Hong Xupeng, Schneider William M, Rice Charles M
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
J Mol Biol. 2025 Apr 30:169182. doi: 10.1016/j.jmb.2025.169182.
Hepatitis B virus (HBV), the prototypical member of the Hepadnaviridae family, is a DNA virus that replicates its genome through reverse transcription of a pregenomic RNA (pgRNA) precursor. The selective packaging of pgRNA and viral polymerase (Pol) into assembling capsids formed by the viral core protein-a process known as nucleocapsid assembly-is an essential step in the HBV lifecycle. Advances in cellular and cell-free systems have provided significant insights into the mechanisms underlying capsid assembly, Pol binding to pgRNA, Pol-pgRNA packaging, and initiation of genome replication. However, the absence of a cell-free system capable of reconstituting selective HBV Pol-pgRNA packaging into fully assembled capsids leaves fundamental questions about nucleocapsid assembly unanswered. This review summarizes the current knowledge of HBV nucleocapsid assembly, focusing on the interplay between Pol-pgRNA interactions, capsid formation, and regulation by host factors. It also highlights the contribution of cellular and cell-free systems to these discoveries and underscores the need for new approaches that reconstitute the complete HBV nucleocapsid assembly process. With the growing interest in developing nucleocapsid assembly inhibitors, some of which are currently in clinical trials, targeting Pol-pgRNA interactions and nucleocapsid assembly represents a promising therapeutic strategy for curing chronic hepatitis B.
乙型肝炎病毒（HBV）是嗜肝DNA病毒科的典型成员，是一种DNA病毒，其基因组通过前基因组RNA（pgRNA）前体的逆转录进行复制。将pgRNA和病毒聚合酶（Pol）选择性包装到由病毒核心蛋白形成的组装衣壳中——这一过程称为核衣壳组装——是HBV生命周期中的关键步骤。细胞和无细胞系统的进展为衣壳组装、Pol与pgRNA结合、Pol-pgRNA包装以及基因组复制起始的潜在机制提供了重要见解。然而，缺乏能够将选择性HBV Pol-pgRNA包装重组到完全组装衣壳中的无细胞系统，使得关于核衣壳组装的基本问题仍未得到解答。本综述总结了目前关于HBV核衣壳组装的知识，重点关注Pol-pgRNA相互作用、衣壳形成以及宿主因子调控之间的相互作用。它还强调了细胞和无细胞系统对这些发现的贡献，并强调需要新的方法来重组完整的HBV核衣壳组装过程。随着对开发核衣壳组装抑制剂的兴趣日益增加，其中一些目前正在进行临床试验，靶向Pol-pgRNA相互作用和核衣壳组装是治疗慢性乙型肝炎的一种有前景的治疗策略。
