Interferon-inducible MX2 is a host restriction factor of hepatitis B virus replication
Interferon-inducible MX2 is a host restriction factor of hepatitis B virus replication
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干扰素诱导的 MX2 是乙型肝炎病毒复制的宿主限制因素
DOI：
10.1016/j.jhep.2019.12.009
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发表时间：
2020-05-01
影响因子：
25.7
通讯作者：
Wen, Yu-Mei
中科院分区：
文献类型：
--
作者：
Wang, Yong-Xiang;Niklasch, Matthias;Wen, Yu-Mei
背景和目标：通过细胞因子（包括I型干扰素（IFN））对HBV感染的肝细胞进行非细胞溶解性治疗对于解决急性和慢性感染具有重要意义。然而，由于IFN刺激数百个基因，那些与HBV抑制最相关的基因在很大程度上仍然未知。其中包括大粘病毒抗性（Mx）GTP酶。人MX 1（或MxA）对许多RNA病毒有活性，而MX2（或MxB）最近被发现限制HIV-1，HCV和疱疹病毒。方法：在转染和HBV感染的肝癌细胞和原代人肝细胞中，采用多种方法分析MX2及其功能变体的抗HBV活性，并分析其对HBV核酸合成和降解的影响。结果：MX2和IFN-α均能显著抑制HBV复制，其作用机制是显著降低病毒RNA的合成速度，并轻微加速病毒RNA的周转。MX2的RNAi敲低显著降低了IFN-α的抑制作用。引人注目的是，MX2通过减少共价闭合环状DNA（cccDNA）来抑制HBV感染，最有可能的是通过间接削弱松弛环状DNA向cccDNA的转化，而不是通过破坏现有cccDNA的稳定。结论：MX2是一种重要的IFN-α诱导型效应子，可降低HBV RNA水平，但也可通过间接损害cccDNA的形成而有效抑制HBV感染。MX2可能具有通过消除cccDNA来治疗HBV感染的治疗应用的潜力。概述：这项研究表明，由干扰素-α诱导的蛋白MX2具有重要的抗B肝炎病毒（HBV）效应子功能。MX2可以减少共价闭合环状DNA的量，这是HBV用于维持肝细胞内病毒持久性的DNA形式。MX2还通过下调病毒RNA的合成来降低HBV RNA水平。MX2可能代表一种新的内在HBV抑制剂，可能具有治疗潜力，并有助于提高我们对HBV复杂生物学和干扰素-α抗病毒机制的理解。(c)2019年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Non-cytolytic cure of HBV-infected hepatocytes by cytokines, including type I interferons (IFNs), is of importance for resolving acute and chronic infection. However, as IFNs stimulate hundreds of genes, those most relevant for HBV suppression remain largely unknown. Amongst them are the large myxovirus resistance (Mx) GTPases. Human MX1 (or MxA) is active against many RNA viruses, while MX2 (or MxB) was recently found to restrict HIV-1, HCV, and herpesviruses. Herein, we investigated the anti-HBV activity of MX2.Methods: The potential anti-HBV activity of MX2 and functional variants were assessed in transfected and HBV-infected hepatoma cells and primary human hepatocytes, employing multiple assays to analyze the synthesis and decay of HBV nucleic acids. The specific roles of MX2 in IFN-alpha-driven inhibition of HBV transcription and replication were assessed by MX2-specific shRNA interference (RNAi).Results: Both MX2 alone and IFN-alpha substantially inhibited HBV replication, due to significant deceleration of the synthesis and slight acceleration of the turnover of viral RNA. RNAi knockdown of MX2 significantly reduced the inhibitory effects of IFN-alpha. Strikingly, MX2 inhibited HBV infection by reducing covalently closed circular DNA (cccDNA), most likely by indirectly impairing the conversion of relaxed circular DNA to cccDNA rather than by destabilizing existing cccDNA. Various mutations affecting the GTPase activity and oligomerization status reduced MX2's anti-HBV activity.Conclusion: MX2 is an important IFN-alpha inducible effector that decreases HBV RNA levels but can also potently inhibit HBV infection by indirectly impairing cccDNA formation. MX2 likely has the potential for therapeutic applications aimed at curing HBV infection by eliminating cccDNA.Lay summary: This study shows that the protein MX2, which is induced by interferon-alpha, has important anti-hepatitis B virus (HBV) effector functions. MX2 can reduce the amount of covalently closed circular DNA, which is the form of DNA that HBV uses to maintain viral persistence within hepatocytes. MX2 also reduces HBV RNA levels by downregulating synthesis of viral RNA. MX2 likely represents a novel intrinsic HBV inhibitor that could have therapeutic potential, as well as being useful for improving our understanding of the complex biology of HBV and the antiviral mechanisms of interferon-alpha. (c) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.