Sarobe P, Pendleton C D, Akatsuka T, Lau D, Engelhard V H, Feinstone S M, Berzofsky J A
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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.
由于对丙型肝炎病毒（HCV）的天然免疫反应通常无法清除感染，为增强免疫原性，我们研究了来自HCV核心蛋白保守区域（DLMGYIPLV）的HCV细胞毒性T淋巴细胞（CTL）表位（C7A2）的替代肽，该表位可被HLA-A2.1(+) HCV感染患者和HLA-A2.1转基因小鼠的CTL系识别。分析了HLA-A2.1结合、人和小鼠CTL识别以及体内免疫原性（使用人HLA-A2转基因小鼠代替免疫人），以确定具有增强免疫原性的肽。在第1位被替代的肽显示出增强的HLA-A2结合亲和力，但矛盾的是免疫原性较差。在第8位被丙氨酸替代的肽（8A）显示出更高的HLA-A2结合亲和力和CTL识别，并且在HLA-A2转基因小鼠中是一种更强效的体内免疫原，与C7A2自身诱导的相比，能诱导出更高的CTL反应，对天然C7A2具有更高的亲和力。这些结果表明，肽8A在体外是比C7A2更有效的抗原，在体内是比C7A2更有效的免疫原，可能用作疫苗成分。它们提供了原理证明，即表位增强策略可以增强人CTL识别的CTL表位的免疫原性。
