Dominant CD4+ T Cell Regulation Causes Chronic Infection

主导的CD4T细胞调节导致慢性感染丙型肝炎病毒(丙型肝炎病毒)感染者中不超过15%的人成功清除病毒，实现完全治愈；其余85%的丙型肝炎病毒感染者发展为慢性病毒感染。强大的CD4T细胞对丙型肝炎病毒/NS3或丙型肝炎病毒/核心蛋白的应答对于发展清除病毒的CD8细胞毒性T细胞至关重要。此外，在常见的高加索人单倍型上存在的两个等位基因-DRB11101和DQB0301都与丙型肝炎病毒感染者更好的预后和更好的病毒清除机会相关。相反，同样流行的人类白细胞抗原-DR7、DQ2单倍型与感染丙型肝炎后发展成慢性病毒疾病的高风险相关。这项拟议的研究将探索这两种非常常见的人类白细胞抗原单倍型如何不同地处理丙型肝炎病毒蛋白、丙型肝炎病毒核心抗原和NS3抗原。基于人类白细胞抗原-DR7、DQ2单倍型等位基因的功能偏向于诱导调节性T细胞，下调病毒特异性T辅助细胞应答的假设，我们建议使用我们的转基因小鼠模型来研究TCR谱系、细胞因子应答和多肽/MHC结合。我们将制备出HLA-DRA/DRB1 1101、DQA 0501/DQB 0301双转基因小鼠，并将其与含有DRA/DRB1 0701、DQA 0201/DQB 0201等位基因的HLAII类转基因小鼠免疫后的丙型肝炎病毒特异性T细胞应答进行比较。这些研究包括CD4T细胞表位定位，改变的多肽配体的开发，以及尝试使用多肽冲击的树突状细胞或DNA/RNA质粒进行免疫，这些研究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.