Zhou X, Xu L, Wang W, Watashi K, Wang Y, Sprengers D, de Ruiter P E, van der Laan L J W, Metselaar H J, Kamar N, Peppelenbosch M P, Pan Q
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan.
J Viral Hepat. 2016 Apr;23(4):294-304. doi: 10.1111/jvh.12491. Epub 2015 Dec 1.
Hepatitis E virus (HEV) represents one of the foremost causes of acute hepatitis globally. Although there is no proven medication for hepatitis E, pegylated interferon-α (IFN-α) has been used as off-label drug for treating HEV. However, the efficacy and molecular mechanisms of how IFN signalling interacts with HEV remain undefined. As IFN-α has been approved for treating chronic hepatitis C (HCV) for decades and the role of interferon signalling has been well studied in HCV infection, this study aimed to comprehensively investigate virus-host interactions in HEV infection with focusing on the IFN signalling, in comparison with HCV infection. A comprehensive screen of human cytokines and chemokines revealed that IFN-α was the sole humoral factor inhibiting HEV replication. IFN-α treatment exerted a rapid and potent antiviral activity against HCV, whereas it had moderate and delayed anti-HEV effects in vitro and in patients. Surprisingly, blocking the basal IFN pathway by inhibiting JAK1 to phosphorylate STAT1 has resulted in drastic facilitation of HEV, but not HCV infection. Gene silencing of the key components of JAK-STAT cascade of the IFN signalling, including JAK1, STAT1 and interferon regulatory factor 9 (IRF9), stimulated HEV infection. In conclusion, compared to HCV, HEV is less sensitive to IFN treatment. In contrast, the basal IFN cascade could effectively restrict HEV infection. This bears significant implications in management of HEV patients and future therapeutic development.
戊型肝炎病毒（HEV）是全球急性肝炎的主要病因之一。尽管尚无经证实的戊型肝炎治疗药物，但聚乙二醇化干扰素-α（IFN-α）已被用作治疗HEV的超说明书用药。然而，IFN信号通路与HEV相互作用的疗效和分子机制仍不明确。由于IFN-α已被批准用于治疗慢性丙型肝炎（HCV）数十年，且干扰素信号通路在HCV感染中的作用已得到充分研究，本研究旨在与HCV感染相比，重点关注IFN信号通路，全面研究HEV感染中的病毒-宿主相互作用。对人类细胞因子和趋化因子的全面筛选显示，IFN-α是唯一抑制HEV复制的体液因子。IFN-α治疗对HCV具有快速且有效的抗病毒活性，而在体外和患者中对HEV具有中度且延迟的抗病毒作用。令人惊讶的是，通过抑制JAK1磷酸化STAT1来阻断基础IFN通路，导致HEV感染显著促进，但不影响HCV感染。IFN信号通路JAK-STAT级联反应的关键成分，包括JAK1、STAT1和干扰素调节因子9（IRF9）的基因沉默，刺激了HEV感染。总之，与HCV相比，HEV对IFN治疗不太敏感。相反，基础IFN级联反应可有效限制HEV感染。这对HEV患者的管理和未来治疗发展具有重要意义。
