Dominant CD4+ T Cell Regulation Causes Chronic Infection

CD4 T 细胞调节占主导地位导致慢性感染 感染丙型肝炎病毒 (HCV) 的人成功清除病毒并实现完全治愈的比例不超过 15%；其余 85% 的 HCV 感染者会发展为慢性病毒感染。 CD4 T 细胞对 HCV/NS3 或 HCV/核心蛋白的有效反应对于病毒清除 CD8 细胞毒性 T 细胞的发育至关重要。此外，HLA-DRB1 1101、DQB 0301 等位基因均存在于常见的白种人单倍型上，与 HCV 感染个体的更好预后和更好的病毒清除机会相关。 相比之下，同样流行的 HLA-DR7、DQ2 单倍型与感染 HCV 后患慢性病毒性疾病的高风险相关。 拟议的研究将探讨这两种非常常见的 HLA 单倍型如何以不同的方式处理 HCV 蛋白、HCV/核心和 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 辅助细胞反应，我们建议使用我们的 HLA 转基因小鼠模型研究 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，并在用重组 HCV/core 或 HCV/NS3 蛋白免疫后，将它们的 HCV 特异性 T 细胞反应与具有 DRA/DRB1 0701、DQA 0201/DQB 0201 等位基因的类似 HLA II 类转基因小鼠系进行比较。这些研究，包括 CD4 T 细胞表位作图、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，可能会直接应用于设计新的更有效的人类 HCV 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.