Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
Cells. 2020 Dec 30;10(1):43. doi: 10.3390/cells10010043.
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.
在自然感染中，乙型肝炎病毒 (HBV) 核心蛋白 (HBc) 会频繁积累突变。慢性乙型肝炎患者中最常见的 HBc 变体是突变体 97L，其在 HBc 氨基酸 97 处由异亮氨酸或苯丙氨酸变为亮氨酸 (L)。HBV 研究领域的一个定论是，野生型 HBV 主要分泌含有成熟双链 DNA 基因组的病毒颗粒。含有单链 RNA 或 DNA 的不成熟基因组在达到基因组成熟之前不会有效地分泌。有趣的是，HBc 变体 97L 在病毒颗粒分泌中不符合这一定论。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颗粒。在不同的自然发生的 HBc 变体中也观察到了其他异常的病毒颗粒分泌行为。通过生物信息学、遗传分析和冷冻电镜，鉴定出氨基酸 97 周围存在一个疏水性口袋。我们推测，这个疏水性口袋可以介导基因组成熟信号从衣壳内部到表面的转导，从而促进包膜。病毒形态发生必须涉及 HBc、包膜蛋白 (HBsAg) 和宿主因子（如 ESCRT（内体分选复合物必需的运输）的组成部分）之间的相互作用。不成熟的分泌可以通过 HBc 或 HBsAg 其他位置的补偿性突变来抵消。最近，我们在小鼠中证明，肝内 HBV DNA 的持续存在与受 HBV 基因组成熟调节的病毒颗粒分泌有关。HBV 病毒颗粒的分泌可能是抗病毒药物的靶点。
