Skip to main content

Mouse models for hepatitis B virus research

Abstract

Hepatitis B virus (HBV) infection remains a major global health problem; indeed, there are 250 million carriers worldwide. The host range of HBV is narrow; therefore, few primates are susceptible to HBV infection. However, ethical constraints, high cost, and large size limit the use of primates as suitable animal models. Thus, in vivo testing of therapies that target HBV has been hampered by the lack of an appropriate in vivo research model. To address this, mouse model systems of HBV are being developed and several are used for studying HBV in vivo. In this review, we summarize the currently available mouse models, including HBV transgenic mice, hydrodynamic injection-mediated HBV replicon delivery systems, adeno-associated virus-mediated HBV replicon delivery systems, and human liver chimeric mouse models. These developed (or being developed) mouse model systems are promising and should be useful tools for studying HBV.

References

  1. Ryu W-S. Molecular virology of human pathogenic viruses. Academic Press,Amsterdam, 2017; pp 247–260.

    Google Scholar 

  2. Dane DS, Cameron CH, Briggs M. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis. Lancet 1970; 1(7649): 695–698.

    Article  CAS  PubMed  Google Scholar 

  3. Bottcher B, Wynne SA, Crowther RA. Determination of the fold of the core protein of hepatitis B virus by electron cryomicroscopy. Nature 1997; 386(6620): 88–91.

    Article  CAS  PubMed  Google Scholar 

  4. Crowther RA, Kiselev NA, Bottcher B, Berriman JA, Borisova GP, Ose V, Pumpens P. Three-dimensional structure of hepatitis B virus core particles determined by electron cryomicroscopy. Cell 1994; 77(6): 943–950.

    Article  CAS  PubMed  Google Scholar 

  5. Gerlich WH, Robinson WS. Hepatitis B virus contains protein attached to the 5’ terminus of its complete DNA strand. Cell 1980; 21(3): 801–809.

    Article  CAS  PubMed  Google Scholar 

  6. Bartenschlager R, Schaller H. The amino-terminal domain of the hepadnaviral P-gene encodes the terminal protein (genome-linked protein) believed to prime reverse transcription. EMBO J 1988; 7(13): 4185–4192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bock CT, Schwinn S, Locarnini S, Fyfe J, Manns MP, Trautwein C, Zentgraf H. Structural organization of the hepatitis B virus minichromosome. J Mol Biol 2001; 307(1): 183–196.

    Article  CAS  PubMed  Google Scholar 

  8. Belloni L, Allweiss L, Guerrieri F, Pediconi N, Volz T, Pollicino T, Petersen J, Raimondo G, Dandri M, Levrero M. 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 Clin Invest 2012; 122(2): 529–537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, Sprinzl MF, Koppensteiner H, Makowska Z, Volz T, Remouchamps C, Chou WM, Thasler WE, Huser N, Durantel D, Liang TJ, Munk C, Heim MH, Browning XL, Dejardin E, Dandri M, Schindler M, Heikenwalder M, Protzer U. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 2014; 343(6176): 1221–1228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Barker LF, Chisari FV, McGrath PP, Dalgard DW, Kirschstein RL, Almeida JD, Edington TS, Sharp DG, Peterson MR. Transmission of type B viral hepatitis to chimpanzees. J Infect Dis 1973; 127(6): 648–662.

    Article  CAS  PubMed  Google Scholar 

  11. Maynard JE, Berquist KR, Krushak DH, Purcell RH. Experimental infection of chimpanzees with the virus of hepatitis B. Nature 1972; 237(5357): 514–515.

    Article  CAS  PubMed  Google Scholar 

  12. Wieland SF. The chimpanzee model for hepatitis B virus infection. Cold Spring Harb Perspect Med 2015; 5(6).

    Google Scholar 

  13. Walter E, Keist R, Niederost B, Pult I, Blum HE. Hepatitis B virus infection of tupaia hepatocytes in vitro and in vivo. Hepatology 1996; 24(1): 1–5.

    CAS  PubMed  Google Scholar 

  14. Schulze A, Gripon P, Urban S. Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Hepatology 2007; 46(6): 1759–1768.

    Article  CAS  PubMed  Google Scholar 

  15. Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, Huang Y, Qi Y, Peng B, Wang H, Fu L, Song M, Chen P, Gao W, Ren B, Sun Y, Cai T, Feng X, Sui J, Li W. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 2012; 1: e00049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Huang HC, Chen CC, Chang WC, Tao MH, Huang C. Entry of hepatitis B virus into immortalized human primary hepatocytes by clathrin-dependent endocytosis. J Virol 2012; 86(17): 9443–9453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schmitz A, Schwarz A, Foss M, Zhou L, Rabe B, Hoellenriegel J, Stoeber M, Pante N, Kann M. Nucleoporin 153 arrests the nuclear import of hepatitis B virus capsids in the nuclear basket. PLoS

  18. Qi Y, Gao Z, Xu G, Peng B, Liu C, Yan H, Yao Q, Sun G, Liu Y, Tang D, Song Z, He W, Sun Y, Guo JT, Li W DNA. Polymerase kappa Is a Key Cellular Factor for the Formation of Covalently Closed Circular DNA of Hepatitis B Virus. PLoS Pathog 2016; 12(10): e1005893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Koniger C, Wingert I, Marsmann M, Rosier C, Beck J, Nassal M. Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses. Proc Natl Acad Sci U S A 2014; 111(40): E4244–4253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tuttleman JS, Pourcel C, Summers J. Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell 1986; 47(3): 451–460.

    Article  CAS  PubMed  Google Scholar 

  21. Rail LB, Standring DN, Laub O, Rutter WJ. Transcription of hepatitis B virus by RNA polymerase II. Mol Cell Biol 1983; 3(10): 1766–1773.

    Article  Google Scholar 

  22. Nassal M, Rieger A. A bulged region of the hepatitis B virus RNA encapsidation signal contains the replication origin for discontinuous first-strand DNA synthesis. J Virol 1996; 70(5): 2764–2773.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Tavis JE, Perri S, Ganem D. Hepadnavirus reverse transcription initiates within the stem-loop of the RNA packaging signal and employs a novel strand transfer. J Virol 1994; 68(6): 3536–3543.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang GH, Seeger C. Novel mechanism for reverse transcription in hepatitis B viruses. J Virol 1993; 67(11): 6507–6512.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Jeong JK, Yoon GS, Ryu WS. Evidence that the 5’-end cap structure is essential for encapsidation of hepatitis B virus pregenomic RNA. J Virol 2000; 74(12): 5502–5508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Summers J, Mason WS. Replication of the genome of a hepatitis B—like virus by reverse transcription of an RNA intermediate. Cell 1982; 29(2): 403–415.

    Article  CAS  PubMed  Google Scholar 

  27. Zoulim F, Seeger C. Reverse transcription in hepatitis B viruses is primed by a tyrosine residue of the polymerase. J Virol 1994; 68(1): 6–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Haines KM, Loeb DD. The sequence of the RNA primer and the DNA template influence the initiation of plus-strand DNA synthesis in hepatitis B virus. J Mol Biol 2007; 370(3): 471–480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Eble BE, Lingappa VR, Ganem D. Hepatitis B surface antigen: an unusual secreted protein initially synthesized as a transmembrane polypeptide. Mol Cell Biol 1986; 6(5): 1454–1463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Eble BE, Lingappa VR, Ganem D. The N-terminal (pre-S2) domain of a hepatitis B virus surface glycoprotein is translocated across membranes by downstream signal sequences. J Virol 1990; 64(3): 1414–1419.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 1991; 351(6324): 317–320.

    Article  CAS  PubMed  Google Scholar 

  32. Milich DR, Jones JE, Hughes JL, Price J, Raney AK, McLachlan A. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci USA 1990; 87(17): 6599–6603.

    CAS  PubMed  Google Scholar 

  33. Milich DR, Jones JE, Hughes JL, Maruyama T, Price J, Melhado I, Jirik F. Extrathymic expression of the intracellular hepatitis B core antigen results in T cell tolerance in transgenic mice. J Immunol 1994; 152(2): 455–466.

    CAS  PubMed  Google Scholar 

  34. Chisari FV, Filippi P, McLachlan A, Milich DR, Riggs M, Lee S, Palmiter RD, Pinkert CA, Brinster RL. Expression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic mice. J Virol 1986; 60(3): 880–887.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Chisari FV, Pinkert CA, Milich DR, Filippi P, McLachlan A, Palmiter RD, Brinster RL. A transgenic mouse model of the chronic hepatitis B surface antigen carrier state. Science 1985; 230(4730): 1157–1160.

    Article  CAS  PubMed  Google Scholar 

  36. Guidotti LG, Matzke B, Schaller H, Chisari FV. High-level hepatitis B virus replication in transgenic mice. J Virol 1995; 69(10): 6158–6169.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Weber O, Schlemmer KH, Hartmann E, Hagelschuer I, Paessens A, Graef E, Deres K, Goldmann S, Niewoehner U, Stoltefuss J, Haebich D, Ruebsamen-Waigmann H, Wohlfeil S. Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model. Antiviral Res 2002; 54(2): 69–78.

    Article  CAS  PubMed  Google Scholar 

  38. Klein C, Bock CT, Wedemeyer H, Wustefeld T, Locarnini S, Dienes HP, Kubicka S, Manns MP, Trautwein C. Inhibition of hepatitis B virus replication in vivo by nucleoside analogues and siRNA. Gastroenterology 2003; 125(1): 9–18.

    Article  CAS  PubMed  Google Scholar 

  39. Wieland SF, Guidotti LG, Chisari FV. Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice. J Virol 2000; 74(9): 4165–4173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Julander XG, Colonno RJ, Sidwell RW, Morrey JD. Characterization of antiviral activity of entecavir in transgenic mice expressing hepatitis B virus. Antiviral Res 2003; 59(3): 155–161.

    Article  CAS  PubMed  Google Scholar 

  41. Moriyama T, Guilhot S, Klopchin K, Moss B, Pinkert CA, Palmiter RD, Brinster RL, Kanagawa O, Chisari FV. Immunobiology and pathogenesis of hepatocellular injury in hepatitis B virus transgenic mice. Science 1990; 248(4953): 361–364.

    Article  CAS  PubMed  Google Scholar 

  42. Yang PL, Althage A, Chung J, Chisari FV. Hydrodynamic injection of viral DNA: a mouse model of acute hepatitis B virus infection. Proc Natl Acad Sci U S A 2002; 99(21): 13825–13830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Huang LR, Wu HL, Chen PJ, Chen DS. An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection. Proc Natl Acad Sci U S A 2006; 103(47): 17862–17867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McCaffrey AP, Nakai H, Pandey K, Huang Z, Salazar FH, Xu H, Wieland SF, Marion PL, Kay MA. Inhibition of hepatitis B virus in mice by RNA interference. Nat Biotechnol 2003; 21(6): 639–644.

    Article  PubMed  Google Scholar 

  45. Lin SR, Yang HC, Kuo YT, Liu CJ, Yang TY, Sung KC, Lin YY, Wang HY, Wang CC, Shen YC, Wu FY, Kao JH, Chen DS, Chen PJ. The CRISPR/Cas9 System Facilitates Clearance of the Intrahepatic HBV Templates In Vivo. Mol Ther Nucleic Acids 2014; 3:el86.

  46. Yan Z, Zeng J, Yu Y, Xiang K, Hu H, Zhou X, Gu L, Wang L, Zhao J, Young JAT, Gao L. HBVcircle: A novel tool to investigate hepatitis B virus covalently closed circular DNA. J Hepatol 2017; 66(6): 1149–1157.

    Article  CAS  PubMed  Google Scholar 

  47. Dion S, Bourgine M, Godon O, Levillayer F, Michel ML. Adeno-associated virus-mediated gene transfer leads to persistent hepatitis B virus replication in mice expressing HLA-A2 and HLA-DR1 molecules. J Virol 2013; 87(10): 5554–5563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yang D, Liu L, Zhu D, Peng H, Su L, Fu YX, Zhang L. A mouse model for HBV immunotolerance and immunotherapy. Cell Mol Immunol 2014; 11(1): 71–78.

    Article  CAS  PubMed  Google Scholar 

  49. Ilan E, Burakova T, Dagan S, Nussbaum O, Lubin I, Eren R, Ben-Moshe O, Arazi J, Berr S, Neville L, Yuen L, Mansour TS, Gillard J, Eid A, Jurim O, Shouval D, Reisner Y, Galun E. The hepatitis B virus-trimera mouse: a model for human HBV infection and evaluation of anti-HBV therapeutic agents. Hepatology 1999; 29(2): 553–562.

    Article  CAS  PubMed  Google Scholar 

  50. Mercer DF, Schiller DE, Elliott JF, Douglas DN, Hao C, Rinfret A, Addison WR, Fischer KP, Churchill TA, Lakey JR, Tyrrell DL, Kneteman NM. Hepatitis C virus replication in mice with chimeric human livers. Nat Med 2001; 7(8): 927–933.

    Article  CAS  PubMed  Google Scholar 

  51. Sandgren EP, Palmiter RD, Heckel XL, Daugherty CC, Brinster RL, Degen XL. Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene. Cell 1991; 66(2): 245–256.

    Article  CAS  PubMed  Google Scholar 

  52. Meuleman P, Libbrecht L, De Vos R, de Hemptinne B, Gevaert K, Vandekerckhove J, Roskams T, Leroux-Roels G. Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera. Hepatology 2005; 41(4): 847–856.

    Article  CAS  PubMed  Google Scholar 

  53. Brezillon NM, DaSilva L, L’Hote D, Bernex F, Piquet J, Binart N, Morosan S, Kremsdorf D. Rescue of fertility in homozygous mice for the urokinase plasminogen activator transgene by the transplantation of mouse hepatocytes. Cell Transplant 2008; 17(7): 803–812.

    Article  PubMed  Google Scholar 

  54. Heckel XL, Sandgren EP, Degen XL, Palmiter RD, Brinster RL. Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator. Cell 1990; 62(3): 447–456.

    Article  CAS  PubMed  Google Scholar 

  55. Azuma H, Paulk N, Ranade A, Dorrell C, Al-Dhalimy M, Ellis E, Strom S, Kay MA, Finegold M, Grompe M. Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/I12rg-/- mice. Nat Biotechnol 2007; 25(8): 903–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Grompe M, al-Dhalimy M, Finegold M, Ou CN, Burlingame T, Kennaway NG, Soriano P. Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Genes Dev 1993; 7(12A): 2298–2307.

    Article  CAS  PubMed  Google Scholar 

  57. Bissig KD, Wieland SF, Tran P, Isogawa M, Le TT, Chisari FV, Verma IM. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. X Clin Invest 2010; 120(3): 924–930.

    Article  CAS  Google Scholar 

  58. Lai CL, Rosmawati M, Lao X, Van Vlierberghe H, Anderson FH, Thomas N, Dehertogh D. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology 2002; 123(6): 1831–1838.

    Article  CAS  PubMed  Google Scholar 

  59. Konishi M, Wu CH, Wu GY. Inhibition of HBV replication by siRNA in a stable HBV-producing cell line. Hepatology 2003; 38(4): 842–850.

    Article  CAS  PubMed  Google Scholar 

  60. Ristig MB, Crippin X, Aberg XA, Powderly WG, Lisker-Melman M, Kessels L, Tebas P. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. X Infect Dis 2002; 186(12): 1844–1847.

    Article  CAS  Google Scholar 

  61. Volz T, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok XM, Alexandrov A, Urban S, Petersen X, Lutgehetmann M, Dandri M. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. X Hepatol 2013; 58(5): 861–867.

    Article  CAS  Google Scholar 

  62. Bility MT, Cheng L, Zhang Z, Luan Y, Li F, Chi L, Zhang L, Tu Z, Gao Y, Fu Y, Niu X, Wang F, Su L. Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages. PLoS Pathog 2014; 10(3): el004032.

    Google Scholar 

  63. Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger XA, Barry W, Ploss A, Rice CM, Su L. A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology 2011; 140(4): 1334–1344.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sung-Gyoo Park.

Rights and permissions

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://doi.org/creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hwang, JR., Park, SG. Mouse models for hepatitis B virus research. Lab Anim Res 34, 85–91 (2018). https://doi.org/10.5625/lar.2018.34.3.85

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.5625/lar.2018.34.3.85

Keywords