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ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 37 Issue 5
May  2021
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Article Contents

Research advances in animal models of hepatitis B virus infection

DOI: 10.3969/j.issn.1001-5256.2021.05.002
  • Received Date: 2021-02-26
  • Accepted Date: 2021-02-26
  • Published Date: 2021-05-20
  • For the ideal preclinical animal model of hepatitis B virus (HBV), its hepatocytes should allow HBV entry and cccDNA generation and have both innate and adaptive immune systems. However, HBV only naturally infects humans and chimpanzees due to highly restricted species specificity, and no effective model has been established so far to truly reflect the immune mechanism and pathogenesis of HBV infection. This article reviews five commonly used mouse models, i.e., HBV transgenic model, HBV plasmid DNA hydrodynamic injection model, AAV-HBV transfection model, cccDNA surrogate model, and human-mouse chimeric liver model, and looks forward to the new models that will appear in the future, such as hNTCP transgenic cynomolgus monkey, rhesus monkey, or pig models, so as to provide a reference for researchers to select these models, accelerate the process of drug screening, validate new therapies, and better solve the problems of HBV biological pathogenesis.

     

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  • [1]
    WANG J, HUANG YX, SHEN Y, et al. Research advances in mouse models of hepatitis B virus infection[J]. J Clin Hepatol, 2016, 32(1): 165-168. DOI: 0.3969/j.issn.1001-5256.2016.01.036.

    王军, 黄豫晓, 沈燕, 等. HBV感染小鼠模型的研究进展[J]. 临床肝胆病杂志, 2016, 32(1): 165-168. DOI: 0.3969/j.issn.1001-5256.2016.01.036.
    [2]
    BLUMBERG BS, ALTER HJ, VISNICH S. A "New" antigen in leukemia sera[J]. JAMA, 1965, 191: 541-546. DOI: 10.1001/jama.1965.03080070025007. PMID: 14239025.
    [3]
    DANE DS, CAMERON CH, BRIGGS M. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis[J]. Lancet, 1970, 1(7649): 695-698. DOI: 10.1016/s0140-6736(70)90926-8. PMID: 4190997.
    [4]
    BURWITZ BJ, ZHOU Z, LI W. Animal models for the study of human hepatitis B and D virus infection: New insights and progress[J]. Antiviral Res, 2020, 182: 104898. DOI: 10.1016/j.antiviral.2020.104898.
    [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]
    LEMPP FA, MUTZ P, LIPPS C, et al. Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor[J]. J Hepatol, 2016, 64(3): 556-564. DOI: 10.1016/j.jhep.2015.10.030.
    [7]
    LEMPP FA, WIEDTKE E, QU B, et al. Sodium taurocholate cotransporting polypeptide is the limiting host factor of hepatitis B virus infection in macaque and pig hepatocytes[J]. Hepatology, 2017, 66(3): 703-716. DOI: 10.1002/hep.29112.
    [8]
    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. DOI: 10.3389/fimmu.2019.03127.
    [9]
    RYBICKA M, BIELAWSKI KP. Recent advances in understanding, diagnosing, and treating hepatitis B virus infection[J]. Microorganisms, 2020, 8(9): 1416. DOI: 10.3390/microorganisms8091416.
    [10]
    BABINET C, FARZA H, MORELLO D, et al. Specific expression of hepatitis B surface antigen (HBsAg) in transgenic mice[J]. Science, 1985, 230(4730): 1160-1163. DOI: 10.1126/science.3865370.
    [11]
    BURK RD, DELOIA JA, ELAWADY MK, et al. Tissue preferential expression of the hepatitis B virus (HBV) surface antigen gene in two lines of HBV transgenic mice[J]. J Virol, 1988, 62(2): 649-654. DOI: 10.1128/JVI.62.2.649-654.1988.
    [12]
    CHISARI FV, PINKERT CA, MILICH DR, et al. A transgenic mouse model of the chronic hepatitis B surface antigen carrier state[J]. Science, 1985, 230: 1157-1160. DOI: 10.1126/science.3865369.
    [13]
    GUIDOTTI LG, MARTINEZ V, LOH YT, et al. Hepatitis B virus nucleocapsid particles do not cross the hepatocyte nuclear membrane in transgenic mice[J]. J Virol, 1994, 68(9): 5469-5475. DOI: 10.1128/JVI.68.9.5469-5475.1994.
    [14]
    MILICH DR, JONES JE, HUGHES JL, et al. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?[J]. Proc Natl Acad Sci U S A, 1990, 87(17): 6599-6603. DOI: 10.1073/pnas.87.17.6599.
    [15]
    KIM CM, KOIKE K, SAITO I, et al. HBx gene of hepatitis B virus induces liver cancer in transgenic mice[J]. Nature, 1991, 351(6324): 317-320. DOI: 10.1038/351317a0.
    [16]
    LEE TH, FINEGOLD MJ, SHEN RF, et al. Hepatitis B virus transactivator X protein is not tumorigenic in transgenic mice[J]. J Virol, 1990, 64(12): 5939-5947. DOI: 10.1128/JVI.64.12.5939-5947.1990.
    [17]
    ARAKI K, MIYAZAKI J, HINO O, et al. Expression and replication of hepatitis B virus genome in transgenic mice[J]. Proc Natl Acad Sci U S A, 1989, 86(1): 207-211. DOI: 10.1073/pnas.86.1.207.
    [18]
    FARZA H, HADCHOUEL M, SCOTTO J, et al. Replication and gene expression of hepatitis B virus in a transgenic mouse that contains the complete viral genome[J]. J Virol, 1988, 62(11): 4144-4152. DOI: 10.1128/JVI.62.11.4144-4152.1988.
    [19]
    GUIDOTTI LG, MATZKE B, SCHALLER H, et al. High-level hepatitis B virus replication in transgenic mice[J]. J Virol, 1995, 69(10): 6158-6169. DOI: 10.1128/JVI.69.10.6158-6169.
    [20]
    CAVANAUGH VJ, GUIDOTTI LG, CHISARI FV. Interleukin-12 inhibits hepatitis B virus replication in transgenic mice[J]. J Virol, 1997, 71(4): 3236-3243. DOI: 10.1128/JVI.71.4.3236-3243.1997.
    [21]
    ISOGAWA M, ROBEK MD, FURUICHI Y, et al. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo[J]. J Virol, 2005, 79(11): 7269-7272. DOI: 10.1128/JVI.79.11.7269-7272.2005.
    [22]
    UPRICHARD SL, BOYD B, ALTHAGE A, et al. Clearance of hepatitis B virus from the liver of transgenic mice by short hairpin RNAs[J]. Proc Natl Acad Sci U S A, 2005, 102(3): 773-778. DOI: 10.1073/pnas.0409028102.
    [23]
    WINER BY, DING Q, GASKA JM, et al. In vivo models of hepatitis B and C virus infection[J]. FEBS Lett, 2016, 590(13): 1987-1999. DOI: 10.1002/1873-3468.12157.
    [24]
    YANG PL, ALTHAGE A, CHUNG J, et al. Hydrodynamic injection of viral DNA: A mouse model of acute hepatitis B virus infection[J]. Proc Natl Acad Sci U S A, 2002, 99(21): 13825-13830. DOI: 10.1073/pnas.202398599.
    [25]
    DANDRI M, PETERSEN J. Animal models of HBV infection[J]. Best Pract Res Clin Gastroenterol, 2017, 31(3): 273-279. DOI: 10.1016/j.bpg.2017.04.014.
    [26]
    HUANG LR, WU HL, CHEN PJ, et al. An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection[J]. Proc Natl Acad Sci U S A, 2006, 103(47): 17862-17867. DOI: 10.1073/pnas.0608578103.
    [27]
    YANG PL, ALTHAGE A, CHUNG J, et al. Immune effectors required for hepatitis B virus clearance[J]. Proc Natl Acad Sci U S A, 2010, 107(2): 798-802. DOI: 10.1073/pnas.0913498107.
    [28]
    CHOU HH, CHIEN WH, WU LL, et al. Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota[J]. Proc Natl Acad Sci U S A, 2015, 112(7): 2175-2180. DOI: 10.1073/pnas.1424775112.
    [29]
    SPRINZL MF, OBERWINKLER H, SCHALLER H, et al. Transfer of hepatitis B virus genome by adenovirus vectors into cultured cells and mice: Crossing the species barrier[J]. J Virol, 2001, 75(11): 5108-5118. DOI: 10.1128/JVI.75.11.5108-5118.2001.
    [30]
    von FREYEND MJ, UNTERGASSER A, ARZBERGER S, et al. Sequential control of hepatitis B virus in a mouse model of acute, self-resolving hepatitis B[J]. J Viral Hepat, 2011, 18(3): 216-226. DOI: 10.1111/j.1365-2893.2010.01302.x.
    [31]
    HARTMAN ZC, KIANG A, EVERETT RS, et al. Adenovirus infection triggers a rapid, MyD88-regulated transcriptome response critical to acute-phase and adaptive immune responses in vivo[J]. J Virol, 2007, 81(4): 1796-1812. DOI: 10.1128/JVI.01936-06.
    [32]
    YANG D, LIU L, ZHU D, et al. A mouse model for HBV immunotolerance and immunotherapy[J]. Cell Mol Immunol, 2014, 11(1): 71-78. DOI: 10.1038/cmi.2013.43.
    [33]
    DION S, BOURGINE M, GODON O, et al. Adeno-associated virus-mediated gene transfer leads to persistent hepatitis B virus replication in mice expressing HLA-A2 and HLA-DR1 molecules[J]. J Virol, 2013, 87(10): 5554-5563. DOI: 10.1128/JVI.03134-12.
    [34]
    LIN SR, YANG HC, KUO YT, et al. The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo[J]. Mol Ther Nucleic Acids, 2014, 3: e186. DOI: 10.1038/mtna.2014.38.
    [35]
    LUCIFORA J, SALVETTI A, MARNIQUET X, et al. Detection of the hepatitis B virus (HBV) covalently-closed-circular DNA (cccDNA) in mice transduced with a recombinant AAV-HBV vector[J]. Antiviral Res, 2017, 145: 14-19. DOI: 10.1016/j.antiviral.2017.07.006.
    [36]
    DUAN D, SHARMA P, YANG J, et al. Circular intermediates of recombinant adeno-associated virus have defined structural characteristics responsible for long-term episomal persistence in muscle tissue[J]. J Virol, 1998, 72(11): 8568-8577. DOI: 10.1128/JVI.72.11.8568-8577.1998.
    [37]
    SU Y, ZHU YF, TIAN QY, et al. In vitro cell model and mouse model of HBV cccDNA[J]. J Clin Hepatol, 2019, 35(6): 1205-1211. DOI: 10.3969/j.issn.1001-5256.2019.06.007.

    苏瑜, 朱园飞, 田青右, 等. HBV cccDNA的体外细胞模型和实验小鼠模型[J]. 临床肝胆病杂志, 2019, 35(6): 1205-1211. DOI: 10.3969/j.issn.1001-5256.2019.06.007.
    [38]
    GUO X, CHEN P, HOU X, et al. The recombined cccDNA produced using minicircle technology mimicked HBV genome in structure and function closely[J]. Sci Rep, 2016, 6: 25552. DOI: 10.1038/srep25552.
    [39]
    QI Z, LI G, HU H, et al. Recombinant covalently closed circular hepatitis B virus DNA induces prolonged viral persistence in immunocompetent mice[J]. J Virol, 2014, 88(14): 8045-8056. DOI: 10.1128/JVI.01024-14.
    [40]
    KAY MA, HE CY, CHEN ZY. A robust system for production of minicircle DNA vectors[J]. Nat Biotechnol, 2010, 28(12): 1287-1289. DOI: 10.1038/nbt.1708.
    [41]
    WU M, WANG C, SHI B, et al. A novel recombinant cccDNA-based mouse model with long term maintenance of rcccDNA and antigenemia[J]. Antiviral Res, 2020, 180: 104826. DOI: 10.1016/j.antiviral.2020.104826.
    [42]
    YAN Z, ZENG J, YU Y, et al. HBVcircle: A novel tool to investigate hepatitis B virus covalently closed circular DNA[J]. J Hepatol, 2017, 66(6): 1149-1157. DOI: 10.1016/j.jhep.2017.02.004.
    [43]
    SANDGREN EP, PALMITER RD, HECKEL JL, et al. Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene[J]. Cell, 1991, 66(2): 245-256. DOI: 10.1016/0092-8674(91)90615-6.
    [44]
    WEGLARZ TC, DEGEN JL, SANDGREN EP. Hepatocyte transplantation into diseased mouse liver. Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes[J]. Am J Pathol, 2000, 157(6): 1963-1974. DOI: 10.1016/S0002-9440(10)64835-3.
    [45]
    TATENO C, YOSHIZANE Y, SAITO N, et al. Near completely humanized liver in mice shows human-type metabolic responses to drugs[J]. Am J Pathol, 2004, 165(3): 901-912. DOI: 10.1016/S0002-9440(10)63352-4.
    [46]
    AZUMA H, PAULK N, RANADE A, et al. Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice[J]. Nat Biotechnol, 2007, 25(8): 903-910. DOI: 10.1038/nbt1326.
    [47]
    HASEGAWA M, KAWAI K, MITSUI T, et al. The reconstituted 'humanized liver' in TK-NOG mice is mature and functional[J]. Biochem Biophys Res Commun, 2011, 405(3): 405-410. DOI: 10.1016/j.bbrc.2011.01.042.
    [48]
    WASHBURN ML, BILITY MT, ZHANG L, et al. A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease[J]. Gastroenterology, 2011, 140(4): 1334-1344. DOI: 10.1053/j.gastro.2011.01.001.
    [49]
    SONG X, GUO Y, DUO S, et al. A mouse model of inducible liver injury caused by tet-on regulated urokinase for studies of hepatocyte transplantation[J]. Am J Pathol, 2009, 175(5): 1975-1983. DOI: 10.2353/ajpath.2009.090349.
    [50]
    XIANG C, DU Y, MENG G, et al. Long-term functional maintenance of primary human hepatocytes in vitro[J]. Science, 2019, 364(6438): 399-402. DOI: 10.1126/science.aau7307.
    [51]
    YANG G, FENG J, LIU Y, et al. HAT1 signaling confers to assembly and epigenetic regulation of HBV cccDNA minichromosome[J]. Theranostics, 2019, 9(24): 7345-7358. DOI: 10.7150/thno.37173.
    [52]
    FENG J, YANG G, LIU Y, et al. LncRNA PCNAP1 modulates hepatitis B virus replication and enhances tumor growth of liver cancer[J]. Theranostics, 2019, 9(18): 5227-5245. DOI: 10.7150/thno.34273.
    [53]
    DU Y, WANG J, JIA J, et al. Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming[J]. Cell Stem Cell, 2014, 14(3): 394-403. DOI: 10.1016/j.stem.2014.01.008.
    [54]
    BILITY MT, CHENG L, ZHANG Z, et al. Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages[J]. PLoS Pathog, 2014, 10(3): e1004032. DOI: 10.1371/journal.ppat.1004032.
    [55]
    STRICK-MARCHAND H, DUSSéAUX M, DARCHE S, et al. A novel mouse model for stable engraftment of a human immune system and human hepatocytes[J]. PLoS One, 2015, 10(3): e0119820. DOI: 10.1371/journal.pone.0119820.
    [56]
    YUAN L, JIANG J, LIU X, et al. HBV infection-induced liver cirrhosis development in dual-humanised mice with human bone mesenchymal stem cell transplantation[J]. Gut, 2019, 68(11): 2044-2056. DOI: 10.1136/gutjnl-2018-316091.
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