Table_1_In Chronic Hepatitis C Infection, Myeloid-Derived Suppressor Cell Accumulation and T Cell Dysfunctions Revert Partially and Late After Successful Direct-Acting Antiviral Treatment.docx

Chronic HCV infection is characterized by several immunological alterations, such as the accumulation of suppressor cells and of hyperactivated T lymphocytes. However, it is unclear whether direct-acting antiviral (DAA)-mediated HCV clearance restores immune dysfunctions. We performed a phenotypic characterization by flow cytometry of different immune cell subsets, including monocytic myeloid-derived suppressor cells (M-MDSCs) and T lymphocytes in 168 patients with persistent HCV infection not treated, under DAA therapies and sustained virological responders. Chronic HCV infection prompted the accumulation of M-MDSCs independently of patient and clinical characteristics, and altered their metabolic properties. HCV RNA was undetectable in the majority of patients just after few weeks of DAA therapy, whereas M-MDSC levels normalized only 6 months after therapy. In addition, HCV infection deeply perturbed the T cell compartment since a re-distribution of memory CD4+ and CD8+ T cells was observed at the expenses of naïve cells, and memory T lymphocytes displayed increased activation. Notably, these features were only partially restored by DAA therapies in the CD4, but not in the CD8, compartment as high immune activation levels persisted in the terminally differentiated memory CD8+ T cells even more than 1 year after sustained virological response. Together, these results suggest that successful DAA therapies do not lead to full immunological reconstitution as fast as viral clearance.

慢性丙型肝炎病毒感染特征为多种免疫学改变，诸如抑制细胞的累积及高度激活的T淋巴细胞。然而，关于直接作用抗病毒药物（DAA）介导的丙型肝炎病毒清除是否能够恢复免疫功能障碍尚无明确结论。本研究通过对168例未经治疗的持续丙型肝炎病毒感染患者、接受DAA治疗的患者以及持续病毒学应答者中的不同免疫细胞亚群进行表型特征描述，包括单核源性髓系抑制细胞（M-MDSCs）和T淋巴细胞，采用流式细胞术进行分析。慢性丙型肝炎病毒感染可独立于患者及临床特征导致M-MDSCs的累积，并改变其代谢特性。在接受DAA治疗数周后，大多数患者中无法检测到丙型肝炎病毒RNA，而M-MDSCs的水平仅在治疗6个月后恢复正常。此外，丙型肝炎病毒感染严重扰乱了T细胞库，观察到记忆CD4+和CD8+ T细胞的重新分布，以牺牲原始细胞为代价，且记忆T淋巴细胞表现出增高的活化状态。值得注意的是，这些特征仅在一定程度上被DAA治疗在CD4细胞库中部分恢复，而在CD8细胞库中并未得到恢复，因为即使在持续病毒学应答超过1年后，终末分化记忆CD8+ T细胞中的高免疫激活水平依然持续存在。综合上述结果，这些发现表明，尽管DAA治疗能够有效清除病毒，但并不能像病毒清除那样迅速地完全恢复免疫功能。