HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B
HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B
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DOI：
10.1136/gutjnl-2015-309809
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发表时间：
2015-12-01
期刊：
影响因子：
24.5
通讯作者：
Nassal, Michael
中科院分区：
文献类型：
--
作者：
Nassal, Michael
全世界至少有2.5亿人慢性感染HBV，这是一种通过逆转录复制的小型嗜肝DNA病毒。慢性感染大大增加了晚期肝病的风险。由于称为共价闭合环状（ccc）DNA的细胞内病毒复制中间体的难治性，目前的疗法很少实现治愈。在感染后，cccDNA作为质粒样附加体在宿主细胞核中从进入的病毒体中的蛋白质连接的松弛环状（RC）DNA基因组产生。它的基本作用是作为所有病毒RNA的模板，从而产生新的病毒体。通过病毒前基因组RNA的逆转录的RC-DNA的生物合成现在被相当详细地理解，然而RC-DNA到cccDNA的转化仍然是模糊的，主要是由于缺乏可行的cccDNA依赖性测定系统。概念和最近的实验数据将cccDNA形成与细胞DNA修复联系起来，这越来越被认为是细胞和病毒之间的关键界面。结合新的体外HBV感染系统，基于胆汁酸转运体牛磺胆酸钠共转运多肽作为HBV进入受体的鉴定，这提供了新的机会来破译并最终干扰HBV持久性储库的形成。在简要概述cccDNA在HBV感染周期中的作用后，本文旨在总结cccDNA分子生物学的现有知识，强调迄今为止阻碍更快进展的实验限制，并讨论cccDNA作为慢性B型肝炎新的潜在治愈性疗法的靶点。
At least 250 million people worldwide are chronically infected with HBV, a small hepatotropic DNA virus that replicates through reverse transcription. Chronic infection greatly increases the risk for terminal liver disease. Current therapies rarely achieve a cure due to the refractory nature of an intracellular viral replication intermediate termed covalently closed circular (ccc) DNA. Upon infection, cccDNA is generated as a plasmid-like episome in the host cell nucleus from the protein-linked relaxed circular (RC) DNA genome in incoming virions. Its fundamental role is that as template for all viral RNAs, and in consequence new virions. Biosynthesis of RC-DNA by reverse transcription of the viral pregenomic RNA is now understood in considerable detail, yet conversion of RC-DNA to cccDNA is still obscure, foremostly due to the lack of feasible, cccDNA-dependent assay systems. Conceptual and recent experimental data link cccDNA formation to cellular DNA repair, which is increasingly appreciated as a critical interface between cells and viruses. Together with new in vitro HBV infection systems, based on the identification of the bile acid transporter sodium taurocholate cotransporting polypeptide as an HBV entry receptor, this offers novel opportunities to decipher, and eventually interfere with, formation of the HBV persistence reservoir. After a brief overview of the role of cccDNA in the HBV infectious cycle, this review aims to summarise current knowledge on cccDNA molecular biology, to highlight the experimental restrictions that have hitherto hampered faster progress and to discuss cccDNA as target for new, potentially curative therapies of chronic hepatitis B.