自然存在的核心抗原变异体的乙型肝炎病毒的病毒粒子分泌

StephenW

Virion Secretion of Hepatitis B Virus Naturally Occurring Core Antigen Variants
Chiaho Shih  1   2 , Szu-Yao Wu  3 , Shu-Fan Chou  4 , Ta-Tung Thomas Yuan  5
Affiliations
Affiliations

    1
    Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
    2
    Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
    3
    Chimera Bioscience Inc., No. 18 Siyuan St., Zhongzheng Dist., Taipei 10087, Taiwan.
    4
    Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
    5
    TFBS Bioscience, Inc. 3F, No. 103, Ln 169, Kangning St., Xizhi Dist., New Taipei City 221, Taiwan.

    PMID: 33396864 DOI: 10.3390/cells10010043

Abstract

In natural infection, hepatitis B virus (HBV) core protein (HBc) accumulates frequent mutations. The most frequent HBc variant in chronic hepatitis B patients is mutant 97L, changing from an isoleucine or phenylalanine to a leucine (L) at HBc amino acid 97. One dogma in the HBV research field is that wild type HBV secretes predominantly virions containing mature double-stranded DNA genomes. Immature genomes, containing single-stranded RNA or DNA, do not get efficiently secreted until reaching genome maturity. Interestingly, HBc variant 97L does not follow this dogma in virion secretion. Instead, it exhibits an immature secretion phenotype, which preferentially secretes virions containing immature genomes. Other aberrant behaviors in virion secretion were also observed in different naturally occurring HBc variants. A hydrophobic pocket around amino acid 97 was identified by bioinformatics, genetic analysis, and cryo-EM. We postulated that this hydrophobic pocket could mediate the transduction of the genome maturation signal for envelopment from the capsid interior to its surface. Virion morphogenesis must involve interactions between HBc, envelope proteins (HBsAg) and host factors, such as components of ESCRT (endosomal sorting complex required for transport). Immature secretion can be offset by compensatory mutations, occurring at other positions in HBc or HBsAg. Recently, we demonstrated in mice that the persistence of intrahepatic HBV DNA is related to virion secretion regulated by HBV genome maturity. HBV virion secretion could be an antiviral drug target.

Keywords: HBV core antigen; compensatory mutation; genome maturation; hepatitis B virus (HBV); hydrodynamic mouse model; hydrophobic pocket; immature virion secretion; naturally occurring mutation; persistence.

StephenW

自然存在的核心抗原变异体的乙型肝炎病毒的病毒粒子分泌
石家豪1 2，吴祖瑶3，周淑芬4，大同东园园5
隶属关系
隶属关系

    1个
    高雄医科大学医学研究所，台湾高雄80708。
    2
    中国科学院生物医学研究所，台湾台北11529
    3
    台湾台北市中正区思远街18号奇美拉生物科技有限公司，台湾台北10087。
    4
    哈佛医学院微生物学系，美国马萨诸塞州02115。
    5
    TFBS Bioscience，Inc.台湾新北市221区西直区康宁街169号103号3楼。

    PMID：33396864 DOI：10.3390 / cells10010043

抽象

在自然感染中，乙型肝炎病毒（HBV）核心蛋白（HBc）会积累频繁的突变。慢性乙型肝炎患者中最常见的HBc变异体是突变体97L，从HBc氨基酸97处的异亮氨酸或苯丙氨酸变为亮氨酸（L）。链DNA基因组。包含单链RNA或DNA的不成熟基因组直到达到成熟的基因组才能被有效地分泌。有趣的是，HBc变体97L在病毒体分泌中没有遵循这一教条。相反，它表现出不成熟的分泌表型，优先分泌含有不成熟基因组的病毒体。在不同的天然存在的HBc变体中也观察到了病毒粒子分泌的其他异常行为。通过生物信息学，遗传分析和cryo-EM鉴定了氨基酸97周围的疏水口袋。我们假设该疏水口袋可以介导从衣壳内部到其表面包被的基因组成熟信号的转导。病毒粒子的形态发生必须涉及HBc，包膜蛋白（HBsAg）和宿主因子（例如ESCRT（转运所需的内体分选复合体））之间的相互作用。 HBc或HBsAg中其他位置发生的代偿性突变可以弥补未成熟的分泌。最近，我们在小鼠中证明了肝内HBV DNA的持久性与受HBV基因组成熟度调节的病毒粒子分泌有关。 HBV病毒粒子分泌可能是抗病毒药物的靶标。

关键词：HBV核心抗原；代偿性突变基因组成熟；乙型肝炎病毒（HBV）；流体动力学小鼠模型；疏水袋病毒体分泌不成熟；自然发生的突变；坚持不懈。

StephenW

https://www.mdpi.com/2073-4409/10/1/43/pdf