Immune Escape Strategies in Hepatitis C

丙型肝炎病毒（HCV）感染是一个主要的公共卫生问题，影响了世界上约3%的人口， 人口（1）。HCV在高达80%的感染者中持续存在（2），慢性感染可导致 进行性肝病，包括肝硬化和肝细胞癌。HCV相关的肝脏疾病是 是全世界肝移植的唯一主要适应症。虽然新的治疗方法 提高了持续应答率，大部分患者对抗病毒治疗无效 或产生显著的药物毒性，因此仍有疾病进展的风险。一部分人是 能够建立有效的抗HCV免疫应答，令人信服的数据强调了 CTL应答在介导HCV自发清除和治疗诱导清除中的质量和性质。 了解HCV-宿主相互作用是对抗这种病毒和开发改进的 治疗我们提出以下相互关联的目标： 具体目的1：全面研究T细胞免疫球蛋白和粘蛋白在免疫系统中的作用 含结构域蛋白-3（Tim-3）/半乳糖凝集素-9途径在赋予保护性免疫与 急性和慢性HCV感染的持续性。 具体目的2：研究操纵多重共刺激/共抑制的作用 调节免疫衰竭和HCV特异性CTL失败的途径，定义了HCV感染的程度。 多功能恢复，并确定不同的细胞内机制。 具体目标3：确定自然杀伤T（NKT）细胞的表型和功能方面， 可以被操纵以增强抗HCV功效。

Hepatitis C virus (HCV) infection is a major public health concern affecting approximately 3% of the worid's population (1). HCV persists in up to 80% of people infected (2), and chronic infection can lead to progressive liver disease including cirrhosis and hepatocellular carcinoma. HCV-related liver disease is the single leading indication for liver transplantation throughout the worid. Although new therapies have improved the rates of sustained response, a large proportion of patients fails to respond to antiviral treatment or develop significant drug toxicity, thus remaining at risk for disease progression. A subset of individuals is able to mount effective anti-HCV immune responses, and compelling data underscore the importance of the quality and nature of the CTL response in mediating spontaneous and treatment-induced clearance of HCV. An understanding of HCV-host interactions is required to combat this virus and to develop improved therapies. We propose the following inter-related aims: Specific Aim 1: To comprehensively investigate the role ofthe T cell immunoglobulin and mucin domain-containing protein-3 (Tim-3)/galectin-9 pathway in conferring protective immunity versus persistence in acute and chronic HCV infection. Specific Aim 2: To investigate the effect of manipulating multiple costimulatory/coinhibitory pathways that regulate immune exhaustion and failure of HCV-specific CTLs, define the extent of polyfunctional restoration, and identify the distinct intracellular mechanisms. Specific Aim 3: Determine the phenotypic and fimctional aspects of natural killer T (NKT) cells that can be manipulated in order to enhance anti-HCV efficacy.