从HBV cccDNA角度谈乙型肝炎的功能性治愈

陈娟; 黄爱龙

doi:10.3969/j.issn.1001-5256.2022.08.003

从HBV cccDNA角度谈乙型肝炎的功能性治愈

DOI: 10.3969/j.issn.1001-5256.2022.08.003

陈娟,
黄爱龙^, ,

重庆医科大学感染性疾病分子生物学教育部重点实验室，重庆 400016

基金项目:

国家自然科学基金 (81861168035);

国家自然科学基金 (81871656);

国家自然科学基金 (81922011)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：陈娟负责收集资料并撰写文章；黄爱龙负责文稿修订并最终定稿。

详细信息

通信作者:
黄爱龙, ahuang1964@163.com

计量
- 文章访问数: 764
- HTML全文浏览量: 317
- PDF下载量: 206
- 被引次数: 0
出版历程
- 收稿日期: 2022-06-02
- 录用日期: 2022-07-04
- 出版日期: 2022-08-20

Functional cure of hepatitis B from the perspective of hepatitis B virus covalently closed circular DNA

Juan CHEN,
Ailong HUANG^{,
,}

Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China

Research funding:

National Natural Science Foundation of China (81861168035);

National Natural Science Foundation of China (81871656);

National Natural Science Foundation of China (81922011)

More Information

Corresponding author: HUANG Ailong, ahuang1964@163.com(ORCID: 0000-0003-0148-7423)

摘要

摘要: HBV共价闭合环状DNA(cccDNA)是HBV转录和复制的模板，以微染色体的形式长期稳定存在于肝细胞内。笔者围绕cccDNA失活或清除机制及药物研发，介绍了对cccDNA形成、转录和降解等功能性事件的认识，并综述了cccDNA靶向药物及生物技术相关的研究进展。
- 乙型肝炎 /
- DNA, 环状 /
- 分子靶向治疗
Abstract: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is the template for HBV transcription and replication and exists stably in hepatocytes in the form of minichromosome. Based on the mechanism of cccDNA inactivation or clearance and the development of related drugs, this article introduces the current knowledge on the formation, transcription, and degradation of cccDNA and reviews the research advances in cccDNA-targeted drugs and biological techniques.
- Hepatitis B /
- DNA, Circular /
- Molecular Targeted Therapy

HTML全文

参考文献(45)

[1]	YUEN MF, CHEN DS, DUSHEIKO GM, et al. Hepatitis B virus infection[J]. Nat Rev Dis Primers, 2018, 4: 18035. DOI: 10.1038/nrdp.2018.35.
[2]	FANNING GC, ZOULIM F, HOU J, et al. Therapeutic strategies for hepatitis B virus infection: towards a cure[J]. Nat Rev Drug Discov, 2019, 18(11): 827-844. DOI: 10.1038/s41573-019-0037-0.
[3]	SHIH C, CHOU SF, YANG CC, et al. Control and eradication strategies of hepatitis B virus[J]. Trends Microbiol, 2016, 24(9): 739-749. DOI: 10.1016/j.tim.2016.05.006.
[4]	REVILL P, TESTONI B, LOCARNINI S, et al. Global strategies are required to cure and eliminate HBV infection[J]. Nat Rev Gastroenterol Hepatol, 2016, 13(4): 239-248. DOI: 10.1038/nrgastro.2016.7.
[5]	YAN H, ZHONG G, XU G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus[J]. Elife, 2012, 1: e00049. DOI: 10.7554/eLife.00049.
[6]	WEI L, PLOSS A. Core components of DNA lagging strand synthesis machinery are essential for hepatitis B virus cccDNA formation[J]. Nat Microbiol, 2020, 5(5): 715-726. DOI: 10.1038/s41564-020-0678-0.
[7]	WEI L, PLOSS A. Hepatitis B virus cccDNA is formed through distinct repair processes of each strand[J]. Nat Commun, 2021, 12(1): 1591. DOI: 10.1038/s41467-021-21850-9.
[8]	NASSAL M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B[J]. Gut, 2015, 64(12): 1972-1984. DOI: 10.1136/gutjnl-2015-309809.
[9]	TURTON KL, MEIER-STEPHENSON V, BADMALIA MD, et al. Host transcription factors in hepatitis B virus RNA synthesis[J]. Viruses, 2020, 12(2): 160. DOI: 10.3390/v12020160.
[10]	KIM DH, KANG HS, KIM KH. Roles of hepatocyte nuclear factors in hepatitis B virus infection[J]. World J Gastroenterol, 2016, 22(31): 7017-7029. DOI: 10.3748/wjg.v22.i31.7017.
[11]	OROPEZA CE, TARNOW G, SRIDHAR A, et al. The regulation of HBV transcription and replication[J]. Adv Exp Med Biol, 2020, 1179: 39-69. DOI: 10.1007/978-981-13-9151-4_3.
[12]	VIVEKANANDAN P, DANIEL HD, KANNANGAI R, et al. Hepatitis B virus replication induces methylation of both host and viral DNA[J]. J Virol, 2010, 84(9): 4321-4329. DOI: 10.1128/JVI.02280-09.
[13]	POLLICINO T, BELLONI L, RAFFA G, et al. Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones[J]. Gastroenterology, 2006, 130(3): 823-837. DOI: 10.1053/j.gastro.2006.01.001.
[14]	BELLONI L, ALLWEISS L, GUERRIERI F, et al. IFN-α inhibits 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. DOI: 10.1172/JCI58847.
[15]	BENHENDA S, DUCROUX A, RIVIÈRE L, et al. Methyltransferase PRMT1 is a binding partner of HBx and a negative regulator of hepatitis B virus transcription[J]. J Virol, 2013, 87(8): 4360-4371. DOI: 10.1128/JVI.02574-12.
[16]	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. DOI: 10.1002/hep.29133.
[17]	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. DOI: 10.1002/hep.29912.
[18]	WEI W, LIU X, CHEN J, et al. Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription[J]. Cell Res, 2017, 27(7): 898-915. DOI: 10.1038/cr.2017.68.
[19]	WANG Y, GUO YR, LIU K, et al. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase[J]. Nature, 2017, 552(7684): 273-277. DOI: 10.1038/nature25003.
[20]	KEBEDE AF, NIEBORAK A, SHAHIDIAN LZ, et al. Histone propionylation is a mark of active chromatin[J]. Nat Struct Mol Biol, 2017, 24(12): 1048-1056. DOI: 10.1038/nsmb.3490.
[21]	ISHIGURO T, TANABE K, KOBAYASHI Y, et al. Malonylation of histone H2A at lysine 119 inhibits Bub1-dependent H2A phosphorylation and chromosomal localization of shugoshin proteins[J]. Sci Rep, 2018, 8(1): 7671. DOI: 10.1038/s41598-018-26114-z.
[22]	LU Y, XU Q, LIU Y, et al. Dynamics and functional interplay of histone lysine butyrylation, crotonylation, and acetylation in rice under starvation and submergence[J]. Genome Biol, 2018, 19(1): 144. DOI: 10.1186/s13059-018-1533-y.
[23]	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. DOI: 10.1073/pnas.0908365106.
[24]	RIVIÈRE L, GEROSSIER L, DUCROUX A, et al. HBx relieves chromatin-mediated transcriptional repression of hepatitis B viral cccDNA involving SETDB1 histone methyltransferase[J]. J Hepatol, 2015, 63(5): 1093-1102. DOI: 10.1016/j.jhep.2015.06.023.
[25]	DECORSIÈRE A, MUELLER H, van BREUGEL PC, et al. Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor[J]. Nature, 2016, 531(7594): 386-389. DOI: 10.1038/nature17170.
[26]	MINOR MM, HOLLINGER FB, MCNEES AL, et al. Hepatitis B virus HBx protein mediates the degradation of host restriction factors through the cullin 4 DDB1 E3 ubiquitin ligase complex[J]. Cells, 2020, 9(4): 834. DOI: 10.3390/cells9040834.
[27]	ZHU Y, YAMAMOTO T, CULLEN J, et al. Kinetics of hepadnavirus loss from the liver during inhibition of viral DNA synthesis[J]. J Virol, 2001, 75(1): 311-322. DOI: 10.1128/JVI.75.1.311-322.2001.
[28]	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. DOI: 10.1128/jvi.76.12.6356-6363.2002.
[29]	XIA Y, STADLER D, LUCIFORA J, et al. Interferon-γ and tumor necrosis factor-α produced by T cells reduce the HBV persistence form, cccDNA, without cytolysis[J]. Gastroenterology, 2016, 150(1): 194-205. DOI: 10.1053/j.gastro.2015.09.026.
[30]	TSIANG M, GIBBS CS. Analysis of hepatitis B virus dynamics and its impact on antiviral development[J]. Methods Mol Med, 2004, 96: 361-377. DOI: 10.1385/1-59259-670-3:361.
[31]	HUANG Q, ZHOU B, CAI D, et al. Rapid turnover of hepatitis B virus covalently closed circular DNA indicated by monitoring emergence and reversion of signature-mutation in treated chronic hepatitis B patients[J]. Hepatology, 2021, 73(1): 41-52. DOI: 10.1002/hep.31240.
[32]	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. DOI: 10.1126/science.1243462.
[33]	STADLER D, KÄCHELE M, JONES AN, et al. Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20[J]. EMBO Rep, 2021, 22(6): e49568. DOI: 10.15252/embr.201949568.
[34]	ZHOU L, REN JH, CHENG ST, et al. A functional variant in ubiquitin conjugating enzyme E2 L3 contributes to hepatitis B virus infection and maintains covalently closed circular DNA stability by inducing degradation of apolipoprotein B mRNA editing enzyme catalytic subunit 3A[J]. Hepatology, 2019, 69(5): 1885-1902. DOI: 10.1002/hep.30497.
[35]	PETERSEN J, DANDRI M, MIER W, et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein[J]. Nat Biotechnol, 2008, 26(3): 335-341. DOI: 10.1038/nbt1389.
[36]	VOLZ T, ALLWEISS L, BEN MBAREK M, et al. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus[J]. J Hepatol, 2013, 58(5): 861-867. DOI: 10.1016/j.jhep.2012.12.008.
[37]	YAN H, PENG B, LIU Y, et al. Viral entry of hepatitis B and D viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide[J]. J Virol, 2014, 88(6): 3273-3284. DOI: 10.1128/JVI.03478-13.
[38]	PENG L, ZHAO Q, LI Q, et al. The p. Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B[J]. Hepatology, 2015, 61(4): 1251-1260. DOI: 10.1002/hep.27608.
[39]	HU HH, LIU J, LIN YL, et al. The rs2296651(S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B[J]. Gut, 2016, 65(9): 1514-1521. DOI: 10.1136/gutjnl-2015-310686.
[40]	CAI D, MILLS C, YU W, et al. Identification of disubstituted sulfonamide compounds as specific inhibitors of hepatitis B virus covalently closed circular DNA formation[J]. Antimicrob Agents Chemother, 2012, 56(8): 4277-4288. DOI: 10.1128/AAC.00473-12.
[41]	SETTEN RL, ROSSI JJ, HAN SP. The current state and future directions of RNAi-based therapeutics[J]. Nat Rev Drug Discov, 2019, 18(6): 421-446. DOI: 10.1038/s41573-019-0017-4.
[42]	CHENG ST, HU JL, REN JH, et al. Dicoumarol, an NQO1 inhibitor, blocks cccDNA transcription by promoting degradation of HBx[J]. J Hepatol, 2021, 74(3): 522-534. DOI: 10.1016/j.jhep.2020.09.019.
[43]	LAMB C, ARBUTHNOT P. Activating the innate immune response to counter chronic hepatitis B virus infection[J]. Expert Opin Biol Ther, 2016, 16(12): 1517-1527. DOI: 10.1080/14712598.2016.1233962.
[44]	KUSCU C, ARSLAN S, SINGH R, et al. Genome-wide analysis reveals characteristics of off-target sites bound by the Cas9 endonuclease[J]. Nat Biotechnol, 2014, 32(7): 677-683. DOI: 10.1038/nbt.2916.
[45]	WANG J, XU ZW, LIU S, et al. Dual gRNAs guided CRISPR/Cas9 system inhibits hepatitis B virus replication[J]. World J Gastroenterol, 2015, 21(32): 9554-9565. DOI: 10.3748/wjg.v21.i32.9554.