MECHANISMS OF HEPATITIS C VIRUS PERSISTENCE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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（APC）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。 这些细胞也是唯一易受凋亡影响的细胞。 最近，我们发现，这些细胞共表达的共刺激分子CD 86在急性感染，但迅速失去这种表达的过渡到病毒的持久性。 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。 我们鉴定了HCV特异性T细胞应应答的完整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。 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（HSC）是肝内免疫反应的关键介质。 HSC是慢性HCV感染中纤维化的细胞类型;然而，我们最近发现，在TGF β存在下，以视黄酸依赖的方式，它们有助于T调节细胞的发育。 我们将继续剖析这些重要观察结果的分子机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We hypothesized that interaction between CD4+ T cells and professional antigen presenting cells (APCs) 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 successfully characterized the phenotype of HCV specific T cells and found the cells expressed high levels of PD-1 and low levels of CD127, an exhausted phenotype correlating with poor effector function. These cells are also uniquely susceptible to apoptosis. Recently we showed that these cells co-express the costimulatory molecule CD 86 during acute infection but rapidly lose this expression with the transition to viral persistence. This suggested that the balance between co-stimulatory and co-inhibitory molecules early in infection may influence infection outcome. We 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 have helped unravel the interplay between the APC and the T cell and elucidate mechanistic failures in the antiviral response. We recently submitted two manuscripts showing, in our murine model systems, that intrahepatic APC and specifically, hepatic stellate cells (HSC) are critical mediators of the intrahepatic immune response. HSC are the cell type responsible for fibrosis in chronic HCV infection; however, we recently showed that in the presence of TGFb, and in a retinoic acid-dependent manner, they contribute to the development of Tregulatory cells. We continue to dissect the molecular mechanisms responsible for these important observations.