Molecular dissection of HBV evasion from restriction factor tetherin: A new perspective for antiviral cell therapy.
Molecular dissection of HBV evasion from restriction factor tetherin: A new perspective for antiviral cell therapy.
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DOI：
10.18632/oncotarget.4808
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发表时间：
2015-09-08
期刊：
影响因子：
--
通讯作者：
Ryo A
中科院分区：
文献类型：
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作者：
Miyakawa K;Matsunaga S;Watashi K;Sugiyama M;Kimura H;Yamamoto N;Mizokami M;Wakita T;Ryo A
病毒已经进化出各种策略来逃避抑制病毒复制和传播的先天细胞机制。大量证据表明干扰素（IFN）治疗慢性B型肝炎病毒（HBV）感染无效，提示HBV存在逃避IFN诱导的抗病毒应答的机制。在我们目前的研究中，我们证明了HBV表面蛋白（HBs）在抵消IFN诱导的由tetherin（也称为BST-2）介导的抗病毒反应中起着至关重要的作用。I型IFN治疗HBV产生细胞轻微但显著抑制HBsAg和病毒DNA的释放，但这种释放通过敲低tetherin而恢复。HBs可以通过其第四跨膜结构域与系链蛋白相互作用，从而抑制其二聚化和抗病毒活性。缺乏HBV结合结构域的Tetherin突变体的表达促进了HBV颗粒产生的显著限制，最终导致诱导多能干细胞（iPSC）衍生肝细胞中caspase-1介导的细胞毒性和白细胞介素-1 β分泌的减轻。因此，我们目前的研究结果揭示了在IFN诱导的抗病毒反应过程中，HBV和tetherin之间先前未描述的分子联系。此外，通过阻碍tetherin-HBs相互作用来增强tetherin的抗病毒活性的策略可能作为针对HBV的治疗干预是可行的。
Viruses have evolved various strategies to escape from the innate cellular mechanisms inhibiting viral replication and spread. Extensive evidence has highlighted the ineffectiveness of interferon (IFN) therapy against chronic hepatitis B virus (HBV) infection, implying the existence of mechanisms by which HBV evades IFN-induced antiviral responses. In our current study, we demonstrate that HBV surface protein (HBs) plays a crucial role in counteracting the IFN-induced antiviral response mediated by tetherin (also known as BST-2). The type I IFN treatment of HBV-producing cells marginally but significantly inhibited the release of HBsAg and viral DNA, but this release was recovered by the knockdown of tetherin. HBs can interact with tetherin via its fourth transmembrane domain thereby inhibiting its dimerization and antiviral activity. The expression of a tetherin mutant devoid of the HBs-binding domain promoted a prominent restriction of HBV particle production that eventually resulted in the alleviation of caspase-1-mediated cytotoxicity and interleukin-1β secretion in induced pluripotent stem cell (iPSC)-derived hepatocytes. Our current results thus reveal a previously undescribed molecular link between HBV and tetherin during the course of an IFN-induced antiviral response. In addition, strategies to augment the antiviral activity of tetherin by impeding tetherin-HBs interactions may be viable as a therapeutic intervention against HBV.