Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
Int J Mol Sci. 2021 Apr 27;22(9):4559. doi: 10.3390/ijms22094559.
Recent evidence suggests that fibrotic liver injury in patients with chronic hepatitis C correlates with cellular senescence in damaged liver tissue. However, it is still unclear how senescence can affect replication of the hepatitis C virus (HCV). In this work, we report that an inhibitor of cyclin-dependent kinases 4/6, palbociclib, not only induced in hepatoma cells a pre-senescent cellular phenotype, including G1 arrest in the cell cycle, but also accelerated viral replicon multiplication. Importantly, suppression of HCV replication by direct acting antivirals (DAAs) was barely affected by pre-senescence induction, and vice versa, the antiviral activities of host-targeting agents (HTAs), such as inhibitors of human histone deacetylases (HDACi), produced a wide range of reactions-from a dramatic reduction to a noticeable increase. It is very likely that under conditions of the G1 arrest in the cell cycle, HDACi exhibit their actual antiviral potency, since their inherent anticancer activity that complicates the interpretation of test results is minimized.
最近的证据表明，慢性丙型肝炎患者的纤维化肝损伤与受损肝组织中的细胞衰老有关。然而，衰老如何影响丙型肝炎病毒（HCV）的复制仍不清楚。在这项工作中，我们报告说，细胞周期蛋白依赖性激酶 4/6 的抑制剂帕博西尼不仅诱导肝癌细胞出现衰老前的细胞表型，包括细胞周期中的 G1 期阻滞，而且还加速了病毒复制子的增殖。重要的是，直接作用抗病毒药物（DAAs）对复制前诱导的 HCV 抑制作用几乎没有影响，反之亦然，宿主靶向药物（HTAs）的抗病毒活性，如人类组蛋白去乙酰化酶抑制剂（HDACi），产生了广泛的反应——从明显减少到明显增加。在细胞周期 G1 期阻滞的情况下，HDACi 很可能表现出其实际的抗病毒效力，因为其固有的抗癌活性使测试结果的解释复杂化，从而最小化。
