免疫控制与慢性乙型肝炎功能性治愈的进展与挑战

郑昕; 刘嘉; 吴珺; 孟忠吉; 陆蒙吉; 杨东亮

doi:10.3969/j.issn.1001-5256.2020.05.001

免疫控制与慢性乙型肝炎功能性治愈的进展与挑战

DOI: 10.3969/j.issn.1001-5256.2020.05.001

1.华中科技大学同济医学院附属协和医院感染病科
2. 湖北医药学院附属太和医院感染病科
3. 德国杜伊斯堡-埃森大学医学院病毒研究所

基金项目:

国家自然科学基金（81461130019,81672022,91742114,8181101231,91642118）；国家传染病防治科技重大专项（2017ZX10202202,2017ZX10202201,2017ZX10202203,2018ZX10302206,2018ZX10723203）；

详细信息

中图分类号: R512.62
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出版历程
- 出版日期: 2020-05-20

Advances and challenges in immune control and functional cure of chronic hepatitis B

Department of Infectious Diseases, Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China

Research funding:

摘要

摘要:
HBV与宿主免疫系统的相互作用决定了HBV感染的结局。虽然迄今尚无彻底根治乙型肝炎的药物,但是随着研究的深入,以血清HBsAg和HBV DNA持续阴转为特征的"功能性治愈"已成为慢性乙型肝炎的可实现治疗目标。而基于对HBV感染免疫控制机制新认识的免疫调控治疗也成为实现慢性乙型肝炎功能性治愈的重要策略之一。本文仅就HBV感染免疫控制及其在功能性治愈策略研究中应用的进展与存在问题做一简要综述。
- 乙型肝炎,慢性 /
- 免疫调节 /
- 功能性治愈
Abstract:
The clinical outcome of hepatitis B virus(HBV) infection mostly depends on the interaction between HBV and host immune system. Although there are still no drugs for the radical treatment of hepatitis B at present, more and more studies have found that functional cure, characterized by persistent negative conversion of HBsAg and HBV DNA in serum, has become an achievable goal for the treatment of chronic hepatitis B. Meanwhile, immunoregulatory therapy based on a new understanding of the mechanism of immune control of HBV infection has been used as one of the important strategies for functional cure of chronic hepatitis B. This article elaborates on the immune control of HBV infection and the advances and challenges of its application in the research on the strategies for functional cure.
- hepatitis B,chronic /
- immunomodulation /
- functional cure

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参考文献(38)

[1] Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016:A modelling study[J]. Lancet Gastroenterol Hepatol, 2018, 3(6):383-403.

[2] COOKE GS, ANDRIEUX-MEYER I, APPLEGATE TL, et al.Accelerating the elimination of viral hepatitis:A Lancet Gastroenterology&Hepatology Commission[J]. Lancet Gastroenterol Hepatol, 2019, 4(2):135-184.

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

[4] YUEN MF, CHEN DS, DUSHEIKO GM, et al. Hepatitis B virus infection[J]. Nat Rev Dis Primers, 2018, 4:18035.

[5] REVILL PA, CHISARI FV, BLOCK JM, et al. A global scientific strategy to cure hepatitis B[J]. Lancet Gastroenterol Hepatol,2019, 4(7):545-558.

[6] 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.

[7] LANCET T. Carving a new path to a hepatitis B cure[J]. Lancet, 2020, 394(10216):2202.

[8] MARTINEZ MG, TESTONI B, ZOULIM F. Biological basis for functional cure of chronic hepatitis B[J]. J Viral Hepat, 2019,26(7):786-794.

[9] 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.

[10] LOK AS, ZOULIM F, DUSHEIKO G, et al. Hepatitis B cure:From discovery to regulatory approval[J]. Hepatology, 2017,66(4):1296-1313.

[11] BERTOLETTI A, LE BERT N. Immunotherapy for chronic hepatitis B virus infection[J]. Gut Liver, 2018, 12(5):497-507.

[12] 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.

[13] HU J, PROTZER U, SIDDIQUI A. Revisiting hepatitis B virus:Challenges of curative therapies[J]. J Virol, 2019, 93(20):e01032-19.

[14] NING Q, WU D, WANG GQ, et al. Roadmap to functional cure of chronic hepatitis B:An expert consensus[J]. J Viral Hepat, 2019, 26(10):1146-1155.

[15] European Association for the Study of the Liver. EASL 2017Clinical Practice Guidelines on the management of hepatitis B virus infection[J]. J Hepatol, 2017, 67(2):370-398.

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

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

[18] LIU J, JIANG M, MA Z, et al. TLR1/2 ligand-stimulated mouse liver endothelial cells secrete IL-12 and trigger CD8+T cell immunity in vitro[J]. J Immunol, 2013, 191(12):6178-6190.

[19] LIU J, YU Q, WU W, et al. TLR2 stimulation strengthens intrahepatic myeloid-derived cell-mediated T cell tolerance through inducing Kupffer cell expansion and IL-10 production[J]. J Immunol, 2018, 200(7):2341-2351.

[20] LANFORD RE, GUERRA B, CHAVEZ D, et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees[J]. Gastroenterology, 2013, 144(7):1508-1517,1517. e1-10.

[21] JO J, TAN AT, USSHER JE, et al. Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver[J]. PLoS Pathog, 2014, 10(6):e1004210.

[22] WALSH R, HAMMOND R, JACKSON K, et al. PS-160-effects of SB9200(Inarigivir)therapy on immune responses in patients with chronic hepatitis B[J]. J Hepatol, 2018, 68(1):s89.

[23] SATO S, LI K, KAMEYAMA T, et al. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus[J]. Immunity, 2015, 42(1):123-132.

[24] HUANG S, ZOU S, CHEN M, et al. Local Stimulation of liver sinusoidal endothelial cells with a NOD1 agonist activates T cells and suppresses hepatitis B virus replication in mice[J].J Immunol, 2018, 200(9):3170-3179.

[25] YANG S, WANG L, PAN W, et al. MMP2/MMP9-mediated CD100 shedding is crucial for inducing intrahepatic anti-HBV CD8 T cell responses and HBV clearance[J]. J Hepatol,2019, 71(4):685-698.

[26] CHENG X, XIA Y, SERTI E, et al. Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages[J]. Hepatology, 2017, 66(6):1779-1793.

[27] BÉNÉCHET AP, de SIMONE G, di LUCIA P, et al. Dynamics and genomic landscape of CD8+T cells undergoing hepatic priming[J]. Nature, 2019, 574(7777):200-205.

[28] BURTON AR, PALLETT LJ, MCCOY LE, et al. Circulating and intrahepatic antiviral B cells are defective in hepatitis B[J]. J Clin Invest, 2018, 128(10):4588-4603.

[29] PHILLIPS S, MISTRY S, RIVA A, et al. Peg-interferon lambda treatment induces robust innate and adaptive immunity in chronic hepatitis B patients[J]. Front Immunol, 2017, 8:621.

[30] SALIMZADEH L, LE BERT N, DUTERTRE CA, et al. PD-1blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection[J]. J Clin Invest, 2018,128(10):4573-4587.

[31] GUO WN, ZHU B, AI L, et al. Animal models for the study of hepatitis B virus infection[J]. Zool Res, 2018, 39(1):25-31.

[32] MENG Z, ZHANG X, PEI R, et al. Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection[J]. Antiviral Res, 2016, 125:14-24.

[33] MA Z, ZHANG E, GAO S, et al. Toward a functional cure for hepatitis B:The rationale and challenges for therapeutic targeting of the B cell immune response[J]. Front Immunol, 2019,10:2308.

[34] BURTON AR, PALLETT LJ, MCCOY LE, et al. Circulating and intrahepatic antiviral B cells are defective in hepatitis B[J]. J Clin Invest, 2018, 128(10):4588-4603.

[35] NEUMANN-HAEFELIN C, THIMME R. Entering the spotlight:Hepatitis B surface antigen-specific B cells[J]. J Clin Invest, 2018, 128(10):4257-4259.

[36] SETO WK, YUEN MF. New pharmacological approaches to a functional cure of hepatitis B[J]. Clin Liver Dis(Hoboken),2016, 8(4):83-88.

[37] LI MH, YI W, ZHANG L, et al. Predictors of sustained functional cure in hepatitis B envelope antigen-negative patients achieving hepatitis B surface antigen seroclearance with interferon-alpha-based therapy[J]. J Viral Hepat, 2019, 26(Suppl 1):32-41.

[38] TESTONI B, LEBOSSÉF, SCHOLTES C, et al. Serum hepatitis B core-related antigen(HBcrAg)correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients[J]. J Hepatol, 2019, 70(4):615-625.

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