Investigation for the development of vaccine against hepatitis C virus

我们利用包含整个核心区域全长的重组HCV核心蛋白，从免疫原性、H-2连锁基因的影响、精细特异性以及与体内抗体产生的关系等方面研究了小鼠T细胞对HCV核心蛋白的反应。与HBcAg相比，HCV核心蛋白在体液和细胞反应方面的免疫原性明显较低。H-2连锁基因对HCV核心蛋白的体液应答的影响是可识别的，鉴定出高应答者（H-2f）、中应答者（H-2b, s）和低应答者（H-2k, d, p）单倍型。T细胞识别位点由小的（18个残基）合成肽确定。每个菌株识别一个主要的T细胞决定因素，这种识别过程的精细特异性取决于响应菌株的H-2单倍型。例如，H-2f菌株主要识别p41-55， H-2b菌株主要识别p11-25， H-2s菌株主要识别p161-175。当B10。用p41-55肽原免疫M （H2-f）小鼠，用HCV核心蛋白二次免疫后产生足够的免疫应答。因此，p41-55肽是抗HCV感染疫苗的良好候选肽。这些结果表明，HCV核心抗原的免疫应答受H-2连锁基因的影响，HCV核心抗原的免疫原性较低，具有临床意义，大多数急性HCV感染患者在早期产生较低的病毒蛋白抗体。

We have examined the murine T cell response to HCV core protein in terms of immunogenicity, the influence of H-2 linked genes, fine specificity, and relationship to in vivo antibody production by using recombinant HCV core protein which contains full length of entire core region. The HCV core protein was shown to have markedly lower immunogenicity compared to HBcAg on humoral and cellular response. The influence of H-2 linked genes on the humoral response to HCV core protein was discernible, and high responder (H-2f), intermediate responder (H-2b, s), and low responder (H-2k, d, p) haplotypes were identified. T cell recognition sites were defined by small (18 residue) synthetic peptides. Each strain recognized a predominant T cell determinant, and the fine specificity of this recognition process was dependent on the H-2 haplotype of the responding strain. For example, H-2f strain recognized p41-55, H-2b strain recognized p11-25, H-2s strain recognized p161-175 predominantly. When B10.M (H2-f) mice were primary immunized by p41-55 peptide, these mice had enough immune response after secondary immunization with HCV core protein. Therefore, p41-55 peptide is a good candidate for vaccine against HCV infection. These results that immune response to HCV core antigen is influenced by H-2 linked genes and that HCV core antigen is low immunogenic have clinical relevance most of patients with acute HCV infection produce lower antibodies against viral proteins in early phase.