中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

HBV cccDNA转录代谢调控机制及沉默清除策略

宰文静 陈捷亮 袁正宏

引用本文:
Citation:

HBV cccDNA转录代谢调控机制及沉默清除策略

DOI: 10.3969/j.issn.1001-5256.2020.05.006
基金项目: 

国家自然科学基金项目(81974304,91842309); 

详细信息
  • 中图分类号: R512.62

Regulatory mechanisms of the transcription and metabolism of hepatitis B virus covalently closed circular DNA and strategies for silencing and elimination

Research funding: 

 

  • 摘要:

    已知HBV cccDNA在感染肝细胞的细胞核内以微染色体的形式持续稳定存在,难以被靶向调控和清除。围绕HBV cccDNA持续沉默或降解清除机制及策略的研究是当前慢性乙型肝炎"功能性治愈"目标下的重点。介绍了目前对cccDNA基本生物学特性、转录和代谢调控机制及相关宿主因子的认知,重点分析了cccDNA沉默清除的可能途径和靶向调控策略。

     

  • [1] LIN CL, YANG HC, KAO JH. Hepatitis B virus:New therapeutic perspectives[J]. Liver Int, 2016, 36(Suppl 1):85-92.
    [2] KÖNIGER C, WINGERT I, MARSMANN M, et al. Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses[J]. Proc Natl Acad Sci U S A, 2014, 111(40):e4244-e4253.
    [3] KITAMURA K, QUE L, SHIMADU M, et al. Flap endonuclease1 is involved in cccDNA formation in the hepatitis B virus[J].PLoS Pathog, 2018, 14(6):e1007124.
    [4] WEI L, PLOSS A. Core components of DNA lagging strand synthesis machinery are essential for hepatitis B virus cccDNA formation[J]. Nat Microbiol, 2020.[Online ahead of print]
    [5] LARAS A, KOSKINAS J, DIMOU E, et al. Intrahepatic levels and replicative activity of covalently closed circular hepatitis B virus DNA in chronically infected patients[J]. Hepatology,2006, 44(3):694-702.
    [6] LENTZ TB, LOEB DD. Roles of the envelope proteins in the amplification of covalently closed circular DNA and completion of synthesis of the plus-strand DNA in hepatitis B virus[J]. J Virol, 2011, 85(22):11916-11927.
    [7] 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.
    [8] 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.
    [9] TSIANG M, GIBBS CS. Analysis of hepatitis B virus dynamics and its impact on antiviral development[J]. Methods Mol Med, 2004, 96:361-377.
    [10] ADDISON WR, WALTERS KA, WONG WW, et al. Half-life of the duck hepatitis B virus covalently closed circular DNA pool in vivo following inhibition of viral replication[J]. J Virol, 2002,76(12):6356-6363.
    [11] HUANG Q, ZHOU B, CAI D, et al. Rapid turnover of HBV cccDNA indicated by monitoring emergence and reversion of signature-mutation in treated chronic hepatitis B patients[J].Hepatology, 2020.[Online ahead of print]
    [12] BOCK CT, SCHWINN S, LOCARNINI S, et al. Structural organization of the hepatitis B virus minichromosome[J]. J Mol Biol, 2001, 307(1):183-196.
    [13] KNIPE DM, CLIFFE A. Chromatin control of herpes simplex virus lytic and latent infection[J]. Nat Rev Microbiol, 2008, 6(3):211-221.
    [14] MOREAU P, COURNAC A, PALUMBO GA, et al. Tridimensional infiltration of DNA viruses into the host genome shows preferential contact with active chromatin[J]. Nat Commun,2018, 9(1):4268.
    [15] ZHANG Y, MAO R, YAN R, et al. Transcription of hepatitis B virus covalently closed circular DNA is regulated by CpG methylation during chronic infection[J]. PLoS One, 2014, 9(10):e110442.
    [16] RAMIÈRE C, SCHOLTÈS C, DIAZ O, et al. Transactivation of the hepatitis B virus core promoter by the nuclear receptor FXRalpha[J]. J Virol, 2008, 82(21):10832-10840.
    [17] KIM BK, LIM SO, PARK YG. Requirement of the cyclic adenosine monophosphate response element-binding protein for hepatitis B virus replication[J]. Hepatology, 2008, 48(2):361-373.
    [18] RALL LB, STANDRING DN, LAUB O, et al. Transcription of hepatitis B virus by RNA polymerase II[J]. Mol Cell Biol,1983, 3(10):1766-1773.
    [19] TROPBERGER P, MERCIER A, ROBINSON M, et al. Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation[J]. Proc Natl Acad Sci U S A, 2015, 112(42):e5715-e5724.
    [20] FLECKEN T, MEIER MA, SKEWES-COX P, et al. Mapping the heterogeneity of histone modifications on hepatitis B virus DNA using liver needle biopsies obtained from chronically infected patients[J]. J Virol, 2019, 93(9):e02036-e02018.
    [21] ZHANG W, CHEN J, WU M, et al. PRMT5 restricts hepatitis B virus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation[J]. Hepatology, 2017, 66(2):398-415.
    [22] REN JH, HU JL, CHENG ST, et al. SIRT3 restricts hepatitis B virus 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.
    [23] DUGGAL NK, EMERMAN M. Evolutionary conflicts between viruses and restriction factors shape immunity[J]. Nat Rev Immunol, 2012, 12(10):687-695.
    [24] WANG YX, NIKLASCH M, LIU T, et al. Interferon-inducible MX2 is a host restriction factor of hepatitis B virus replication[J]. J Hepatol, 2020, 72(5):865-876.
    [25] CHEN EQ, DAI J, BAI L, et al. The efficacy of zinc finger antiviral protein against hepatitis B virus transcription and replication in tansgenic mouse model[J]. Virol J, 2015, 12:25.
    [26] BELLONI L, ALLWEISS L, GUERRIERI F, et al. IFN-αinhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome[J]. J Clin Invest, 2012, 122(2):529-537.
    [27] LIU F, CAMPAGNA M, QI Y, et al. Alpha-interferon suppresses hepadnavirus transcription by altering epigenetic modification of cccDNA minichromosomes[J]. PLoS Pathog,2013, 9(9):e1003613.
    [28] PALUMBO GA, SCISCIANI C, PEDICONI N, et al. Correction:IL6 inhibits HBV transcription by targeting the epigenetic control of the Nuclear cccDNA minichromosome[J]. PLoS One, 2015, 10(12):e0145555.
    [29] REHERMANN B, FERRARI C, PASQUINELLI C, et al. The hepatitis B virus persists for decades after patients’ recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response[J]. Nat Med, 1996, 2(10):1104-1108.
    [30] COUGOT D, WU Y, CAIRO S, et al. The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300in the regulation of CREB-mediated transcription[J]. J Biol Chem, 2007, 282(7):4277-4287.
    [31] BELLONI L, POLLICINO T, de NICOLA F, et al. Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function[J]. Proc Natl Acad Sci U S A,2009, 106(47):19975-19979.
    [32] MURPHY CM, XU Y, LI F, et al. Hepatitis B virus X protein promotes degradation of SMC5/6 to enhance HBV replication[J]. Cell Rep, 2016, 16(11):2846-2854.
    [33] BAUMERT TF, RÖSLER C, MALIM MH, et al. Hepatitis B virus DNA is subject to extensive editing by the human deaminase APOBEC3C[J]. Hepatology, 2007, 46(3):682-689.
    [34] STRAY SJ, BOURNE CR, PUNNA S, et al. A heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly[J]. Proc Natl Acad Sci U S A, 2005, 102(23):8138-8143.
    [35] GUIDOTTI LG, ISHIKAWA T, HOBBS MV, et al. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes[J]. Immunity, 1996, 4(1):25-36.
    [36] GUIDOTTI LG, ROCHFORD R, CHUNG J, et al. Viral clearance without destruction of infected cells during acute HBV infection[J]. Science, 1999, 284(5415):825-829.
    [37] XIA Y, STADLER D, LUCIFORA J, et al. Interferon-γand tumor necrosis factor-αproduced by T cells reduce the HBV persistence form, cccDNA, without cytolysis[J]. Gastroenterology, 2016, 150(1):194-205.
    [38] GUIDOTTI LG, BORROW P, HOBBS MV, et al. Viral cross talk:Intracellular inactivation of the hepatitis B virus during an unrelated viral infection of the liver[J]. Proc Natl Acad Sci U S A, 1996, 93(10):4589-4594.
    [39] 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.
    [40] THIMME R, WIELAND S, STEIGER C, et al. CD8(+)T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection[J]. J Virol, 2003, 77(1):68-76.
    [41] ZHANG Z, ZHANG JY, WHERRY EJ, et al. Dynamic programmed death 1 expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B[J]. Gastroenterology, 2008, 134(7):1938-1949, 1949.e1-3.
    [42] MENG Z, CHEN Y, LU M. Advances in targeting the innate and adaptive immune systems to cure chronic hepatitis B virus infection[J]. Front Immunol, 2019, 10:3127.
    [43] LUTGEHETMANN M, VOLZ T, KÖPKE A, et al. In vivo proliferation of hepadnavirus-infected hepatocytes induces loss of covalently closed circular DNA in mice[J]. Hepatology,2010, 52(1):16-24.
    [44] AYDIN I, SCHELHAAS M. Viral genome tethering to host cell chromatin:Cause and consequences[J]. Traffic, 2016, 17(4):327-340.
    [45] SUMMERS J, JILBERT AR, YANG W, et al. Hepatocyte turnover during resolution of a transient hepadnaviral infection[J].Proc Natl Acad Sci U S A, 2003, 100(20):11652-11659.
    [46] GUO JT, ZHOU H, LIU C, et al. Apoptosis and regeneration of hepatocytes during recovery from transient hepadnavirus infections[J]. J Virol, 2000, 74(3):1495-1505.
    [47] ALLWEISS L, VOLZ T, GIERSCH K, et al. Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo[J]. Gut,2018, 67(3):542-552.
    [48] DONG C, QU L, WANG H, et al. Targeting hepatitis B virus cccDNA by CRISPR/Cas9 nuclease efficiently inhibits viral replication[J]. Antiviral Res, 2015, 118:110-117.
    [49] CHEN J, ZHANG W, LIN J, et al. An efficient antiviral strategy for targeting hepatitis B virus genome using transcription activator-like effector nucleases[J]. Mol Ther, 2014, 22(2):303-311.
    [50] BLOOM K, MAEPA MB, ELY A, et al. Gene therapy for chronic HBV-can we eliminate cccDNA?[J]. Genes(Basel),2018, 9(4):207.
  • 加载中
计量
  • 文章访问数:  1464
  • HTML全文浏览量:  82
  • PDF下载量:  352
  • 被引次数: 0
出版历程
  • 出版日期:  2020-05-20
  • 分享
  • 用微信扫码二维码

    分享至好友和朋友圈

目录

    /

    返回文章
    返回