IMMUNOLOGICAL STRATEGIES FOR CURING CHRONIC HEPATITIS VIRUS INFECTIONS

这个子项目是许多利用 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。 在美国，持续性HCV感染的有害长期后遗症现在是肝移植的主要指征。定义免疫应答的要素，失败或不足以介导大多数感染者的HCV感染解决是至关重要的，以推进我们的理解如何治疗干预HCV疾病的发病机制，是我们工作的重点。我们的目标是表征HCV特异性T细胞的表型和功能差异，重点是共抑制分子，如PD-1，B7分子家族的成员。 这项工作最近导致了一个出版物，显示了一个耗尽的表型与高PD-1表达的肝脏浸润HCV特异性淋巴细胞在慢性感染HCV的患者。 获得一个慢性感染的患者队列，其中肝活检组织是一个很大的资源，研究特征的作用，共抑制分子在HCV发病机制。 我们现在已经能够扩展我们的队列，包括因HCV相关肝功能衰竭而接受肝移植的患者。我们获得了供体和受体肝脏的大楔形样本进行离体分析，并且由于这个队列，现在已经能够将我们的研究扩展到负责刺激抗HCV应答的肝内抗原呈递细胞。 T细胞的功能研究显示，随着PD-1/PD-L1相互作用的阻断，增殖能力增强。 然而，这些HCV特异性T细胞在HCV感染期间经历大量凋亡。 有趣的是，在感染的急性期，HCV特异性T细胞也表达共刺激分子CD 86，但随着病毒持续存在而迅速失去表达。这些数据表明，共刺激和共抑制分子之间的相互作用可能是至关重要的免疫控制病毒血症，并提供进一步的支持和兴奋，为即将到来的治疗研究。

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. The detrimental long-term sequelae of persistent HCV infection now comprise the leading indication for liver transplantation in the United States. Defining the elements of the immune response that fail or are insufficient to mediate HCV infection resolution in the majority of those infected is critical for advancing our understanding of how to therapeutically intervene in HCV disease pathogenesis and is the focus of our work. We have aimed to characterize phenotypic and functional differences of HCV-specific T cells with a focus on co-inhibitory molecules such as PD-1, a member of the B7 family of molecules. This work recently resulted in a publication showing an exhausted phenotype with high PD-1 expression on liver infiltrating HCV-specific lymphocytes in patients chronically infected with HCV. Access to a chronically infected patient cohort in whom liver biopsy tissue is available represents a great resource for studies characterizing the role of co-inhibitory molecules in HCV pathogenesis. We have now been able to extend our cohort to include patients undergoing liver transplant for HCV related liver failure. We obtain large wedge samples of donor and recipient liver for ex vivo analysis and have now, because of this cohort, been able to extend our studies to the intrahepatic antigen presenting cells responsible for stimulating the anti-HCV response. Functional studies of the T cells show enhanced proliferative capacity with blockade of the PD-1/PD-L1 interaction. However, these HCV specific T cells undergo massive apoptosis during HCV infection. Interestingly, in the acute phase of infection the HCV specific T cells also express the costimulatory molecule CD86 but rapidly lose expression with the transition to viral persistence. These data suggest that the interplay between costimulatory and coinhibitory molecules may be critical for immune control of viremia and provide further support and excitement for the forthcoming therapeutic studies.