丁型肝炎病毒诱导的干扰素反应和施用的干扰素控制细胞分

StephenW

丁型肝炎病毒诱导的干扰素反应和施用的干扰素控制细胞分裂介导的病毒传播

    张振峰
    依妮
    弗洛里安·A·伦普
    帕斯卡·穆茨
    拉尔夫·巴滕施拉格
    斯蒂芬·厄本
    显示所有作者

开放存取发布时间：2022 年 5 月 27 日 DOI：https://doi.org/10.1016/j.jhep.2022.05.023
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强调

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    除了 HBV 依赖的从头感染外，HDV 还通过细胞分裂传播。
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    干扰素反应有效地抑制细胞分裂介导的 HDV 传播。
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    当 HDV 诱导的 IFN 反应较低时，IFN 治疗的效果更有效。
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    IFN 反应在细胞分裂过程中破坏 HDV RNA 的稳定性。

背景与目标
除了 HBV 依赖的从头感染外，细胞分裂介导的传播有助于 HDV 持续存在并抑制抗病毒药物消除从头感染的作用。尽管如此，这些抗病毒药物与干扰素 (IFNs) 的组合在最近的临床试验中显示出强烈的协同作用，这意味着 IFNs 具有互补的作用模式。因此，我们研究了 IFN 反应对细胞分裂介导的 HDV 传播的影响。
方法
将感染 HDV 的细胞传代进行细胞分裂。通过阻断 HDV 诱导的 IFN 活化、应用不同的 IFN 治疗方案和调整 HDV 感染剂量来评估 IFN 反应的效果。
结果
细胞分裂介导的 HDV 传播在感染 HuH7NTCP 细胞（干扰素产生缺陷）后非常有效，但在受感染的干扰素能力强的 HepaRGNTCP 细胞中受到严重限制。用 IFN-α/-λ1 处理可抑制 HDV 在分裂的 HuH7NTCP 细胞中的传播，但对静息细胞中的 HDV 复制表现出边际效应。用 JAK1/2 抑制剂鲁索替尼阻断 HDV 诱导的 IFN 反应或敲低 MDA5 可增强 HDV 在分裂的 HepaRGNTCP 细胞中的传播。病毒诱导的 IFN 反应也使分裂细胞中的 HDV RNA 不稳定。此外，外源性干扰素对细胞分裂介导的 HDV 传播的影响在感染复数低且病毒诱导的干扰素反应较弱的情况下更为明显。
结论
HDV 诱导的 IFN 反应和外源性 IFN 治疗均抑制细胞分裂介导的 HDV 传播，可能是通过加速 HDV RNA 衰变。我们的研究结果证明了 IFN 的一种新的作用模式，解释了 IFN 治疗在 HDV 血清 RNA 水平较低的患者中更显着的效果，并为联合治疗的开发提供了见解。
总结
慢性丁型肝炎是一个主要的健康问题。致病病原体丁型肝炎病毒 (HDV) 可以通过病毒颗粒介导的感染和受感染细胞的分裂传播。尽管最近开发的药物可以阻断病毒颗粒依赖性感染，但针对细胞分裂途径的疗法尚未见报道。利用相关的细胞培养模型，我们证明了广泛使用的免疫调节剂干扰素可以有效地抑制 HDV 通过细胞分裂传播。这项工作揭示了干扰素的新功能，并阐明了潜在的治愈性联合疗法。

StephenW

Hepatitis D virus-induced interferon response and administered interferons control cell division-mediated virus spread

    Zhenfeng Zhang
    Yi Ni
    Florian A. Lempp
    Pascal Mutz
    Ralf Bartenschlager
    Stephan Urban
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Open AccessPublished:May 27, 2022DOI:https://doi.org/10.1016/j.jhep.2022.05.023
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Highlights

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    Besides HBV-dependent de novo infection, HDV also propagates through cell division.
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    IFN response efficiently suppresses cell division-mediated HDV spread.
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    The effect of IFN treatment is more efficient when HDV-induced IFN response is low.
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    IFN response destabilizes HDV RNA during cell division.

Background & aims
Besides HBV-dependent de novo infection, cell division-mediated spread contributes to HDV persistence and dampens the effect of antivirals that abrogate de novo infection. Nonetheless, the combination of these antivirals with interferons (IFNs) showed strong synergism in recent clinical trials, implying a complementary mode-of-action of IFNs. Therefore, we investigated the effect of IFN response on cell division-mediated HDV spread.
Methods
Cells infected with HDV were passaged to undergo cell division. The effect of the IFN response was evaluated by blocking HDV-induced IFN activation, by applying different IFN treatment regimens, and by adjusting HDV infection doses.
Results
Cell division-mediated HDV spread was highly efficient following infection of HuH7NTCP cells (defective in IFN production), but profoundly restricted in infected IFN-competent HepaRGNTCP cells. Treatment with IFN-α/-λ1 inhibited HDV spread in dividing HuH7NTCP cells, but exhibited a marginal effect on HDV replication in resting cells. Blocking the HDV-induced IFN response with the JAK1/2 inhibitor ruxolitinib or knocking down MDA5 augmented HDV spread in dividing HepaRGNTCP cells. The virus-induced IFN response also destabilized HDV RNA in dividing cells. Moreover, the effect of exogenous IFNs on cell division-mediated HDV spread was more pronounced at low multiplicities of infection with weak virus-induced IFN responses.
Conclusions
Both HDV-induced IFN response and exogenous IFN treatment suppress cell division-mediated HDV spread, presumably through acceleration of HDV RNA decay. Our findings demonstrate a novel mode-of-action of IFN, explain the more pronounced effect of IFN therapy in patients with lower HDV serum RNA levels, and provide insights for the development of combination therapies.
Lay summary
Chronic hepatitis D is a major health problem. The causative pathogen hepatitis D virus (HDV) can propagate through viral particle-mediated infection and the division of infected cells. Although viral particle-dependent infection can be blocked by recently developed drugs, therapies addressing the cell division route have not been reported. Taking advantage of relevant cell culture models, we demonstrate that the widely used immune modulator interferon can efficiently suppress HDV spread through cell division. This work unveils a new function of interferon and sheds light on potentially curative combination therapies.

StephenW

http://www.journal-of-hepatology.eu/article/S0168827822003385/pdf