D018936:Hepatitis C Antigens; D009842:Oligopeptides; D014758:Viral Core Proteins; D014761:Viral Hepatitis Vaccines; C069130:nucleocapsid protein, Hepatitis C virus; D000409:Alanine