MECHANISMS OF HEPATITIS C VIRUS PERSISTENCE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们假设，在HCV感染的个体中，CD 4 + T细胞和专职抗原呈递细胞之间的相互作用不足，并且由此产生的不能产生和维持稳健的CD 4 + T辅助应答通过改变CD 8 + T细胞效应应答而导致病毒持续存在。我们已经成功地表征了HCV特异性T细胞的表型，并发现细胞表达高水平的PD-1和低水平的CD 127，这是一种与效应子功能差相关的耗竭表型。 最近，我们发现这些细胞在急性感染过程中共表达共刺激分子CD 86，但随着病毒持续存在而迅速失去这种表达。 这表明感染早期共刺激和共抑制分子之间的平衡可能影响感染结果。 我们还鉴定了HCV特异性T细胞应该应答的完整的HCV表位组，这将允许鉴定可能是免疫增强靶点的特异性免疫缺陷。 总之，这些研究将有助于解开APC和T细胞之间的相互作用，并阐明抗病毒反应的机制失败。 重要的是，我们最近提交的两份手稿显示，在我们的小鼠模型系统中，肝内APC，特别是肝星状细胞是肝内免疫应答的关键介质。 HSC是负责慢性HCV感染中纤维化的细胞类型;然而，我们最近也表明，在TGFb存在下，以视黄酸依赖性方式，它们有助于T调节细胞的发育。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We hypothesized that interaction between CD4+ T cells and professional antigen presenting cells is insufficient in HCV infected individuals, and that the resultant failure to generate and maintain a robust CD4+ T helper response contributes to viral persistence through alteration of the CD8+ T cell effector response. We have successfully characterized the phenotype of HCV specific T cells and have found that the cells express high levels of PD-1 and low levels of CD127, an exhausted phenotype correlating with poor effector function. Recently we showed that these cells co-express the costimulatory molecule CD86 during acute infection but rapidly lose this expression with the transition to viral persistence. This suggests that the balance between co-stimulatory and co-inhibitory molecules early in infection may influence infection outcome. We have also identified a complete panel of HCV epitopes to which HCV specific T cells should respond which will now allow for identification of specific immune deficits that may be targets for immune augmentation. Together, these studies will help unravel the interplay between the APC and the T cell and elucidate mechanistic failures in the antiviral response. Importantly, we recently submitted two manuscripts showing, in our murine model systems, that intrahepatic APC and, specifically, hepatic stellate cells are critical mediators of the intrahepatic immune response. HSC are the cell type responsible for fibrosis in chronic HCV infection; however, we have also recently shown that in the presence of TGFb, and in a retinoic acid-dependent manner, they contribute to the development of T regulatory cells.