Kim Doo Hyun, Kang Hong Seok, Kim Kyun-Hwan
Doo Hyun Kim, Hong Seok Kang, Kyun-Hwan Kim, Department of Pharmacology, and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul 143-701, South Korea.
World J Gastroenterol. 2016 Aug 21;22(31):7017-29. doi: 10.3748/wjg.v22.i31.7017.
Approximately 350 million people are estimated to be persistently infected with hepatitis B virus (HBV) worldwide. HBV maintains persistent infection by employing covalently closed circular DNA (cccDNA), a template for all HBV RNAs. Chronic hepatitis B (CHB) patients are currently treated with nucleos(t)ide analogs such as lamivudine, adefovir, entecavir, and tenofovir. However, these treatments rarely cure CHB because they are unable to inhibit cccDNA transcription and inhibit only a late stage in the HBV life cycle (the reverse transcription step in the nucleocapsid). Therefore, an understanding of the factors regulating cccDNA transcription is required to stop this process. Among numerous factors, hepatocyte nuclear factors (HNFs) play the most important roles in cccDNA transcription, especially in the generation of viral genomic RNA, a template for HBV replication. Therefore, proper control of HNF function could lead to the inhibition of HBV replication. In this review, we summarize and discuss the current understanding of the roles of HNFs in the HBV life cycle and the upstream factors that regulate HNFs. This knowledge will enable the identification of new therapeutic targets to cure CHB.
据估计，全球约有3.5亿人持续感染乙型肝炎病毒（HBV）。HBV通过利用共价闭合环状DNA（cccDNA）维持持续感染，cccDNA是所有HBV RNA的模板。慢性乙型肝炎（CHB）患者目前接受核苷（酸）类似物治疗，如拉米夫定、阿德福韦、恩替卡韦和替诺福韦。然而，这些治疗方法很少能治愈CHB，因为它们无法抑制cccDNA转录，仅抑制HBV生命周期的晚期阶段（核衣壳中的逆转录步骤）。因此，需要了解调节cccDNA转录的因素以阻止这一过程。在众多因素中，肝细胞核因子（HNFs）在cccDNA转录中发挥着最重要的作用，尤其是在病毒基因组RNA的产生过程中，病毒基因组RNA是HBV复制的模板。因此，适当控制HNF功能可能导致抑制HBV复制。在本综述中，我们总结并讨论了目前对HNFs在HBV生命周期中的作用以及调节HNFs的上游因素的理解。这些知识将有助于确定治愈CHB的新治疗靶点。
