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病例性和综合性乙型肝炎转录组映射揭示了具有药物耐药性潜力的异质性

James M Harris¹, James Lok², Nadina Wand¹

¹Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Nature communications

|September 26, 2025

概括

新的测序方法揭示了复杂的乙型肝炎病毒 (HBV) 转录组,揭示了来自共价闭环DNA (cccDNA) 和集成DNA的多种病毒RNA. 这种复杂性挑战了当前的治疗方法,并为HBV演变提供了洞察力.

科学领域:

病毒学病毒学
肝病学肝病学是一种肝病学.
基因组学就是基因组学.

背景情况:

乙型肝炎病毒 (HBV) 导致慢性感染,肝病和癌症,影响全球超过2.5亿人.
乙型肝炎病毒的复制涉及环状共价闭环DNA (cccDNA) 和集成DNA,这两者都与致癌有关.
目前的治疗方法可以抑制HBV复制,但不能消除病毒,因此需要新的基因组向疗法.

研究的目的:

在以前未接受治疗的患者中全面地图化乙肝病毒 (HBV) 转录组.
从ccDNA和集成病毒DNA衍生出的HBVRNA的特征.
评估病毒转录多样性对当前和未来HBV疗法的影响.

主要方法:

针对性长读测序用于11名以前未接受治疗的患者的肝脏活检样本.
样本丰富策略被用来生成强大的测序库.
病毒转录被映射并分配给它们各自的DNA模板 (cccDNA或集成DNA).

主要成果:

鉴定出了多样化的HBV转录组,包括以前未经鉴定的拼接,截断和仿真病毒RNA.
cccDNA和综合病毒DNA模板表现出差异性促进活性.
综合体衍生转录在病毒宿主结合处显示出显著的多样性,这对向核酸治疗提出了挑战.
cccDNA被确定为遗传多态的来源,揭示了不同的病毒系.

结论:

肝炎病毒转录组比以前理解的要复杂得多,ccccDNA和集成DNA都有显著的贡献.
病毒转录和病毒宿主结合的多样性影响了现有和新兴的HBV疗法的疗效.
了解HBV转录组对于开发有效的基因组向治疗是至关重要的,并提供了对hepadnavirus演变的见解.

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