Hepatitis C Virus Immunobiology and Pathogenesis

描述（由申请人提供）：丙型肝炎病毒（HCV）是一种正链RNA病毒，感染超过1亿人，并引起急性和慢性肝炎以及肝细胞癌。HCV感染的结果被认为是由病毒的高复制和突变率以及T细胞应答的动力学、幅度、质量和持续时间决定的。特别是，许多可以用HLA I类四聚体显现的HCV特异性CD 8（T）细胞不能产生干扰素γ（IFN γ），尤其是在慢性感染期间。我们最近的观察表明，这种功能障碍表型在HCV感染的发病机制中具有潜在的重要性：（a）它也预示着CD 8+细胞的发病，（B）它与急性病毒性肝炎期间的高病毒滴度和显著的肝细胞损伤相关;（c）当病毒被清除时，它恢复或被产生IFN γ的CD 8 + T细胞取代。我们认为，T细胞功能的动态变化，如这一点，和其他尚未被检查，可能有一个重要的影响HCV感染的过程和结果。因此，在本申请中，我们将通过比较急性和慢性感染的人和黑猩猩中对HCV的CD 4（和CD 8（T细胞应答的表型和功能演变与感染的严重程度和持续时间来检验这一假设。我们还将进行体内耗竭实验，以直接检查CD 4+或CD 8 + T细胞是否控制HCV感染，并确定IFN γ介导其抗病毒潜力的程度。这些信息不仅将为HCV感染的免疫生物学提供基本的见解，还可能导致免疫学和抗病毒方法的发展，以预防和治疗这种严重的疾病。

DESCRIPTION (provided by applicant): The hepatitis C virus (HCV) is a plus-stranded RNA virus that infects more than 100 million people and causes acute and chronic hepatitis and hepatocellular carcinoma. The outcome of HCV infection is thought to be determined by the high replication and mutation rates of the virus, and by the kinetics, magnitude, quality and duration of the T cell response. In particular, many HCV-specific CD8( T cells that can be visualized with HLA class I tetramers fail to produce inteferon gamma (IFNgamma), especially during chronic infection. The potential importance of this dysfunctional phenotype in the pathogenesis of HCV infection is suggested by our recent observations that: (a) it also heralds the onset of the CD8( T cell response to HCV during the incubation phase of infection; (b) it correlates with high viral titers and significant liver cell injury during acute viral hepatitis; (c) it recovers or is replaced by CD8+ T cells that produce IFNgamma when the virus is cleared. We suggest that dynamic changes in T cell function such as this, and others that have not yet been examined, may have an important impact on the course and outcome of HCV infection. In the current application, therefore, we will test this hypothesis by comparing the phenotypic and functional evolution of the CD4( and CD8( T cell responses to HCV with the severity and duration of infection in acutely and chronically infected humans and chimpanzees. We will also perform in vivo depletion experiments to directly examine whether CD4+ or CD8+ T cells control HCV infection, and to determine the extent to which their antiviral potential is mediated by IFNgamma. This information will not only provide fundamental insight into the immunobiology of HCV infection, it may also lead to the development of immunotherapeutic and antiviral approaches to prevent and treat this serious disease.