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，影响着世界上约3%的 人口(1)。丙型肝炎病毒在高达80%的感染者中持续存在(2)，慢性感染可导致 进行性肝病，包括肝硬变和肝细胞癌。丙型肝炎病毒相关的肝病是 全球肝移植的单一领先适应症。尽管新的疗法已经 提高持续应答率，很大比例的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。个体的子集是 能够建立有效的抗丙型肝炎病毒免疫反应，令人信服的数据强调了 在调节自发和治疗诱导的丙型肝炎病毒清除中CTL反应的性质和性质。 需要了解丙型肝炎病毒与宿主之间的相互作用，以对抗这种病毒并改进 治疗。我们提出了以下相互关联的目标： 特异性目标1：全面研究T细胞免疫球蛋白和粘蛋白的作用 含结构域蛋白-3(TIM-3)/Galectin-9途径在保护性免疫中的作用 在急性和慢性丙型肝炎病毒感染中的持久性。 特定目标2：研究操纵多个共刺激/共抑制的效果 调节免疫衰竭和丙型肝炎病毒特异性CTL失效的途径，定义了 多功能修复，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 可以通过操控来增强抗丙型肝炎病毒的疗效。

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.