Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany.
J Hepatol. 2019 Nov;71(5):889-899. doi: 10.1016/j.jhep.2019.06.025. Epub 2019 Jul 8.
BACKGROUND & AIMS: Hepatitis C virus (HCV)-specific CD8+ T cells are functionally impaired in chronic hepatitis C. Even though HCV can now be rapidly and sustainably cleared from chronically infected patients, the repercussions of HCV clearance on virus-specific CD8+ T cells remain elusive. Here, we aimed to investigate if HCV clearance by direct-acting antivirals (DAAs) could restore the functionality of exhausted HCV-specific CD8+ T cell responses.
HCV-specific CD8+ T cells in peripheral blood were obtained from 40 patients with chronic HCV infection, during and 6 months following IFN-free DAA therapy. These cells were analyzed for comprehensive phenotypes, proliferation, cytokine production, mitochondrial fitness and response to immune-checkpoint blockade.
We show that, unlike activation markers that decreased, surface expression of multiple co-regulatory receptors on exhausted HCV-specific CD8+ T cells remained unaltered after clearance of HCV. Likewise, cytokine production by HCV-specific CD8+ T cells remained impaired following HCV clearance. The proliferative capacity of HCV multimer-specific CD8+ T cells was not restored in the majority of patients. Enhanced in vitro proliferative expansion of HCV-specific CD8+ T cells during HCV clearance was more likely in women, patients with low liver stiffness and low alanine aminotransferase levels in our cohort. Interestingly, HCV-specific CD8+ T cells that did not proliferate following HCV clearance could preferentially re-invigorate their proliferative capacity upon in vitro immune-checkpoint inhibition. Moreover, altered mitochondrial dysfunction exhibited by exhausted HCV-specific CD8+ T cells could not be normalized after HCV clearance.
Taken together, our data implies that exhausted HCV-specific CD8+ T cells remain functionally and metabolically impaired at multiple levels following HCV clearance in most patients with chronic hepatitis C. Our results might have implications in cases of re-infection with HCV and for HCV vaccine development.
Direct-acting antiviral therapy results in cure of hepatitis C virus (HCV) in almost all treated patients. However, the impacts of HCV cure on immune responses remain controversial. Whether immune responses to HCV recover is important in cases of re-exposure, or for the resolution of extrahepatic manifestations. The main finding of our study was that HCV-specific T cells remain functionally impaired despite HCV clearance. This finding could explain the fact that HCV cure does not lead to protective immunity and that re-infections have frequently been observed.
慢性丙型肝炎病毒（HCV）特异性 CD8+T 细胞功能受损。尽管现在可以快速且持续地从慢性感染患者中清除 HCV，但 HCV 清除对病毒特异性 CD8+T 细胞的影响仍难以捉摸。在这里，我们旨在研究直接作用抗病毒药物（DAA）是否可以恢复耗竭的 HCV 特异性 CD8+T 细胞反应的功能。
从 40 例慢性 HCV 感染患者中获得外周血中的 HCV 特异性 CD8+T 细胞，在无干扰素 DAA 治疗期间和治疗后 6 个月进行分析。分析这些细胞的全面表型、增殖、细胞因子产生、线粒体功能和对免疫检查点阻断的反应。
我们发现，与减少的激活标志物不同，清除 HCV 后，耗竭的 HCV 特异性 CD8+T 细胞表面表达的多种共调节受体保持不变。同样，HCV 特异性 CD8+T 细胞的细胞因子产生在 HCV 清除后仍然受损。在大多数患者中，HCV 多聚体特异性 CD8+T 细胞的增殖能力未得到恢复。在我们的队列中，女性、肝硬度低和丙氨酸氨基转移酶水平低的患者在 HCV 清除期间更有可能增强 HCV 特异性 CD8+T 细胞的体外增殖扩增。有趣的是，清除 HCV 后未能增殖的 HCV 特异性 CD8+T 细胞在体外免疫检查点抑制下可以优先重新激活其增殖能力。此外，耗竭的 HCV 特异性 CD8+T 细胞表现出的改变的线粒体功能障碍在 HCV 清除后无法恢复正常。
综上所述，我们的数据表明，在大多数慢性丙型肝炎患者中，HCV 清除后，耗竭的 HCV 特异性 CD8+T 细胞在多个水平上仍然存在功能和代谢受损。我们的研究结果可能对 HCV 再次感染和 HCV 疫苗开发具有重要意义。
直接作用抗病毒疗法几乎可以治愈所有接受治疗的丙型肝炎病毒（HCV）感染患者。然而，HCV 清除对免疫反应的影响仍存在争议。在再次暴露或解决肝外表现的情况下，对 HCV 的免疫反应是否恢复是重要的。我们研究的主要发现是，尽管清除了 HCV，但 HCV 特异性 T 细胞仍保持功能受损。这一发现可以解释 HCV 清除不会导致保护性免疫以及经常观察到再感染的事实。
