乙型肝炎病毒cccDNA体外实验模型研究进展  

In vitro experimental models for the study of hepatitis B virus cccDNA

作　　者：朱园飞 苏瑜 邓强 Yuanfei Zhu;Yu Su;Qiang Deng(Key Laboratory of Medical Molecular Virology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China)

机构地区：[1]复旦大学基础医学院病原生物学系医学分子病毒学重点实验室

出　　处：《科学通报》2019年第30期3061-3069,共9页Chinese Science Bulletin

基　　金：国家自然科学基金(81672034,81871647);上海市教育委员会科研创新计划(2017-01-07-00-07-E00057);国家科技重大专项(2018ZX10301208)资助

摘　　要：乙型肝炎病毒(hepatitis B virus,HBV)是一种小的DNA包膜病毒,属于嗜肝DNA病毒科.在细胞核内,HBV部分双链的DNA基因组修复为共价闭合环状DNA(covalently closed circular DNA,cccDNA),后者作为HBV复制的原始模板起始病毒转录.cccDNA具有显著的稳定性,是HBV持续感染的分子基础,也是抗病毒药物设计的关键靶点.HBV cccDNA研究常受限于细胞内较低的拷贝数,以及缺乏灵敏、可靠的检测方法,因此,建立合适的cccDNA实验模型具有重要意义.本文对近年来HBV cccDNA体外实验模型方面的主要研究进展进行综述,以期为深入研究HBV病毒学和抗病毒药物研发提供帮助.Chronic infection of hepatitis B virus(HBV)remains a global public health problem and affects at least 240 million people worldwide.HBV is a small enveloped DNA virus belonging to the Hepadnaviridae family.The virus has a narrow host range,limited to humans and chimpanzees.In the nucleus of infected hepatocytes,the partially double-stranded DNA(rcDNA)HBV genome is converted to covalent closed circular DNA(cccDNA),which serves as the sole template for HBV transcription.HBV cccDNA exists as an episomal minichromosome in the nucleus,with a turnover rate that correlates with the mitosis or death of virus-infected hepatocytes.It is thus regarded as a primary molecular mechanism for viral persistence.In the past decade,significant progress has been made in HBV research and the related antiviral development.Sodium taurocholate co-transporting polypeptide(NTCP)has been identified as a receptor for HBV entry into hepatocytes.It was recently shown that HBV x(HBx),an enigmatic viral protein,achieves its regulatory function by hijacking the cellular DDB1-containing E3 ubiquitin ligase to target the Smc5/6 complex for degradation.Although still controversial,type I interferon has been implicated to either affect the epigenetic control of cccDNA minichromosome,or induce cytidine deaminases-mediated specific degradation of the episomal cccDNA.Of particular note,core protein allosteric modulator(Cp AM)has been most widely investigated.These studies represent a new frontier in the development of antivirals against HBV infection.Despite continuing progress in HBV research,a complete cure of HBV infection is still not achievable.Current antiviral therapies with nucleos(t)ide analogs(NUC)and pegylated IFN-αcan efficiently inhibit HBV replication,but the treatments fail to eliminate the preexisting cccDNA pool that is responsible for a viral rebound after therapy cessation.Therefore,it is widely held that cccDNA elimination is a prerequisite for complete cure of chronic HBV infection.To this end,it is essential to understand the mec

关 键 词：乙型肝炎病毒 共价闭合环状DNA 病毒复制 持续性感染 实验模型 

分 类 号：R51[医药卫生—内科学]