Dominant CD4+ T Cell Regulation Causes Chronic Infection

在感染丙型肝炎病毒（HCV）的人中，不超过15%的人能够成功清除病毒并获得完全治愈；其余85%的丙型肝炎病毒感染者发展为慢性病毒感染。CD4+ T细胞对HCV/NS3或HCV/core蛋白的有效应答对于CD8+细胞毒性T细胞的发展至关重要。此外，HLA-DRB1 1101和DQB 0301等位基因都存在于一个常见的高加索单倍型中，与HCV感染个体更好的预后和更好的病毒清除机会相关。相反，同样普遍的HLA-DR7、DQ2单倍型与HCV感染后发生慢性病毒性疾病的高风险相关。该研究将探索这两种非常常见的HLA单倍型如何以不同的方式处理HCV蛋白、HCV/core和NS3抗原。假设HLA- dr7、DQ2单倍型等位基因的功能偏向于诱导调节性T细胞，从而下调病毒特异性T辅助细胞的反应，我们建议使用我们的HLA转基因小鼠模型来研究TCR库、细胞因子反应和肽/MHC结合。我们将生产HLA-DRA/DRB1 1101、DQA 0501/DQB 0301双转基因小鼠，并在重组HCV/core或HCV/NS3蛋白免疫后，比较它们与具有DRA/DRB1 0701、DQA 0201/DQB 0201等位基因的HLA II类转基因小鼠的HCV特异性T细胞应答。这些研究，包括CD4+ T细胞表位定位、改变肽配体的开发以及使用肽脉冲树突状细胞或DNA/RNA质粒进行免疫的尝试，可能直接适用于设计新的更有效的人类丙型肝炎疫苗。

Dominant CD4+ T Cell Regulation Causing Chronic Infection No more than 15 percent of humans who become infected with hepatitis C virus (HCV) succeed in clearing the virus achieving a complete cure; the remaining 85 percent of HCV infected humans develop chronic viral infection. Potent CD4+ T cell responses to either the HCV/NS3 or the HCV/core proteins are critical for development of virus clearing CD8+ cytotoxic T cells. Further, the HLA-DRB1 1101,DQB 0301 alleles both present on a frequent Caucasian haplotype are associated with a better prognosis and a better chance of virus clearance in HCV infected individuals. In contrast, the equally prevalent HLA-DR7, DQ2 haplotype is associated with high risk of developing chronic viral disease after infection with HCV. The proposed research will explore how these two very common HLA haplotypes handle the HCV proteins, HCV/core and NS3 antigens differently. With the hypothesis, that the HLA-DR7, DQ2 haplotype alleles are functioning with a bias for inducing regulatory T cells, which down-regulate the virus specific T helper cell responses, we propose to study TCR repertoires, cytokine responses, and peptide/MHC binding using our HLA transgenic mouse model. We will produce HLA-DRA/DRB1 1101, DQA 0501/DQB 0301 double transgenic mice and compare their HCV specific T cell responses with a similar line of HLA class II transgenic mice with the DRA/DRB1 0701, DQA 0201/DQB 0201 alleles after immunization with recombinant HCV/core or HCV/NS3 protein. These studies, including CD4+ T cell epitope mapping, development of altered peptide ligands and attempts using peptide pulsed dendritic cells or DNA/RNA plasmids for immunization, may be directly applicable in designs of new more effective HCV vaccines for humans.