Lab Anim Res.  2018 Sep;34(3):85-91. 10.5625/lar.2018.34.3.85.

Mouse models for hepatitis B virus research

• Hwang JR
• Park SG

• KMID: 2420820
• DOI: http://doi.org/10.5625/lar.2018.34.3.85

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.

Keyword

Hepatitis B virus; mouse model; alb-uPA/SCID; FRG

MeSH Terms

Animals
Global Health
Hepatitis B virus*
Hepatitis B*
Hepatitis*
Host Specificity
Humans
Hydrodynamics
Liver
Mice*
Mice, Transgenic
Models, Animal
Primates
Replicon

Figure

• 

  Figure 1 Schematic illustration of the life cycle of HBV.

• 

  Figure 2 Schematic illustration of the different mouse models of HBV.

Reference

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

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.

3. Böttcher 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.

4. Crowther RA, Kiselev NA, Böttcher 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.

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.

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.

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.

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.

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 JL, 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.

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.

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.

12. Wieland SF. The chimpanzee model for hepatitis B virus infection. Cold Spring Harb Perspect Med. 2015; 5(6):pii: a021469.

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.

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.

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.

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.

17. Schmitz A, Schwarz A, Foss M, Zhou L, Rabe B, Hoellenriegel J, Stoeber M, Panté N, Kann M. Nucleoporin 153 arrests the nuclear import of hepatitis B virus capsids in the nuclear basket. PLoS Pathog. 2010; 6(1):e1000741.

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.

19. Königer C, Wingert I, Marsmann M, Rösler 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–E4253.

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.

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

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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 U S A. 1990; 87(17):6599–6603.

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.

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.

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.

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.

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.

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.

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.

40. Julander JG, 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.

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.

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.

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.

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.

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:e186.

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.

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.

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.

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.

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.

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

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.

53. Brezillon NM, DaSilva L, L'Hôte 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.

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

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-/-/Il2rg-/- mice. Nat Biotechnol. 2007; 25(8):903–910.

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.

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. J Clin Invest. 2010; 120(3):924–930.

58. Lai CL, Rosmawati M, Lao J, 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.

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.

60. Ristig MB, Crippin J, Aberg JA, 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. J Infect Dis. 2002; 186(12):1844–1847.

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

62. Bility MT, Cheng L, Zhang Z, Luan Y, Li F, Chi L, Zhang L, Tu Z, Gao Y, Fu Y, Niu J, 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):e1004032.

63. Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger JA, 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.