IMMUNOLOGICAL STRATEGIES FOR CURING CHRONIC HEPATITIS VIRUS INFECTIONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 持续的丙型肝炎病毒感染的有害的长期后遗症现在构成了美国肝移植的主要适应症。确定不能或不足以在大多数感染者中介导丙型肝炎病毒感染消退的免疫应答元件，对于促进我们对如何通过治疗干预丙型肝炎疾病发病机制的理解至关重要，也是我们工作的重点。我们的目标是表征丙型肝炎病毒特异性T细胞的表型和功能差异，重点放在共抑制分子上，如B7分子家族的成员PD-1。 这项工作最近发表了一篇文章，显示了慢性丙型肝炎患者肝脏浸润性丙型肝炎病毒特异性淋巴细胞上PD-1高表达的耗竭表型。接触到可获得肝脏活检组织的慢性感染患者队列是研究共抑制分子在丙型肝炎发病机制中的作用的重要资源。我们现在已经能够将我们的队列扩大到包括因丙型肝炎相关肝功能衰竭而接受肝移植的患者。我们获得了大量供体和受体肝脏的楔形样本用于体外分析，由于这一队列，我们现在能够将研究扩展到负责刺激抗-HCV反应的肝内抗原提呈细胞。 T细胞的功能研究表明，通过阻断PD-1/PD-L1相互作用，T细胞的增殖能力增强。然而，这些丙型肝炎病毒特异性T细胞在丙型肝炎病毒感染过程中经历了大量的凋亡。有趣的是，在感染的急性期，丙型肝炎病毒特异性T细胞也表达共刺激分子CD86，但随着向病毒持续状态的转变，其表达迅速丧失。这些数据表明，共刺激分子和共抑制分子之间的相互作用可能对病毒血症的免疫控制至关重要，并为即将到来的治疗研究提供进一步的支持和兴奋。

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.