Molecular analysis of hepatitis C virus - dendritic cell interaction

据估计，全球有1.7亿人感染丙型肝炎病毒(丙型肝炎病毒)，对公众健康有重大影响。治疗选择有限，也没有预防丙型肝炎病毒感染的疫苗。树突状细胞(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。丙型肝炎病毒的成功清除主要与强大的和维持的丙型肝炎病毒特异性的CD4+和CD8+T细胞反应有关，这表明DC有效地启动了T细胞。然而，丙型肝炎病毒感染的特点是其高度慢性化。丙型肝炎病毒建立持久性的机制以及DC在这一过程中的作用尚不清楚。长期以来，由于合成和纯化足够数量的感染性病毒粒子的困难，了解丙型肝炎病毒与DC的相互作用的努力一直受到阻碍。最近，几个实验室成功地建立了一个强大的丙型肝炎病毒细胞培养感染系统，该系统基于一名患有暴发型丙型肝炎的日本患者的病毒分离株的克隆，该克隆可以生产高滴度的传染性病毒*。为了了解丙型肝炎病毒感染的免疫发病机制，本项目将集中于对DC识别、摄取和呈递丙型肝炎病毒的分子分析，以及研究丙型肝炎病毒对DC功能的影响。识别DC处理和呈递丙型肝炎病毒所需的分子机制将有助于理解丙型肝炎病毒的免疫发病机制，并最终可能有助于开发预防和/或治疗性疫苗策略。

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.