靶向乙肝病毒核心蛋白治疗慢性乙型肝炎的研究进展

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摘要乙型肝炎病毒（HBV）核心蛋白是HBV核衣壳的组成部分，参与病毒包装、病毒成熟以及病毒向细胞外释放等过程，具有cccDNA调节功能并参与诱导机体免疫反应。本文就HBV核心蛋白的结构、功能以及在HBV治疗中的研究进展等方面，综述了近年来靶向HBV核心蛋白治疗慢性乙型肝炎的研究现状，表明核心蛋白质变构调节剂（CpAMs）可作为抗HBV药物直接靶向HBV核心蛋白而干扰其活性，利用HBV核心蛋白为靶抗原诱导HBV特异性免疫反应具有抗HBV及免疫调节作用，以期为慢性乙型肝炎的治疗发展提供参考。

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	戴胜兰姚俊许亚平

关键词 ：乙型肝炎病毒, 慢性乙型肝炎, 核心蛋白, 共价闭合环状DNA, 免疫反应

Abstract：Hepatitis B virus (HBV) core protein is an integral part of HBV nucleocapsid, which is involved in viral packaging, viral maturation and viral releasing to the outside of cells. Core protein participates in regulation of cccDNA function and the induction of immune responses. This paper summarizes the research progress of targeting hepatitis B virus core protein in the treatment of chronic hepatitis B in recent years, starting from the structure and function of HBV core protein and the progress in the treatment of HBV. All of these indicate that core protein allosteric modulators (CpAMs) can directly interfere with the activity of HBV core protein as anti-HBV drugs, and the use of HBV core protein as a target antigen to induce HBV-specific immune responses has anti-HBV and immunomodulatory effects.These provide a theoretical reference for the development of treatment for chronic hepatitis B.

Key words： Hepatitis B virus Chronic hepatitis B Core protein Covalently closed circular DNA Immune response

基金资助:江苏省镇江市科技创新（重点研发计划-社会发展）项目（SH2016040）。

作者简介: 戴胜兰（1979.8-），女，博士；研究方向：病毒性肝炎的免疫治疗。

引用本文:

戴胜兰姚俊许亚平. 靶向乙肝病毒核心蛋白治疗慢性乙型肝炎的研究进展[J]. 中国医药导报, 2018, 15(22): 35-38.
DAI Shenglan YAO Jun XU Yaping. Research progress of targeting hepatitis B virus core protein in treatment of chronichepatitis B. 中国医药导报, 2018, 15(22): 35-38.

链接本文:

http://www.yiyaodaobao.com.cn/CN/ 或 http://www.yiyaodaobao.com.cn/CN/Y2018/V15/I22/35

[1] Schweitzer A，Horn J，Mikolajczyk RT，et al. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013 [J]. Lancet，2015，386（10003）：1546-1555.
[2] Kwon H，Lok AS. Hepatitis B therapy [J]. Nat Rev Gastroenterol Hepatol，2011，8（5）：275-284.
[3] Tang TJ，De Man RA，Kusters JG，et al. Intrahepatic CD8 T-lymphocytes and HBV core expression in relation to response to antiviral therapy for chronic hepatitis B patients [J]. J Med Virol，2004，72（2）：215-222.
[4] Zlotnick A，Venkatakrishnan B，Tan Z，et al. Core protein：A pleiotropic keystone in the HBV lifecycle [J]. Antiviral Res，2015，121：82-93.
[5] Pairan A，Bruss V. Functional surfaces of the hepatitis B virus capsid [J]. J Virol，2009，83（22）：11 616-11 623.
[6] Gish RG，Lok AS，Chang TT，et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B [J]. Gastroenterology，2007，133（5）：1437-1444.
[7] 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.
[8] Guo YH，Li YN，Zhao JR，et al. HBc binds to the CpG islands of HBV cccDNA and promotes an epigenetic permissive state [J]. Epigenetics，2011，6（6）：720-726.
[9] 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）：e110 442.
[10] Bourne C，Lee S，Venkataiah B，et al. Small-molecule effectors of hepatitis B virus capsid assembly give insight into virus life cycle [J]. J Virol，2008，82（20）：10 262-10 270.
[11] Qian G，Hu B，Zhou D，et al. NIRF，a novel ubiquitin ligase，inhibits hepatitis B virus replication through effect on HBV Core protein and H3 histones [J]. DNA Cell Biol，2015，34（5）：327-332.
[12] Qian G，Jin F，Chang L，et al. NIRF，a novel ubiquitin ligase，interacts with hepatitis B virus core protein and promotes its degradation [J]. Biotechnol Lett，2012，34（1）：29-36.
[13] 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.
[14] Li L，Lei QS，Zhang SJ，et al. Suppression of USP18 potentiates the anti-HBV activity of interferon alpha in HepG2.2.15 cells via JAK/STAT signaling [J]. PLoS One，2016，11（5）：e0 156 496.
[15] Du J，Liang X，Liu Y，et al. Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression [J]. Cell Death Differ，2009，16（2）：219-229.
[16] Pumpens P，Grens E. HBV core particles as a carrier for B cell/T cell epitopes [J]. Intervirology，2001，44（2-3）：98-114.
[17] Alexopoulou A，Baltayiannis G，Eroglu C，et al. Core mutations in patients with acute episodes of chronic HBV infection are associated with the emergence of new immune recognition sites and the development of high IgM anti-HBc index values [J]. J Med Virol，2009，81（1）：34-41.
[18] Khakoo SI，Ling R，Scott I，et al. Cytotoxic T lymphocyte responses and CTL epitope escape mutation in HBsAg，anti-HBe positive individuals [J]. Gut，2000，47（1）：137-143.
[19] Mohamadkhani A，Jazii FR，Poustchi H，et al. The role of mutations in core protein of hepatitis B virus in liver fibrosis [J]. Virol J，2009，6：209.
[20] 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.
[21] Li L，Chirapu SR，Finn MG，et al. Phase diagrams map the properties of antiviral agents directed against hepatitis B virus core assembly [J]. Antimicrob Agents Chemother，2013，57（3）：1505-1508.
[22] Delaney WET，Edwards R，Colledge D，et al. Phenylpropenamide derivatives AT-61 and AT-130 inhibit replication of wild-type and lamivudine-resistant strains of hepatitis B virus in vitro [J]. Antimicrob Agents Chemother，2002，46（9）：3057-3060.
[23] Katen SP，Chirapu SR，Finn MG，et al. Trapping of hepatitis B virus capsid assembly intermediates by phenylpropenamide assembly accelerators [J]. ACS Chem Biol，2010，5（12）：1125-1136.
[24] Feld JJ，Colledge D，Sozzi V，et al. The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging [J]. Antiviral Res，2007，76（2）：168-177.
[25] Zhou Z，Hu T，Zhou X，et al. Heteroaryldihydropyrimidine （HAP） and Sulfamoylbenzamide （SBA） inhibit hepatitis B virus replication by different molecular mechanisms [J]. Sci Rep，2017，7：42 374.
[26] Maini MK，Boni C，Lee CK，et al. The role of virus-specific CD8（+） cells in liver damage and viral control during persistent hepatitis B virus infection [J]. J Exp Med，2000，191（8）：1269-1280.
[27] Heathcote J，Mchutchison J，Lee S，et al. A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with hepatitis B virus. The CY1899 T Cell Vaccine Study Group [J]. Hepatology，1999，30（2）：531-536.
[28] Akbar SM，Yoshida O，Chen S，et al. Immune modulator and antiviral potential of dendritic cells pulsed with both hepatitis B surface antigen and core antigen for treating chronic HBV infection [J]. Antivir Ther，2010，15（6）：887-895.
[29] Miller DS，Halpern M，Kotlarski I，et al. Vaccination of ducks with a whole-cell vaccine expressing duck hepatitis B virus core antigen elicits antiviral immune responses that enable rapid resolution of de novo infection [J]. Virology，2006，348（2）：297-308.
[30] Yin Y，Wu C，Song J，et al. DNA immunization with fusion of CTLA-4 to hepatitis B virus （HBV） core protein enhanced Th2 type responses and cleared HBV with an accelerated kinetic [J]. PLoS One，2011，6（7）：e22 524.
[31] Chen JH，Yu YS，Chen XH，et al. Enhancement of CTLs induced by DCs loaded with ubiquitinated hepatitis B virus core antigen [J]. World J Gastroenterol，2012，18（12）：1319-1327.
[32] Chen JH，Yu YS，Liu HH，et al. Ubiquitin conjugation of hepatitis B virus core antigen DNA vaccine leads to enhanced cell-mediated immune response in BALB/c mice [J]. Hepat Mon，2011，11（8）：620-628.
[33] 周丽芹，卓萌，陈小华，等.强制泛素化HBcAg融合基因重组慢病毒对小鼠体内细胞毒性T细胞的诱导作用[J].国际流行病学传染病学杂志，2013，40（4）：217-221.
[34] Dai S，Zhuo M，Song L，et al. Dendritic cell-based vaccination with lentiviral vectors encoding ubiquitinated hepatitis B core antigen enhances hepatitis B virus-specific immune responses in vivo [J]. Acta Biochim Biophys Sin （Shanghai），2015，47（11）：870-879.
[35] Dai S，Zhuo M，Song L，et al. Lentiviral vector encoding ubiquitinated hepatitis B core antigen induces potent cellular immune responses and therapeutic immunity in HBV transgenic mice [J]. Immunobiology，2016，221（7）：813-821.