干扰素和核苷(酸)类似物治疗对HBV cccDNA的影响与慢性乙型肝炎的功能性治愈

陈捷亮; 袁正宏

doi:10.3969/j.issn.1001-5256.2019.06.002

干扰素和核苷(酸)类似物治疗对HBV cccDNA的影响与慢性乙型肝炎的功能性治愈

DOI: 10.3969/j.issn.1001-5256.2019.06.002

基金项目:

国家自然科学基金(81772189)；国家科技重大专项(2018ZX10301208)；中国医学科学院科研基金(2018PT31044)；上海市教委科研创新计划(201701070007E00057)；

详细信息

中图分类号: R512.62
计量
- 文章访问数: 451
- HTML全文浏览量: 35
- PDF下载量: 263
- 被引次数: 0
出版历程
- 收稿日期: 2019-04-09
- 出版日期: 2019-06-20

Influence of interferon and nucleos (t) ide analogues on HBV cccDNA and functional cure of chronic hepatitis B

Research funding:

摘要

摘要: 目前临床治疗慢性乙型肝炎的药物主要包括干扰素和核苷(酸)类似物两大类,但均无法有效清除病毒和治愈乙型肝炎。HBV共价闭合环状DNA(cccDNA)作为HBV转录复制的模板,以微小染色体形式持续存在于细胞核内,被认为是HBV慢性感染和难以治愈的关键核心。鉴于cccDNA很难被彻底清除,近年来以cccDNA持续沉默为基础的慢性乙型肝炎功能性治愈已成为临床和基础研究的主要目标。从现有治疗手段对cccDNA的影响切入,介绍当前对cccDNA含量和活性受控因素的认知,探讨cccDNA池难以清除的关键特性环节,在此基础上展望功能性治愈慢性乙型肝炎目标下研究cccDNA的重点。
- 乙型肝炎病毒 /
- 抗病毒药 /
- 共价闭合环状DNA
Abstract: At present, interferon (IFN) and nucleos (t) ide analogues (NAs) remain the most important methods for the treatment of chronic hepatitis B in clinical practice, but neither of them can effectively eliminate the virus and cure hepatitis B. As the template for HBV transcription and replication, HBV covalently closed circular DNA (cccDNA) persistently exists in the nucleus in the form of minichromosome and is considered the most important reason for chronic and refractory HBV infection. Since it is hard to completely eliminate cccDNA, functional cure of chronic hepatitis B through sustained silencing of cccDNA has become a major goal of clinical and basic research in recent years. This article reviews the influence of current treatment methods on cccDNA, the factors regulating the amount and activity of cccDNA, and the key obstacles to eradication of cccDNA pool, with perspectives of cccDNA research towards a functional cure of chronic hepatitis B.
- hepatitis B virus /
- antiviral agents /
- covalently closed circular DNA

HTML全文

参考文献(70)

[1]TANG LSY, COVERT E, WILSON E, et al.Chronic hepatitis Binfection:A review[J].JAMA, 2018, 319 (17) :1802-1813.

[2]MILLER RH, ROBINSON WS.Hepatitis B virus DNA forms in nuclear and cytoplasmic fractions of infected human liver[J].Virology, 1984, 137 (2) :390-399.

[3]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.

[4]NASSAL M.HBV cccDNA:Viral persistence reservoir and key obstacle for a cure of chronic hepatitis B[J].Gut, 2015, 64 (12) :1972-1984.

[5] ALLWEISS L, DANDRI M.The role of cccDNA in HBV maintenance[J].Viruses, 2017, 9 (6) :156.

[6]ZHENG Q, ZHU YY, CHEN J, et al.Decline in intrahepatic cccDNA and increase in immune cell reactivity after 12 weeks of antiviral treatment were associated with HBe Ag loss[J].JViral Hepat, 2014, 21 (12) :909-916.

[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]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.

[9]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.

[10]Experts attending the discussion on long-treatment of chronic hepatitis B.Long-term treatment of chronic hepatitis B[J].JClin Hepatol, 2014, 30 (11) :1099-1105. (in Chinese) 慢性乙型肝炎长期治疗讨论会专家.核苷和核苷酸类药物治疗慢性乙型肝炎的长期性[J].临床肝胆病杂志, 2014, 30 (11) :1099-1105.

[11]LIANG KH, HSU CW, CHANG ML, et al.Peginterferon is superior to nucleos (t) ide analogues for prevention of hepatocellular carcinoma in chronic hepatitis B[J].J Infect Dis, 2016, 213 (6) :966-974.

[12]MURATA K, ASANO M, MATSUMOTO A, et al.Induction of IFN-lambda3 as an additional effect of nucleotide, not nucleoside, analogues:A new potential target for HBV infection[J].Gut, 2018, 67 (2) :362-371.

[13] CHOI J, KIM HJ, LEE J, et al.Risk of hepatocellular carcinoma in patients treated with entecavir vs tenofovir for chronic hepatitis B:A Korean nationwide cohort study[J].JAMA oncology, 2019, 5 (1) :30-36.

[14]TAN G, SONG H, XU F, et al.When hepatitis B virus meets interferons[J].Front Microbiol, 2018, 9:1611.

[15]CHEN JL, LI JH, ZHANG XN, et al.Interplay between hepatitis B virus and the type I interferon system and new therapeutic strategies[J].Fudan Univ J Med Sci, 2017, 44 (6) :793-798. (in Chinese) 陈捷亮, 李建华, 张小楠, 等.乙型肝炎病毒与I型干扰素系统相互作用新机制及治疗策略的研究[J].复旦学报:医学版, 2017, 44 (6) :793-798.

[16]LI J, LIU K, LIU Y, et al.Exosomes mediate the cell-to-cell transmission of IFN-alpha-induced antiviral activity[J].Nat Immunol, 2013, 14 (8) :793-803.

[17]YAO Z, QIAO Y, LI X, et al.Exosomes exploit the virus entry machinery and pathway to transmit alpha interferon-induced antiviral activity[J].J Virol, 2018, 92 (24) :e01578-18.

[18]MICCO L, PEPPA D, LOGGI E, et al.Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B[J].J Hepatol, 2013, 58 (2) :225-233.

[19]LU HY, ZHUANG LW, YU YY, et al.Effects of antiviral agents on intrahepatic ccc DNA in HBe Ag-positive chronic hepatitis B patients[J].Chin J Hepatol, 2008, 16 (3) :198-202. (in Chinese) 陆海英, 庄立伟, 于岩岩, 等.抗病毒药物对肝组织乙型肝炎病毒共价闭合环状DNA的影响[J].中华肝脏病杂志, 2008, 16 (3) :198-202.

[20]WURSTHORN K, LUTGEHETMANN M, DANDRI M, et al.Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBs Ag reduction in patients with chronic hepatitis B[J].Hepatology, 2006, 44 (3) :675-684.

[21]HAGIWARA S, KUDO M, OSAKI Y, et al.Impact of peginterferon alpha-2b and entecavir hydrate combination therapy on persistent viral suppression in patients with chronic hepatitis B[J].J Med Virol, 2013, 85 (6) :987-995.

[22]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.

[23]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]

[24]BELLONI L, ALLWEISS L, GUERRIERI F, et al.IFN-alpha 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.

[25]SHEN F, LI Y, WANG Y, et al.Hepatitis B virus sensitivity to interferon-alpha in hepatocytes is more associated with cellular interferon response than with viral genotype[J].Hepatology, 2018, 67 (4) :1237-1252.

[26]MUTZ P, METZ P, LEMPP FA, et al.HBV bypasses the innate immune response and does not protect HCV from antiviral activity of interferon[J].Gastroenterology, 2018, 154 (6) :1791-1804, e22.

[27]ALLWEISS L, VOLZ T, LUTGEHETMANN M, et al.Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-alpha administration[J].J Hepatol, 2014, 60 (3) :500-507.

[28]YEO W, CHAN TC, LEUNG NW, et al.Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab[J].JClin Oncol, 2009, 27 (4) :605-611.

[29]HSU C, TSOU HH, LIN SJ, et al.Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection:A prospective study[J].Hepatology, 2014, 59 (6) :2092-2100.

[30]FISICARO P, VALDATTA C, BONI C, et al.Early kinetics of innate and adaptive immune responses during hepatitis B virus infection[J].Gut, 2009, 58 (7) :974-982.

[31]ZEISSIG S, MURATA K, SWEET L, et al.Hepatitis B virusinduced lipid alterations contribute to natural killer T cell-dependent protective immunity[J].Nat Med, 2012, 18 (7) :1060-1068.

[32]XIA Y, PROTZER U.Control of hepatitis B virus by cytokines[J].Viruses, 2017, 9 (1) :18.

[33]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.

[34]XIA Y, STADLER D, LUCIFORA J, et al.Interferon-gamma and tumor necrosis factor-alpha produced by T cells reduce the HBV persistence form, cccDNA, without cytolysis[J].Gastroenterology, 2016, 150 (1) :194-205.

[35]LEBOSSE F, TESTONI B, FRESQUET J, et al.Intrahepatic innate immune response pathways are downregulated in untreated chronic hepatitis B[J].J Hepatol, 2017, 66 (5) :897-909.

[36]PARK JJ, WONG DK, WAHED AS, et al.Hepatitis B virusspecific and global T-cell dysfunction in chronic hepatitis B[J].Gastroenterology, 2016, 150 (3) :684-695, e5.

[37]BONI C, LACCABUE D, LAMPERTICO P, et al.Restored function of HBV-specific T cells after long-term effective therapy with nucleos (t) ide analogues[J].Gastroenterology, 2012, 143 (4) :963-973, e9.

[38]de NIET A, STELMA F, JANSEN L, et al.Restoration of T cell function in chronic hepatitis B patients upon treatment with interferon based combination therapy[J].J Hepatol, 2016, 64 (3) :539-546.

[39]CORTI D, BENIGNI F, SHOUVAL D.Viral envelope-specific antibodies in chronic hepatitis B virus infection[J].Curr Opin Virol, 2018, 30:48-57.

[40]NEUMANN AU, PHILLIPS S, LEVINE I, et al.Novel mechanism of antibodies to hepatitis B virus in blocking viral particle release from cells[J].Hepatology, 2010, 52 (3) :875-885.

[41]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.

[42]MASON WS, LOW HC, XU C, et al.Detection of clonally expanded hepatocytes in chimpanzees with chronic hepatitis Bvirus infection[J].J Virol, 2009, 83 (17) :8396-8408.

[43]BAR-YISHAY I, SHAUL Y, SHLOMAI A.Hepatocyte metabolic signalling pathways and regulation of hepatitis B virus expression[J].Liver Int, 2011, 31 (3) :282-290.

[44]XIA Y, CHENG X, LI Y, et al.Hepatitis B virus deregulates the cell cycle to promote viral replication and a premalignant phenotype[J].J Virol, 2018, 92 (19) :e00722-18.

[45]LI B, WANG Y, SHEN F, et al.Identification of retinoic acid receptor agonists as potent hepatitis B virus inhibitors via a drug repurposing screen[J].Antimicrob Agents Chemother, 2018, 62 (12) :e00465-18.

[46]SONNEVELD MJ, WONG VW, WOLTMAN AM, et al.Polymorphisms near IL28B and serologic response to peginterferon in HBe Ag-positive patients with chronic hepatitis B[J].Gastroenterology, 2012, 142 (3) :513-520, e1.

[47]JIANG DK, WU X, QIAN J, et al.Genetic variation in STAT4predicts response to interferon-alpha therapy for hepatitis B e antigen-positive chronic hepatitis B[J].Hepatology, 2016, 63 (4) :1102-1111.

[48]ZHOU L, REN JH, CHENG ST, et al.A functional variant in ubiquitin conjugating enzyme E2 L3 contributes to hepatitis Bvirus infection and maintains covalently closed circular DNAstability by inducing degradation of apolipoprotein B mRNAediting enzyme catalytic subunit 3A[J].Hepatology, 2019, 69 (5) :1885-1902.

[49]MORALEDA G, SAPUTELLI J, ALDRICH CE, et al.Lack of effect of antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus[J].J Virol, 1997, 71 (12) :9392-9399.

[50]QUETIER I, BREZILLON N, DURIEZ M, et al.Hepatitis B virus HBx protein impairs liver regeneration through enhanced expression of IL-6 in transgenic mice[J].J Hepatol, 2013, 59 (2) :285-291.

[51]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].JVirol, 2011, 85 (22) :11916-11927.

[52]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.

[53] TONG S, REVILL P.Overview of hepatitis B viral replication and genetic variability[J].J Hepatol, 2016, 64 (1 Suppl) :s4-s16.

[54]COFFIN CS, MULROONEY-COUSINS PM, van MARLE G, et al.Hepatitis B virus quasispecies in hepatic and extrahepatic viral reservoirs in liver transplant recipients on prophylactic therapy[J].Liver Transpl, 2011, 17 (8) :955-962.

[55]ZOULIM F.Inhibition of hepatitis B virus gene expression:Astep towards functional cure[J].J Hepatol, 2018, 68 (3) :386-388.

[56]WANG XY, WEN YM.A"sandwich"strategy for functional cure of chronic hepatitis B[J].Emerg Microbes Infect, 2018, 7 (1) :91.

[57]HU J, LIN YY, CHEN PJ, et al.Cell and animal models for studying hepatitis B virus infection and drug development[J].Gastroenterology, 2019, 156 (2) :338-354.

[58]LI X, ZHAO J, YUAN Q, et al.Detection of HBV covalently closed circular DNA[J].Viruses, 2017, 9 (6) :139.

[59]LU FM, DOU XG, ZHANG WH, et al.Clinical significance of serum HBV RNA measurement in chronic hepatitis B patients[J].J Clin Hepatol, 2018, 34 (5) :934-938. (in Chinese) 鲁凤民, 窦晓光, 张文宏, 等.慢性乙型肝炎患者血清HBV RNA检测的临床意义[J].临床肝胆病杂志, 2018, 34 (5) :934-938.

[60]BAI L, ZHANG X, KOZLOWSKI M, et al.Extracellular hepatitis B virus RNAs are heterogeneous in length and circulate as capsid-antibody complexes in addition to virions in chronic hepatitis B patients[J].J Virol, 2018, 92 (24) :e00798-18.

[61]WONG DK, SETO WK, CHEUNG KS, et al.Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA[J].Liver Int, 2017, 37 (7) :995-1001.

[62]WOODDELL CI, YUEN MF, CHAN HL, et al.RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HB-s Ag[J].Sci Transl Med, 2017, 9 (409) :eaan0241.

[63]LI J, ZHANG X, CHEN L, et al.Circulating miR-210 and miR-22 combined with ALT predict the virological response to interferon-alpha therapy of CHB patients[J].Sci Rep, 2017, 7 (1) :15658.

[64]CHEN J, WU M, WANG F, et al.Hepatitis B virus spliced variants are associated with an impaired response to interferon therapy[J].Sci Rep, 2015, 5:16459.

[65]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) :e02036-18.

[66]GUO F, ZHAO Q, SHERAZ M, et al.HBV core protein allosteric modulators differentially alter cccDNA biosynthesis from de novo infection and intracellular amplification pathways[J].PLo S Pathog, 2017, 13 (9) :e1006658.

[67] DECORSIERE 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.

[68]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.

[69]REHERMANN B, THIMME R.Insights from antiviral therapy into immune responses to hepatitis B and C virus infection[J].Gastroenterology, 2019, 156 (2) :369-383.

[70]WU D, NING Q.Toward a cure for hepatitis B virus infection:Combination therapy involving viral suppression and immune modulation and long-term outcome[J].J Infect Dis, 2017, 216 (Suppl 8) :s771-s777.

施引文献

资源附件(0)

访问统计