核衣壳和包膜相互作用对乙型肝炎病毒病毒粒子释放和包膜

StephenW

核衣壳和包膜相互作用对乙型肝炎病毒病毒粒子释放和包膜时间的调节
作者：姬希、刘海涛、胡建明 https://orcid.org/0000-0002-3967-2133 [email protected] Info & Affiliations
DOI：
https://doi.org/10.1128/JVI.01305-21
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合资公司
第 96 卷，第 1 期
2022 年 1 月 12 日

    抽象的
    参考

抽象的
N 端（组装）结构域 (NTD)、乙型肝炎病毒 (HBV) 衣壳蛋白的接头区域和大 (L) 包膜蛋白之间的相互作用是病毒粒子形成所必需的，病毒粒子通过细胞质成熟核衣壳的出芽而发生(NC) 将含有松弛的环状 (RC) DNA 基因组放入含有病毒包膜蛋白的细胞内膜隔室中。 L-衣壳相互作用也负调节共价闭合环状 (CCC) DNA 形成，这发生在 RC DNA 从成熟 NC 释放和核输入之后。我们现在发现 L 可以增加细胞质成熟 NCs 中的 RC DNA，这些 NCs 由于 NTD 或接头的突变而不稳定，即使在那些明显不能支持细胞外分泌完整病毒粒子的细胞中也是如此。衣壳接头中的其他突变可以阻断 L 对细胞质 NC DNA 和核 CCC DNA 的影响。此外，细胞质 NC 中 RC DNA 的成熟度被 L 增强或在分泌的病毒体中发现，受到衣壳接头序列的调节。细胞质 RC DNA 的水平和成熟度进一步受到依赖于病毒基因型特异性包膜蛋白的细胞外病毒粒子分泌效率的影响。这些结果表明，衣壳和包膜蛋白之间的相互作用在病毒粒子分泌过程中调节了一个或多个步骤，超出了最初的衣壳包膜，并突出了衣壳接头在调节衣壳-包膜相互作用中的关键作用，包括 NC 成熟过程中包膜的时间。
重要性 乙型肝炎病毒 (HBV) 是一种主要的人类病原体，可导致包括癌症在内的严重肝病。 HBV衣壳和大（L）包膜蛋白之间的相互作用是感染性病毒颗粒形成所必需的，并且还负调节宿主细胞核中HBV DNA附加体的形成，它是能够支持所有病毒基因的唯一转录模板表达以维持 HBV 复制，因此是 HBV 持续存在的分子基础。在这里，我们报告的证据表明 L-衣壳相互作用在复制过程中调节传染性 HBV 颗粒的形成时间，并促进它们形成后的细胞外释放。此外，衣壳蛋白中的短接头序列在这些过程中起关键作用，并控制核附加体的扩增。这些发现为 HBV 复制的基本机制以及针对 HBV 衣壳和 DNA 附加体的抗病毒开发提供了信息。

StephenW

Regulation of Hepatitis B Virus Virion Release and Envelopment Timing by Nucleocapsid and Envelope Interactions
Authors: Ji Xi, Haitao Liu, Jianming Hu https://orcid.org/0000-0002-3967-2133 [email protected] Info & Affiliations
DOI:
https://doi.org/10.1128/JVI.01305-21
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JVI
Volume 96, Number 1
12 January 2022

    ABSTRACT
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ABSTRACT
Interactions between the N-terminal (assembly) domain (NTD), the linker region of the hepatitis B virus (HBV) capsid protein, and the large (L) envelope protein are required for virion formation, which occurs via budding of cytoplasmic mature nucleocapsids (NCs) containing the relaxed circular (RC) DNA genome into an intracellular membrane compartment containing viral envelope proteins. L-capsid interactions also negatively regulate covalently closed circular (CCC) DNA formation, which occurs after RC DNA release from mature NCs and nuclear import. We have now found that L could increase RC DNA in cytoplasmic mature NCs that are destabilized due to mutations in the NTD or the linker, even in those that apparently fail to support secretion of complete virions extracellularly. Other mutations in the capsid linker could block the effects of L on both cytoplasmic NC DNA and nuclear CCC DNA. Furthermore, the maturity of RC DNA in cytoplasmic NCs that was enhanced by L or found in secreted virions was modulated by the capsid linker sequence. The level and maturity of the cytoplasmic RC DNA were further influenced by the efficiency of extracellular virion secretion dependent on viral genotype-specific envelope proteins. These results suggest that interactions between the capsid and envelope proteins regulate one or more steps during virion secretion beyond initial capsid envelopment and highlight the critical role of the capsid linker in regulating capsid-envelope interaction, including the timing of envelopment during NC maturation.
IMPORTANCE Hepatitis B virus (HBV) is a major human pathogen causing serious liver diseases, including cancer. Interactions between the HBV capsid and the large (L) envelope protein are required for formation of infectious viral particles and also negatively regulate formation of an HBV DNA episome in the host cell nucleus, which serves as the sole transcriptional template capable of supporting all viral gene expression to sustain HBV replication and, therefore, is the molecular basis of HBV persistence. Here, we report evidence indicating that L-capsid interactions modulate the timing of formation of infectious HBV particles during replication and facilitate extracellular release following their formation. Furthermore, a short linker sequence in the capsid protein plays a critical role in these processes as well as controls the amplification of the nuclear episome. These findings inform fundamental mechanisms of HBV replication as well as antiviral development targeting the HBV capsid and DNA episome.