Molle Jennifer, Duponchel Sarah, Rieusset Jennifer, Ovize Michel, Ivanov Alexander V, Zoulim Fabien, Bartosch Birke
INSERM U1052, CNRS UMR5286, Université Claude Bernard Lyon 1, Hospices Civils de Lyon, Lyon Hepatology Institute (IHU Everest), 69003 Lyon, France.
CarMeN Laboratory, INSERM U1060, INRA U1397, Lyon Hepatology Institute, 69007 Lyon, France.
Viruses. 2024 Dec 25;17(1):11. doi: 10.3390/v17010011.
Cyclophilin (Cyp) inhibitors are of clinical interest in respect to their antiviral activities in the context of many viral infections including chronic hepatitis B and C. Cyps are a group of enzymes with peptidyl-prolyl isomerase activity (PPIase), known to be required for replication of diverse viruses including hepatitis B and C viruses (HBV and HCV). Amongst the Cyp family, the molecular mechanisms underlying the antiviral effects of CypA have been investigated in detail, but potential roles of other Cyps are less well studied in the context of viral hepatitis. Furthermore, most studies investigating the role of Cyps in viral hepatitis did not investigate the potential therapeutic effects of their inhibition in already-established infections but have rather been performed in the context of neo-infections. Here, we investigated the effects of genetically silencing Cyps on persistent HCV and HBV infections. We confirm antiviral effects of CypA and CypD knock down and demonstrate novel roles for CypG and CypH in HCV replication. We show, furthermore, that CypA silencing has a modest but reproducible impact on persistent HBV infections in cultured human hepatocytes.
亲环蛋白（Cyp）抑制剂在包括慢性乙型和丙型肝炎在内的多种病毒感染中具有抗病毒活性，因此具有临床研究价值。亲环蛋白是一组具有肽基脯氨酰异构酶活性（PPIase）的酶，已知多种病毒（包括乙型和丙型肝炎病毒，即HBV和HCV）的复制都需要它们。在亲环蛋白家族中，已对CypA抗病毒作用的分子机制进行了详细研究，但在病毒性肝炎背景下，其他亲环蛋白的潜在作用研究较少。此外，大多数研究亲环蛋白在病毒性肝炎中作用的实验，并未研究其抑制作用对已建立感染的潜在治疗效果，而是在新发感染的背景下进行的。在此，我们研究了基因沉默亲环蛋白对持续性HCV和HBV感染的影响。我们证实了敲低CypA和CypD的抗病毒作用，并证明了CypG和CypH在HCV复制中的新作用。此外，我们还表明，沉默CypA对培养的人肝细胞中的持续性HBV感染有适度但可重复的影响。
