HBV cccDNA研究现状与挑战
|
摘要
现有的抗病毒治疗方案很难清除HBV感染而达到"完全"治愈,导致许多患者需要长期、甚至终身接受核苷(酸)类似物抗病毒治疗,其根本的原因是肝细胞核内存在具有转录活性的共价闭合环状DNA(cccDNA)。为了让读者了解HBV cccDNA方面的研究进展,本期邀请了国内权威专家,就抗HBV治疗与慢性乙型肝炎的功能性治愈、靶向HBV cccDNA的药物及生物技术、HBV cccDNA转录调控机制与抗HBV治疗前景、HBV cccDNA的体外细胞模型和实验小鼠模型、原位杂交技术在检测HBV核酸和cccDNA中的应用、HBV cccDNA定量检测方法等6个方面的研究进展分别加以介绍。
Current antiviral treatment regimens seldom clear hepatitis B virus(HBV) infection and achieve complete cure,and therefore,many patients need long-term or even life-long antiviral therapy with nucleos(t) ide analogues. The root cause is the presence of covalently closed circular DNA(cccDNA) with transcriptional activity within hepatocytes. In order to help readers understand the research advances in HBV cccDNA,this issue invites leading experts in China to introduce the research advances from the following six aspects: anti-HBV treatment and functional cure of chronic hepatitis B,drugs and biotechniques targeting HBV cccDNA,transcriptional regulation of HBV cccDNA and prospects of anti-HBV treatment,in vitro cell models and experimental mouse models of HBV cccDNA,application of in situ hybridization in detection of HBV nucleic acid and cccDNA,and quantification of HBV cccDNA.
Current antiviral treatment regimens seldom clear hepatitis B virus(HBV) infection and achieve complete cure,and therefore,many patients need long-term or even life-long antiviral therapy with nucleos(t) ide analogues. The root cause is the presence of covalently closed circular DNA(cccDNA) with transcriptional activity within hepatocytes. In order to help readers understand the research advances in HBV cccDNA,this issue invites leading experts in China to introduce the research advances from the following six aspects: anti-HBV treatment and functional cure of chronic hepatitis B,drugs and biotechniques targeting HBV cccDNA,transcriptional regulation of HBV cccDNA and prospects of anti-HBV treatment,in vitro cell models and experimental mouse models of HBV cccDNA,application of in situ hybridization in detection of HBV nucleic acid and cccDNA,and quantification of HBV cccDNA.
引文
[1]LAI CL,WONG D,IP P,et al.Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B[J].J Hepatol,2017,66(2):275-281.
[2]ZHENG Q,ZHU YY,CHEN J,et al.Decline in intrahepatic cccD-NA and increase in immune cell reactivity after 12 weeks of antiviral treatment were associated with HBe Ag loss[J].J Viral Hepat,2014,21(12):909-916.
[3]WERLE-LAPOSTOLLE B,BOWDEN S,LOCARNINI S,et al.Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy[J].Gastroenterology,2004,126(7):1750-1758.
[4]BOYD A,LACOMBE K,LAVOCAT F,et al.Decay of cccDNA marks persistence of intrahepatic viral DNA synthesis under tenofovir in HIV-HBV co-infected patients[J].J Hepatol,2016,65(4):683-691.
[5]ZHANG X,LU W,ZHENG Y,et al.In situ analysis of intrahepatic virological events in chronic hepatitis B virus infection[J].J Clin Invest,2016,126(3):1079-1092.
[6]LUCIFORA J,XIA Y,REISINGER F,et al.Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA[J].Science,2014,343(6176):1221-1228.
[7]BOCKMANN JH,STADLER D,XIA Y,et al.Comparative analysis of the antiviral effects mediated by type I and III interferons in hepatitis B virus infected hepatocytes[J].J Infect Dis,2019.[Epub ahead of print]
[8]WEBER ND,STONE D,SEDLAK RH,et al.AAV-mediated delivery of zinc finger nucleases targeting hepatitis B virus inhibits active replication[J].PLo S One,2014,9(5):e97579.
[9]BLOOM K,ELY A,MUSSOLINO C,et al.Inactivation of hepatitis B virus replication in cultured cells and in vivo with engineered transcription activator-like effector nucleases[J].Mol Ther,2013,21(10):1889-1897.
[10]LIN SR,YANG HC,KUO YT,et al.The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo[J].Mol Ther Nucleic Acids,2014,3(2162-2531):e186.
[11]WANG J,XU ZW,LIU S,et al.Dual gRNAs guided CRISPR/Cas9 system inhibits hepatitis B virus replication[J].World JGastroenterol,2015,21(32):9554-9565.
[12]WANG J,CHEN R,ZHANG R,et al.The gRNA-miRNA-gRNA ternary cassette combining CRISPR/Cas9 with RNAi approach strongly inhibits hepatitis B virus replication[J].Theranostics,2017,7(12):3090-3105.
[13]WANG J.Epigenetic regulation of HBV covalently closed circular DNA:Implications for epigenetic treatment of chronic hepatitis B[J].Chin Heptol,2018,23(3):191-193.(in Chinese)王杰.HBV共价闭合环状DNA的表观遗传调控:对慢性乙型肝炎进行表观遗传治疗的启示[J].肝脏,2018,23(3):191-193.
[14]MARTINEZ MG,TESTONI B,ZOULIM F.Biological basis for functional cure of chronic hepatitis B[J].J Viral Hepat,2019.[Epub ahead of print]
[15]ZHANG W,CHEN J,WU M,et al.PRMT5 restricts hepatitis Bvirus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation[J].Hepatology,2017,66(2):398-415.
[16]REN JH,HU JL,CHENG ST,et al.SIRT3 restricts hepatitis Bvirus transcription and replication through epigenetic regulation of covalently closed circular DNA involving suppressor of variegation 3-9 homolog 1 and SET domain containing 1A histone methyltransferases[J].Hepatology,2018,68(4):1260-1276.
[17]GUO JT,GUO H.Metabolism and function of hepatitis B virus cccDNA:Implications for the development of cccDNA-targeting antiviral therapeutics[J].Antiviral Res,2015,122:91-100.
[18]QI Z,LI G,HU H,et al.Recombinant covalently closed circular hepatitis B virus DNA induces prolonged viral persistence in immunocompetent mice[J].J Virol,2014,88(14):8045-8056.
[19]YAN Z,ZENG J,YU Y,et al.HBVcircle:A novel tool to investigate hepatitis B virus covalently closed circular DNA[J].JHepatol,2017,66(6):1149-1157.
[20]ZHANG X,YUE L,ZHANG Z,et al.Establishment of a fluorescent in situ hybridization assay for imaging hepatitis B virus nucleic acids in cell culture models[J].Emerg Microbes Infect,2017,6(11):e98.
[21]LUO J,CUI X,HU J.Identification of intermediate in hepatitis B virus cccDNA.Formation and sensitive and selective cccD-NA detection[J].J Virol,2017,8(3):539-556.
[22]JIANG PX,MAO RC,ZHANG JM,et al.Exonuclease I and IIIimprove the detection efficacy of hepatitis B virus covalently closed circular DNA[J].Hepatobiliary Pancreat Dis Int,2018,19(18):261-269.
[23]GIAN PC,MARIA LA,FRANCESCO T,et al.Quantitation of HBV cccDNA in anti-HBc-positive liver donors by droplet digital PCR:A new tool to detect occult infection[J].J Hepatol,2018,69(2):301-307.
[2]ZHENG Q,ZHU YY,CHEN J,et al.Decline in intrahepatic cccD-NA and increase in immune cell reactivity after 12 weeks of antiviral treatment were associated with HBe Ag loss[J].J Viral Hepat,2014,21(12):909-916.
[3]WERLE-LAPOSTOLLE B,BOWDEN S,LOCARNINI S,et al.Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy[J].Gastroenterology,2004,126(7):1750-1758.
[4]BOYD A,LACOMBE K,LAVOCAT F,et al.Decay of cccDNA marks persistence of intrahepatic viral DNA synthesis under tenofovir in HIV-HBV co-infected patients[J].J Hepatol,2016,65(4):683-691.
[5]ZHANG X,LU W,ZHENG Y,et al.In situ analysis of intrahepatic virological events in chronic hepatitis B virus infection[J].J Clin Invest,2016,126(3):1079-1092.
[6]LUCIFORA J,XIA Y,REISINGER F,et al.Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA[J].Science,2014,343(6176):1221-1228.
[7]BOCKMANN JH,STADLER D,XIA Y,et al.Comparative analysis of the antiviral effects mediated by type I and III interferons in hepatitis B virus infected hepatocytes[J].J Infect Dis,2019.[Epub ahead of print]
[8]WEBER ND,STONE D,SEDLAK RH,et al.AAV-mediated delivery of zinc finger nucleases targeting hepatitis B virus inhibits active replication[J].PLo S One,2014,9(5):e97579.
[9]BLOOM K,ELY A,MUSSOLINO C,et al.Inactivation of hepatitis B virus replication in cultured cells and in vivo with engineered transcription activator-like effector nucleases[J].Mol Ther,2013,21(10):1889-1897.
[10]LIN SR,YANG HC,KUO YT,et al.The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo[J].Mol Ther Nucleic Acids,2014,3(2162-2531):e186.
[11]WANG J,XU ZW,LIU S,et al.Dual gRNAs guided CRISPR/Cas9 system inhibits hepatitis B virus replication[J].World JGastroenterol,2015,21(32):9554-9565.
[12]WANG J,CHEN R,ZHANG R,et al.The gRNA-miRNA-gRNA ternary cassette combining CRISPR/Cas9 with RNAi approach strongly inhibits hepatitis B virus replication[J].Theranostics,2017,7(12):3090-3105.
[13]WANG J.Epigenetic regulation of HBV covalently closed circular DNA:Implications for epigenetic treatment of chronic hepatitis B[J].Chin Heptol,2018,23(3):191-193.(in Chinese)王杰.HBV共价闭合环状DNA的表观遗传调控:对慢性乙型肝炎进行表观遗传治疗的启示[J].肝脏,2018,23(3):191-193.
[14]MARTINEZ MG,TESTONI B,ZOULIM F.Biological basis for functional cure of chronic hepatitis B[J].J Viral Hepat,2019.[Epub ahead of print]
[15]ZHANG W,CHEN J,WU M,et al.PRMT5 restricts hepatitis Bvirus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation[J].Hepatology,2017,66(2):398-415.
[16]REN JH,HU JL,CHENG ST,et al.SIRT3 restricts hepatitis Bvirus transcription and replication through epigenetic regulation of covalently closed circular DNA involving suppressor of variegation 3-9 homolog 1 and SET domain containing 1A histone methyltransferases[J].Hepatology,2018,68(4):1260-1276.
[17]GUO JT,GUO H.Metabolism and function of hepatitis B virus cccDNA:Implications for the development of cccDNA-targeting antiviral therapeutics[J].Antiviral Res,2015,122:91-100.
[18]QI Z,LI G,HU H,et al.Recombinant covalently closed circular hepatitis B virus DNA induces prolonged viral persistence in immunocompetent mice[J].J Virol,2014,88(14):8045-8056.
[19]YAN Z,ZENG J,YU Y,et al.HBVcircle:A novel tool to investigate hepatitis B virus covalently closed circular DNA[J].JHepatol,2017,66(6):1149-1157.
[20]ZHANG X,YUE L,ZHANG Z,et al.Establishment of a fluorescent in situ hybridization assay for imaging hepatitis B virus nucleic acids in cell culture models[J].Emerg Microbes Infect,2017,6(11):e98.
[21]LUO J,CUI X,HU J.Identification of intermediate in hepatitis B virus cccDNA.Formation and sensitive and selective cccD-NA detection[J].J Virol,2017,8(3):539-556.
[22]JIANG PX,MAO RC,ZHANG JM,et al.Exonuclease I and IIIimprove the detection efficacy of hepatitis B virus covalently closed circular DNA[J].Hepatobiliary Pancreat Dis Int,2018,19(18):261-269.
[23]GIAN PC,MARIA LA,FRANCESCO T,et al.Quantitation of HBV cccDNA in anti-HBc-positive liver donors by droplet digital PCR:A new tool to detect occult infection[J].J Hepatol,2018,69(2):301-307.