NUCLEIC ACID VACCINE AS PREVENTIVE AND THERAPEUTIC MODALITY

该计划的启动是为了阐明一种新认识的模式， 疫苗接种和延长我们的免疫反应的长期研究， 丙型肝炎病毒（HCV）感染的临床后遗症。之一 基因免疫的优点是， 蛋白质可以被I类MHC分子识别并在细胞表面表达。 细胞表面细胞表面上的MHC-抗原复合物可以是 被细胞毒性T淋巴细胞（CTL）识别，而CTL又被激活 攻击受感染的细胞诱导免疫反应的可能性 HCV核心蛋白的DNA免疫提供了一个有吸引力的 传统疫苗的替代品。有很多问题 与丙型肝炎疫苗开发相关。主要关注的问题之一 是传染源HCV的遗传稳定性。有两 在假定的HCV包膜蛋白的高变区。免疫逃逸 观察到的突变体归因于这些区域中的突变。 实验感染的黑猩猩和HCV患者被发现有 HCV同源株或新株的反复感染。 这也可能是80%以上的感染 变成慢性病。直接诱导强烈的细胞免疫， 特别是保护性细胞毒性T淋巴细胞，可能不仅有助于 预防初始HCV感染，但也可能产生免疫调节 以克服现有的感染。在过去的一年里，我们建立了 几种不同的含有HCV基因的质粒，并能够评估 在小鼠中诱导针对HCV核心蛋白的抗体。我们正在 开发测定小鼠模型中CTL活性的测定法的过程。

This program was initiated to elucidate a newly recognized modality of vaccination and to extend our long-term study of the immune response and clinical sequelae of hepatitis C virus (HCV) infection. One of the advantages of genetic immunization is that the endogenously expressed proteins can be recognized by class I MHC molecules and expressed on the cell surface. The MHC-antigen complex on the cell surface can be recognized by cytotoxic T lymphocytes (CTL), which in turn are activated and attack infected cells. The possibility of inducing an immune response to HCV core protein using DNA immunization provides an attractive alternative to classic vaccination. There are many problematic issues related to vaccine development for hepatitis C. One of the major concerns is the genetic stability of the infectious agent, HCV. There are two hypervariable regions in the putative HCV envelope proteins. Immune escape mutants observed were attributed to mutations in these regions. Experimentally infected chimpanzees and HCV patients were found to have repeated bouts of infection with either homologous or new strains of HCV. This-could also be one of the reasons that more than 80% of the infections become chronic. Directly inducing strong cell-mediated immunity, especially protective cytotoxic T lymphocyte, may not only help in preventing initial HCV infection, but may also produce immune modulation to overcome existing infection. During the past year, we have constructed several different plasmids containing HCV genes and were able to evaluate the induction of antibodies to HCV core proteins in mice. We are in the process of developing assays to measure CTL activity in the mouse model.