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首页> 美国卫生研究院文献>Journal of Virology >Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress
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Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress

机译：三氧化二砷通过调节谷胱甘肽氧化还原系统和氧化应激抑制丙型肝炎病毒RNA复制。

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Arsenic trioxide (ATO), a therapeutic reagent used for the treatment of acute promyelocytic leukemia, has recently been reported to increase human immunodeficiency virus type 1 infectivity. However, in this study, we have demonstrated that replication of genome-length hepatitis C virus (HCV) RNA (O strain of genotype 1b) was notably inhibited by ATO at submicromolar concentrations without cell toxicity. RNA replication of HCV-JFH1 (genotype 2a) and the release of core protein into the culture supernatants were also inhibited by ATO after the HCV infection. To clarify the mechanism of the anti-HCV activity of ATO, we examined whether or not PML is associated with this anti-HCV activity, since PML is known to be a target of ATO. Interestingly, we observed the cytoplasmic translocation of PML after treatment with ATO. However, ATO still inhibited the HCV RNA replication even in the PML knockdown cells, suggesting that PML is dispensable for the anti-HCV activity of ATO. In contrast, we found that N-acetyl-cysteine, an antioxidant and glutathione precursor, completely and partially eliminated the anti-HCV activity of ATO after 24 h and 72 h of treatment, respectively. In this context, it is worth noting that we found an elevation of intracellular superoxide anion radical, but not hydrogen peroxide, and the depletion of intracellular glutathione in the ATO-treated cells. Taken together, these findings suggest that ATO inhibits the HCV RNA replication through modulation of the glutathione redox system and oxidative stress.
机译：三氧化二砷（ATO）是一种用于治疗急性早幼粒细胞白血病的治疗剂，最近已报道其可提高人类1型免疫缺陷病毒的感染力。但是，在这项研究中，我们证明了亚微摩尔浓度的ATO可以明显抑制基因组长度的丙型肝炎病毒（HCV）RNA（基因型1b的O株）的复制，而不会产生细胞毒性。 HCV感染后，ATO也抑制了HCV-JFH1（基因型2a）的RNA复制和核心蛋白向培养上清液的释放。为了阐明ATO抗HCV活性的机制，我们检查了PML是否与该抗HCV活性相关，因为已知PML是ATO的靶标。有趣的是，我们观察到ATO处理后PML的胞质易位。然而，即使在PML敲低的细胞中，ATO仍能抑制HCV RNA复制，这表明PML对于ATO的抗HCV活性是必不可少的。相反，我们发现，抗氧化剂和谷胱甘肽前体N-乙酰半胱氨酸分别在治疗24小时和72小时后完全和部分消除了ATO的抗HCV活性。在这种情况下，值得注意的是，我们在ATO处理的细胞中发现了细胞内超氧阴离子自由基的升高，但未发现过氧化氢的升高，以及细胞内谷胱甘肽的消耗。综上所述，这些发现表明ATO通过调节谷胱甘肽氧化还原系统和氧化应激来抑制HCV RNA复制。

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