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.
P Sarobe, C D Pendleton, T Akatsuka, D Lau, V H Engelhard, S M Feinstone, J A Berzofsky
Title and authors | Publication | Year |
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Progress on new vaccine strategies against chronic viral infections
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Journal of Clinical Investigation | 2004 |
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The HIV-1 HLA-A2-SLYNTVATL Is a Help-Independent CTL Epitope
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Journal of immunology (Baltimore, Md. : 1950) | 2004 |
Human CTLs to Wild-Type and Enhanced Epitopes of a Novel Prostate and Breast Tumor-Associated Protein, TARP, Lyse Human Breast Cancer Cells
SK Oh, M Terabe, CD Pendleton, A Bhattacharyya, TK Bera, M Epel, Y Reiter, J Phillips, WM Linehan, C Kasten-Sportes, I Pastan, JA Berzofsky |
Cancer research | 2004 |