UNDERSTANDING MECHANISMS OF HCV 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。 我们的工作旨在确定宿主免疫反应中的缺陷，导致剩余的80%无法自然清除HCV感染。我们假设细胞免疫应答是决定HCV感染是否急性消退或建立持久性的主要因素，我们正在寻求阐明和理解有效的抗HCV免疫应答的基本组成部分。 我们正在利用大量慢性感染的人类患者，以及新的细胞培养系统来剖析抗HCV免疫反应。我们开始建立一个因HCV相关肝功能衰竭而接受肝移植的患者队列。 该队列包括具有各种纤维化评分的患者，而不仅仅是肝硬化。 我们能够从供体和受体肝脏获得大的楔形样本，从而对HCV的肝内免疫反应进行全面的表型和一些功能分析。我们确定了抗HCV肝脏浸润T细胞的表型标志物，其与T细胞功能障碍相关，可能是免疫增强的靶点。 我们描述了HCV特异性细胞在急性感染期间在外周血中和慢性感染期间在肝脏中经历大量凋亡的倾向增加，以及促进免疫刺激和抑制的分子之间的关键平衡。 对移植患者进行纵向随访的能力至关重要，因为大多数患者将再次出现HCV病毒血症。 这个独特的感染时间轴窗口使我们能够对免疫反应进行前所未有的评估。

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. Our work is designed to identify the defect in the host immune response responsible for the inability of the remaining 80% to naturally clear HCV infection. We hypothesized that the cellular immune response is the principal determinant of whether HCV infection is acutely resolved or establishes persistence and we are seeking to elucidate and understand the essential components of an effective anti-HCV immune response. We are utilizing a large cohort of chronically infected human patients, as well as novel cell culture systems to dissect the anti-HCV immune response. We began building a cohort of patients undergoing liver transplantation for HCV related liver failure. This cohort comprises patients with a wide variety of fibrosis scores, not just cirrhosis. We were able to obtain large wedge samples from both the donor and recipient livers allowing comprehensive phenotypic and some functional analysis of the intrahepatic immune response to HCV. We identified phenotypic markers of anti-HCV liver infiltrating T cells that correlate with T cell dysfunction that may be targets for immune augmentation. We described an increased propensity of HCV specific cells to undergo massive apoptosis in the peripheral blood during acute infection and in the liver during chronic infection as well as a critical balance between molecules facilitating immune stimulation and inhibition. The ability to follow transplant patients longitudinally is critical, since the majority will again manifest HCV viremia. This unique window into the infection timeline is allowing us unprecedented assessment of the immune response.