A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation-and Beyond?
A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation-and Beyond?
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DOI：
10.3390/v9050125
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发表时间：
2017-05-22
期刊：
影响因子：
--
通讯作者：
Nassal M
中科院分区：
文献类型：
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作者：
Schreiner S;Nassal M
慢性B型肝炎病毒（HBV）感染使超过2.5亿人患终末期肝病的风险大大增加。与所有嗜肝DNA病毒一样，HBV通过前基因组（pg）RNA的蛋白质引发逆转录进行复制，产生结构异常的病毒聚合酶连接的松弛环状（RC）DNA作为感染性颗粒中的基因组。感染后，RC-DNA转化为核共价闭合环状（ccc）DNA。cccDNA与细胞蛋白结合形成附加型微型染色体，作为新病毒RNA的模板，确保子代病毒体的形成。因此，cccDNA代表当前抗HBV疗法不直接靶向的病毒持久性储库。因此，消除cccDNA将成为慢性B型肝炎治疗的核心。在大多数实验模型中HBV cccDNA的低产量和可靠cccDNA定量的相关问题长期阻碍了对cccDNA分子生物学的更深入理解。包括cccDNA依赖性细胞培养系统在内的最新进展已经开始鉴定HBV篡夺用于RC-DNA至cccDNA转化的选择宿主DNA修复酶。虽然这个列表肯定会增长，但它可能只是与细胞DNA损伤反应（DDR）更广泛相互作用的一个方面，DDR是一种感知和修复异常DNA结构的途径网络，并在此过程中深刻影响细胞周期，如果修复失败则诱导细胞死亡。考虑到其他病毒和DDR之间的不同相互作用，观察HBV如何应对这种多管齐下的宿主系统将是有趣的。
Chronic hepatitis B virus (HBV) infection puts more than 250 million people at a greatly increased risk to develop end-stage liver disease. Like all hepadnaviruses, HBV replicates via protein-primed reverse transcription of a pregenomic (pg) RNA, yielding an unusually structured, viral polymerase-linked relaxed-circular (RC) DNA as genome in infectious particles. Upon infection, RC-DNA is converted into nuclear covalently closed circular (ccc) DNA. Associating with cellular proteins into an episomal minichromosome, cccDNA acts as template for new viral RNAs, ensuring formation of progeny virions. Hence, cccDNA represents the viral persistence reservoir that is not directly targeted by current anti-HBV therapeutics. Eliminating cccDNA will thus be at the heart of a cure for chronic hepatitis B. The low production of HBV cccDNA in most experimental models and the associated problems in reliable cccDNA quantitation have long hampered a deeper understanding of cccDNA molecular biology. Recent advancements including cccDNA-dependent cell culture systems have begun to identify select host DNA repair enzymes that HBV usurps for RC-DNA to cccDNA conversion. While this list is bound to grow, it may represent just one facet of a broader interaction with the cellular DNA damage response (DDR), a network of pathways that sense and repair aberrant DNA structures and in the process profoundly affect the cell cycle, up to inducing cell death if repair fails. Given the divergent interactions between other viruses and the DDR it will be intriguing to see how HBV copes with this multipronged host system.