Alisporivir inhibition of hepatocyte cyclophilins reduces HBV replication and hepatitis B surface antigen production.
Alisporivir inhibition of hepatocyte cyclophilins reduces HBV replication and hepatitis B surface antigen production.
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DOI：
10.1053/j.gastro.2014.10.004
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发表时间：
2015-03
期刊：
影响因子：
29.4
通讯作者：
Naoumov NV
中科院分区：
文献类型：
--
作者：
Phillips S;Chokshi S;Chatterji U;Riva A;Bobardt M;Williams R;Gallay P;Naoumov NV
亲环蛋白是丙型肝炎病毒复制所需的宿主因子。阿拉泊韦等亲环蛋白抑制剂在体外和临床研究中显示出强大的抗丙型肝炎病毒活性。然而，对于肝细胞亲环蛋白是否参与乙型肝炎病毒（HBV）生命周期知之甚少。我们研究了 2 种亲环蛋白抑制剂（阿拉泊韦和 NIM811）对细胞系中 HBV 复制和乙型肝炎表面抗原 (HBsAg) 产生的影响。由于稳定 (HepG2215) 或瞬时 (HuH-7) 转染或感染 HBV（HepaRG 细胞；Invitrogen [卡尔斯巴德，加利福尼亚州]），产生全长 HBV 和 HBsAg 颗粒的肝源性细胞系与单独的阿拉泊韦或 NIM811 或阿拉泊韦与直接抗病毒药物（替比夫定）联合孵育。通过 HepG2215 细胞中亲环蛋白 (CYP)A、CYPC 或 CYPD 的小干扰 RNA 敲低，或 HuH-7 细胞中 CYPA 敲低来评估各个亲环蛋白在药物反应中的作用。根据 HBV DNA 和 HBsAg 水平以及 Southern 印迹分析评估抗病毒活性动力学。在 HepG2215、HuH-7 和 HepaRG 细胞中，阿拉泊韦以剂量依赖性方式减少细胞内和分泌的 HBV DNA。 CYPA、CYPC 或 CYPD 的敲低（减少 80%）可显着降低 HBV DNA 和分泌的 HBsAg 水平。 CYPA的敲低显着减少HBsAg的分泌，导致细胞内HBsAg的积累；添加阿拉泊韦大大降低了这些细胞中 HBsAg 的水平。阿拉泊韦和替比夫定的组合比单独的替比夫定或阿拉泊韦具有更大的抗病毒作用。 Alisporivir 对肝细胞系中亲环蛋白的抑制可减少 HBV DNA 的复制以及 HBsAg 的产生和分泌。与针对 HBV-DNA 聚合酶的直接抗病毒药物联合使用可增强这些作用。
Cyclophilins are host factors required for hepatitis C virus replication. Cyclophilin inhibitors such as alisporivir have shown strong anti–hepatitis C virus activity in vitro and in clinical studies. However, little is known about whether hepatocyte cyclophilins are involved in the hepatitis B virus (HBV) life cycle. We investigated the effects of 2 cyclophilin inhibitors (alisporivir and NIM811) on HBV replication and hepatitis B surface antigen (HBsAg) production in cell lines. Liver-derived cell lines producing full-length HBV and HBsAg particles, owing to stable (HepG2215) or transient (HuH-7) transfection, or infected with HBV (HepaRG cells; Invitrogen [Carlsbad, CA]), were incubated with alisporivir or NIM811 alone, or alisporivir in combination with a direct antiviral (telbivudine). The roles of individual cyclophilins in drug response was evaluated by small interfering RNA knockdown of cyclophilin (CYP)A, CYPC, or CYPD in HepG2215 cells, or CYPA knockdown in HuH-7 cells. The kinetics of antiviral activity were assessed based on levels of HBV DNA and HBsAg and Southern blot analysis. In HepG2215, HuH-7, and HepaRG cells, alisporivir reduced intracellular and secreted HBV DNA, in a dose-dependent manner. Knockdown of CYPA, CYPC, or CYPD (reduced by 80%) significantly reduced levels of HBV DNA and secreted HBsAg. Knockdown of CYPA significantly reduced secretion of HBsAg, leading to accumulation of intracellular HBsAg; the addition of alisporivir greatly reduced levels of HBsAg in these cells. The combination of alisporivir and telbivudine had greater antiviral effects than those of telbivudine or alisporivir alone. Alisporivir inhibition of cyclophilins in hepatocyte cell lines reduces replication of HBV DNA and HBsAg production and secretion. These effects are potentiated in combination with direct antiviral agents that target HBV-DNA polymerase.
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