Molecular analysis of hepatitis C virus - dendritic cell interaction

据估计，全世界有1.7亿感染者，丙型肝炎病毒（HCV）对公共卫生有重大影响。治疗选择有限，并且没有预防HCV感染的疫苗。树突状细胞（Dendritic cells，DC）作为抗原提呈细胞在抗病毒免疫的产生和调节中起着至关重要的作用。HCV的成功病毒清除主要与强且维持的HCV特异性CD 4+和CD 8 + T细胞应答相关，表明DC的有效T细胞引发。然而，HCV感染的特征在于其高度慢性化倾向。HCV建立持久性的机制以及DC在此过程中的作用尚不清楚。由于难以合成和纯化足够数量的感染性病毒粒子，长期以来，理解HCV与DC相互作用的努力受到阻碍。最近，几个实验室成功地建立了一个强大的HCV细胞培养感染系统，该系统基于来自日本暴发性丙型肝炎患者的病毒分离株的克隆，可以生产高滴度感染性病毒 *。本项目旨在了解HCV感染的免疫发病机制，重点研究DC对HCV的识别、摄取和提呈的分子机制，以及HCV对DC功能的影响。识别的分子机制所需的丙型肝炎病毒的加工和介绍的DC将有助于显着的理解丙型肝炎病毒的免疫发病机制，并最终可能有助于预防和/或治疗性疫苗策略的发展。

With an estimated 170 million infected individuals worldwide, hepatitis C virus (HCV) has a major impact on public health. Treatment options are limited and a vaccine for prevention against HCV infection is not available. Dendritic cells (DCs) play as antigen-presenting cells a crucial role in the generation and regulation of anti-viral immunity. Successful viral clearance of HCV is mainly associated with a strong and maintained HCV-specific CD4+ and CD8+ T cell response indicating efficient T cell priming by DCs. However, infection by HCV is characterized by its high tendency to chronicity. The mechanisms by which HCV establishes persistence and the role of DCs in this process are unkown. Efforts to understand the interaction of HCV with DCs have been hampered for a long time due to the difficulties to synthesize and purify sufficient quantities of infectious virions. Most recently, several laboratories succeeded in establishing a robust HCV cell culture infection system based on a clone derived from a viral isolate of a Japanese patient with fulminant hepatitis C, that allows the production of high titre infectious virus*. Aiming to understand the immunopathogenesis of an HCV infection, this project will focus on the molecular analysis of HCV recognition, uptake and presentation by DCs as well as study effects of HCV on DC function. The identification of molecular mechanisms required for HCV processing and presentation by DCs will contribute significantly to the understanding of HCV immunopathogenesis and may finally contribute to the development of preventive and/or therapeutic vaccine strategies.