MECHANISMS OF HEPATITIS C VIRUS PERSISTENCE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们假设，在感染丙型肝炎病毒的个体中，CD4+T细胞和专业抗原提呈细胞之间的相互作用不足，由此导致的未能产生和维持强大的CD4+T辅助应答有助于通过改变CD8+T细胞效应应答而导致病毒持续存在。我们已经成功地鉴定了丙型肝炎病毒特异性T细胞的表型，并发现这些细胞表达高水平的PD-1和低水平的CD127，这种耗尽的表型与较差的效应器功能相关。最近，我们发现这些细胞在急性感染期间共表达共刺激分子CD86，但在过渡到病毒持续期间迅速失去这种表达。这表明，在感染早期，共刺激分子和共抑制分子之间的平衡可能会影响感染结果。我们还确定了一组完整的丙型肝炎病毒表位，丙型肝炎病毒特异性T细胞应该对其做出反应，这将使我们能够识别可能成为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，并阐明抗病毒反应中的机械故障。重要的是，我们最近提交了两篇手稿，表明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反应的关键介质。HSC是慢性丙型肝炎病毒感染中导致纤维化的细胞类型；然而，我们最近也表明，在TGFb存在的情况下，并且以维甲酸依赖的方式，HSC有助于T调节细胞的发展。

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.