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，导致急性和慢性肝炎和肝细胞癌。HCV感染的结果被认为是由病毒的高复制和突变率以及T细胞反应的动力学、大小、质量和持续时间决定的。特别是，许多hcv特异性CD8(T细胞可以用HLA I类四聚体可视化，不能产生干扰素γ (IFNgamma)，特别是在慢性感染期间。我们最近的观察结果表明，这种功能失调表型在HCV感染发病机制中的潜在重要性：(a)它也预示着在感染的潜伏期CD8(T)细胞对HCV的反应的开始；(b)它与急性病毒性肝炎期间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IFNgamma的CD8+ T细胞所取代。我们认为，像这样的T细胞功能的动态变化，以及其他尚未被研究的变化，可能对HCV感染的过程和结果有重要影响。因此，在当前的应用中，我们将通过比较急性和慢性感染人类和黑猩猩中CD4（和CD8） T细胞对HCV的反应的表型和功能进化，以及感染的严重程度和持续时间来验证这一假设。我们还将进行体内消耗实验，直接检查CD4+或CD8+ T细胞是否控制HCV感染，并确定其抗病毒潜力在多大程度上是由IFNgamma介导的。这一信息不仅将为HCV感染的免疫生物学提供基本的见解，还可能导致免疫治疗和抗病毒方法的发展，以预防和治疗这种严重疾病。

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.