Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
Front Immunol. 2019 Aug 13;10:1926. doi: 10.3389/fimmu.2019.01926. eCollection 2019.
Chronic hepatitis C virus (HCV) infection disrupts immune functions, including that of cytotoxic CD8 T-cells which are important mediators of immune response. While HCV cure aims to eliminate long term sequelae of infection, whether direct-acting antiviral (DAA) treatment results in immune reconstitution remains unclear. We and others have reported generalized CD8 T-cell dysfunction in chronic HCV infection and our research suggests that the degree of liver damage is a factor in this process. Our recent research indicates that liver fibrosis is not readily reversed after DAA-mediated clearance of chronic HCV infection. We therefore examined the function of circulating CD8 T-cell subsets in chronic HCV infection in the context of liver fibrosis severity, determined by ultrasound elastography and Metavir F-score system. We observed progressive shifts in CD8 T-cell subset distribution in HCV-infected individuals with advanced liver fibrosis (F4) compared to minimal fibrosis (F0-1) or uninfected controls, and this remained unchanged after viral cure. Impaired CD8 T-cell function was observed as a reduced proportion of CD107 and perforin late effector memory cells in HCV(F4) and HCV(F0-1) individuals, respectively. In HCV(F4) individuals, nearly all CD8 T-cell subsets had an elevated proportion of perforin cells while naïve cells had increased proportions of IFN-γ and CD107 cells. These exaggerated CD8 T-cell activities were not resolved when evaluated 24 weeks after completion of DAA therapy and HCV clearance. This was further supported by sustained, high levels of cell proliferation and cytolytic activity. Furthermore, DAA therapy had no effect on elevated concentrations of systemic inflammatory cytokines and decreased levels of inhibitory TGF-β in the plasma of HCV(F4) individuals, suggesting HCV infection and advanced liver disease result in a long-lasting immune activating microenvironment. These data demonstrate that in chronic HCV infection, liver fibrosis severity is associated with generalized hyperfunctional CD8 T-cells, particularly with perforin production and cytotoxicity, and this persists after viral clearance. Whether DAA therapy will eliminate other related long-term sequelae in HCV(F4) individuals remains an important research question.
慢性丙型肝炎病毒(HCV)感染会破坏免疫功能,包括细胞毒性 CD8 T 细胞,其是免疫反应的重要介质。虽然 HCV 治愈旨在消除感染的长期后遗症,但直接作用抗病毒(DAA)治疗是否会导致免疫重建尚不清楚。我们和其他人已经报道了慢性 HCV 感染中普遍存在的 CD8 T 细胞功能障碍,我们的研究表明,肝损伤程度是这一过程的一个因素。我们最近的研究表明,在 DAA 介导清除慢性 HCV 感染后,肝纤维化不易逆转。因此,我们在超声弹性成像和 Metavir F 评分系统确定的肝纤维化严重程度的背景下,研究了慢性 HCV 感染中循环 CD8 T 细胞亚群的功能。我们观察到,与轻微纤维化(F0-1)或未感染对照相比,晚期纤维化(F4)的 HCV 感染个体中 CD8 T 细胞亚群分布发生渐进性变化,而在病毒治愈后则保持不变。在 HCV(F4)个体中,CD107 和穿孔素晚期效应记忆细胞的比例分别观察到 CD8 T 细胞功能受损,表现为比例降低。在 HCV(F4)个体中,几乎所有 CD8 T 细胞亚群的穿孔素细胞比例升高,而幼稚细胞的 IFN-γ 和 CD107 细胞比例升高。在 DAA 治疗和 HCV 清除后 24 周评估时,这些夸大的 CD8 T 细胞活性并未得到解决。这进一步得到了持续高水平的细胞增殖和细胞毒性活性的支持。此外,DAA 治疗对 HCV(F4)个体血浆中升高的全身性炎症细胞因子浓度和降低的抑制性 TGF-β水平没有影响,表明 HCV 感染和晚期肝病导致持久的免疫激活微环境。这些数据表明,在慢性 HCV 感染中,肝纤维化严重程度与普遍的高功能 CD8 T 细胞有关,特别是与穿孔素的产生和细胞毒性有关,并且在病毒清除后仍然存在。DAA 治疗是否会消除 HCV(F4)个体的其他相关长期后遗症仍然是一个重要的研究问题。