Small Animal Model Systems for Studying Hepatitis B Virus Replication and Pathogenesis

ABSTRACT

The lack of reliable in vitro infection systems and convenient animal models has hindered progress in hepatitis B virus (HBV) research and the development of new treatment options. Due to various restraints encountered using chimpanzees and other models of HBV infection that are based on HBV-related viruses, and due to the necessity to work with small and well-characterized animal systems, it is not surprising that most recent developments have focused on mice. Various strains of transgenic mice harboring the entire HBV genome, or selected viral genes, were developed and proved to be very useful to elucidate mechanisms of HBV replication and pathogenesis. Furthermore, novel, exciting alternative mouse models have been developed recently, which allow not only studies on viral replication, but also the investigation of mechanisms of viral entry and clearance. This article provides an overview and discussion of the different mouse models of HBV replication and infection that are currently available.

KEYWORDS

Hepatitis B virus - transgenic mice - severe combined immunodeficiency - trimera - urokinase plasminogen activator mice

REFERENCES

• 1 Chen M, Sallberg M, Hughes J et al.. Immune tolerance split between hepatitis B virus precore and core proteins.  J Virol. 2005;  79 3016-3027
• 2 Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms.  Gastroenterology. 2004;  127(suppl 1) S56-S61
• 3 Bruns M, Miska S, Chassot S, Will H. Enhancement of hepatitis B virus infection by noninfectious subviral particles.  J Virol. 1998;  72 1462-1468
• 4 Sells M A, Chen M L, Acs G. Production of hepatitis B virus particles in Hep G2 cells transfected with cloned hepatitis B virus DNA.  Proc Natl Acad Sci U S A. 1987;  84 1005-1009
• 5 Galle P R, Hagelstein J, Kommerell B, Volkmann M, Schranz P, Zentgraf H. In vitro experimental infection of primary human hepatocytes with hepatitis B virus.  Gastroenterology. 1994;  106 664-673
• 6 Gripon P, Diot C, Guguen-Guillouzo C. Reproducible high level infection of cultured adult human hepatocytes by hepatitis B virus: effect of polyethylene glycol on adsorption and penetration.  Virology. 1993;  192 534-540
• 7 Gripon P, Diot C, Theze N et al.. Hepatitis B virus infection of adult human hepatocytes cultured in the presence of dimethyl sulfoxide.  J Virol. 1988;  62 4136-4143
• 8 Schulze-Bergkamen H, Untergasser A, Dax A et al.. Primary human hepatocytes-a valuable tool for investigation of apoptosis and hepatitis B virus infection.  J Hepatol. 2003;  38 736-744
• 9 Gripon P, Rumin S, Urban S et al.. Infection of a human hepatoma cell line by hepatitis B virus.  Proc Natl Acad Sci U S A. 2002;  99 15655-15660
• 10 Jaeschke H. Are cultured liver cells the right tool to investigate mechanisms of liver disease or hepatotoxicity?.  Hepatology. 2003;  38 1053-1055
• 11 Barker L F, Chisari F V, McGrath P P et al.. Transmission of type B viral hepatitis to chimpanzees.  J Infect Dis. 1973;  127 648-662
• 12 Bertoni R, Sette A, Sidney J et al.. Human class I supertypes and CTL repertoires extend to chimpanzees.  J Immunol. 1998;  161 4447-4455
• 13 Will H, Cattaneo R, Koch H G et al.. Cloned HBV DNA causes hepatitis in chimpanzees.  Nature. 1982;  299 740-742
• 14 Berthelot P, Courouce A M, Eyquem A et al.. Hepatitis B vaccine safety monitoring in the chimpanzee: interpretation of results.  J Med Primatol. 1984;  13 119-133
• 15 Ohmura T, Ohmizu A, Sumi A et al.. Properties of recombinant hepatitis B vaccine.  Biochem Biophys Res Commun. 1987;  149 1172-1178
• 16 Fujisawa Y, Kuroda S, Van Eerd P M, Schellekens H, Kakinuma A. Protective efficacy of a novel hepatitis B vaccine consisting of M (pre- S2 + S) protein particles (a third generation vaccine).  Vaccine. 1990;  8 192-198
• 17 Ogata N, Cote P J, Zanetti A R et al.. Licensed recombinant hepatitis B vaccines protect chimpanzees against infection with the prototype surface gene mutant of hepatitis B virus.  Hepatology. 1999;  30 779-786
• 18 Baumert T F, Yang C, Schurmann P et al.. Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primary Tupaia hepatocytes.  Hepatology. 2005;  41 247-256
• 19 von Weizsacker F, Kock J, MacNelly S, Ren S, Blum H E, Nassal M. The tupaia model for the study of hepatitis B virus: direct infection and HBV genome transduction of primary tupaia hepatocytes.  Methods Mol Med. 2004;  96 153-161
• 20 Lin E, Luscombe C, Colledge D, Wang Y Y, Locarnini S. Long-term therapy with the guanine nucleoside analog penciclovir controls chronic duck hepatitis B virus infection in vivo.  Antimicrob Agents Chemother. 1998;  42 2132-2137
• 21 Nicoll A J, Colledge D L, Toole J J, Angus P W, Smallwood R A, Locarnini S A. Inhibition of duck hepatitis B virus replication by 9-(2- phosphonylmethoxyethyl)adenine, an acyclic phosphonate nucleoside analogue.  Antimicrob Agents Chemother. 1998;  42 3130-3135
• 22 Korba B E, Cote P J, Menne S et al.. Clevudine therapy with vaccine inhibits progression of chronic hepatitis and delays onset of hepatocellular carcinoma in chronic woodchuck hepatitis virus infection.  Antivir Ther. 2004;  9 937-952
• 23 Foster W K, Miller D S, Scougall C A, Kotlarski I, Colonno R J, Jilbert A R. Effect of antiviral treatment with entecavir on age- and dose-related outcomes of duck hepatitis B virus infection.  J Virol. 2005;  79 5819-5832
• 24 Summers J, Mason W S. Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate.  Cell. 1982;  29 403-415
• 25 Chen H S, Kaneko S, Girones R et al.. The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks.  J Virol. 1993;  67 1218-1226
• 26 Zoulim F, Saputelli J, Seeger C. Woodchuck hepatitis virus X protein is required for viral infection in vivo.  J Virol. 1994;  68 2026-2030
• 27 Dandri M, Schirmacher P, Rogler C E. Woodchuck hepatitis virus X protein is present in chronically infected woodchuck liver and woodchuck hepatocellular carcinomas which are permissive for viral replication.  J Virol. 1996;  70 5246-5254
• 28 Summers J, Jilbert A R, Yang W et al.. Hepatocyte turnover during resolution of a transient hepadnaviral infection.  Proc Natl Acad Sci U S A. 2003;  100 11652-11659
• 29 Summers J, Mason W S. Residual integrated viral DNA after hepadnavirus clearance by nucleoside analog therapy.  Proc Natl Acad Sci U S A. 2004;  101 638-640
• 30 Mason W S, Jilbert A R, Summers J. Clonal expansion of hepatocytes during chronic woodchuck hepatitis virus infection.  Proc Natl Acad Sci U S A. 2005;  102 1139-1144
• 31 Chisari F V, Pinkert C A, Milich D R et al.. A transgenic mouse model of the chronic hepatitis B surface antigen carrier state.  Science. 1985;  230 1157-1160
• 32 Araki K, Miyazaki J, Hino O et al.. Expression and replication of hepatitis B virus genome in transgenic mice.  Proc Natl Acad Sci U S A. 1989;  86 207-211
• 33 Kim C M, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice.  Nature. 1991;  351 317-320
• 34 Guidotti L G, Matzke B, Schaller H, Chisari F V. High-level hepatitis B virus replication in transgenic mice.  J Virol. 1995;  69 6158-6169
• 35 Guidotti L G, Rochford R, Chung J, Shapiro M, Purcell R, Chisari F V. Viral clearance without destruction of infected cells during acute HBV infection.  Science. 1999;  284 825-829
• 36 Julander J G, Colonno R J, Sidwell R W, Morrey J D. Characterization of antiviral activity of entecavir in transgenic mice expressing hepatitis B virus.  Antiviral Res. 2003;  59 155-161
• 37 Julander J G, Sidwell R W, Morrey J D. Characterizing antiviral activity of adefovir dipivoxil in transgenic mice expressing hepatitis B virus.  Antiviral Res. 2002;  55 27-40
• 38 Weber O, Schlemmer K H, Hartmann E et al.. Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model.  Antiviral Res. 2002;  54 69-78
• 39 Kimura K, Kakimi K, Wieland S, Guidotti L G, Chisari F V. Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice.  J Virol. 2002;  76 10702-10707
• 40 Kakimi K, Lane T E, Wieland S et al.. Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes.  J Exp Med. 2001;  194 1755-1766
• 41 Uprichard S L, Boyd B, Althage A, Chisari F V. Clearance of hepatitis B virus from the liver of transgenic mice by short hairpin RNAs.  Proc Natl Acad Sci U S A. 2005;  102 773-778
• 42 Chang J, Taylor J M. Susceptibility of human hepatitis delta virus RNAs to small interfering RNA action.  J Virol. 2003;  77 9728-9731
• 43 Shlomai A, Shaul Y. RNA interference: small RNAs effectively fight viral hepatitis.  Liver Int. 2004;  24 526-531
• 44 Shlomai A, Shaul Y. Inhibition of hepatitis B virus expression and replication by RNA interference.  Hepatology. 2003;  37 764-770
• 45 Moriyama T, Guilhot S, Klopchin K et al.. Immunobiology and pathogenesis of hepatocellular injury in hepatitis B virus transgenic mice.  Science. 1990;  248 361-364
• 46 Guidotti L G, Guilhot S, Chisari F V. Interleukin-2 and alpha/beta interferon down-regulate hepatitis B virus gene expression in vivo by tumor necrosis factor-dependent and -independent pathways.  J Virol. 1994;  68 1265-1270
• 47 Guidotti L G, Matzke B, Pasquinelli C, Schoenberger J M, Rogler C E, Chisari F V. The hepatitis B virus (HBV) precore protein inhibits HBV replication in transgenic mice.  J Virol. 1996;  70 7056-7061
• 48 Guidotti L G, Ishikawa T, Hobbs M V, Matzke B, Schreiber R, Chisari F V. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes.  Immunity. 1996;  4 25-36
• 49 Heise T, Guidotti L G, Cavanaugh V J, Chisari F V. Hepatitis B virus RNA-binding proteins associated with cytokine-induced clearance of viral RNA from the liver of transgenic mice.  J Virol. 1999;  73 474-481
• 50 Wieland S F, Vega R G, Muller R et al.. Searching for interferon-induced genes that inhibit hepatitis B virus replication in transgenic mouse hepatocytes.  J Virol. 2003;  77 1227-1236
• 51 Sitia G, Isogawa M, Iannacone M, Campbell I L, Chisari F V, Guidotti L G. MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs.  J Clin Invest. 2004;  113 1158-1167
• 52 Larkin J, Clayton M, Sun B et al.. Hepatitis B virus transgenic mouse model of chronic liver disease.  Nat Med. 1999;  5 907-912
• 53 Baron J L, Gardiner L, Nishimura S, Shinkai K, Locksley R, Ganem D. Activation of a nonclassical NKT cell subset in a transgenic mouse model of hepatitis B virus infection.  Immunity. 2002;  16 583-594
• 54 Petersen J, Dandri M, Burkle A, Zhang L, Rogler C E. Increase in the frequency of hepadnavirus DNA integrations by oxidative DNA damage and inhibition of DNA repair.  J Virol. 1997;  71 5455-5463
• 55 Dandri M, Burda M R, Burkle A et al.. Increase in de novo HBV DNA integrations in response to oxidative DNA damage or inhibition of poly(ADP-ribosyl)ation.  Hepatology. 2002;  35 217-223
• 56 Chisari F V, Filippi P, McLachlan A et al.. Expression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic mice.  J Virol. 1986;  60 880-887
• 57 Chisari F V, Filippi P, Buras J et al.. Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice.  Proc Natl Acad Sci U S A. 1987;  84 6909-6913
• 58 Bouchard M J, Schneider R J. The enigmatic X gene of hepatitis B virus.  J Virol. 2004;  78 12725-12734
• 59 Slagle B L, Lee T H, Medina D, Finegold M J, Butel J S. Increased sensitivity to the hepatocarcinogen diethylnitrosamine in transgenic mice carrying the hepatitis B virus X gene.  Mol Carcinog. 1996;  15 261-269
• 60 Koike K, Moriya K, Iino S et al.. High-level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice.  Hepatology. 1994;  19 810-819
• 61 Ueda H, Ullrich S J, Gangemi J D et al.. Functional inactivation but not structural mutation of p53 causes liver cancer.  Nat Genet. 1995;  9 41-47
• 62 Delaney W E, Isom H C. Hepatitis B virus replication in human HepG2 cells mediated by hepatitis B virus recombinant baculovirus.  Hepatology. 1998;  28 1134-1146
• 63 Sprinzl M F, Oberwinkler H, Schaller H, Protzer U. Transfer of hepatitis B virus genome by adenovirus vectors into cultured cells and mice: crossing the species barrier.  J Virol. 2001;  75 5108-5118
• 64 Ren S, Nassal M. Hepatitis B virus (HBV) virion and covalently closed circular DNA formation in primary tupaia hepatocytes and human hepatoma cell lines upon HBV genome transduction with replication-defective adenovirus vectors.  J Virol. 2001;  75 1104-1116
• 65 Hofmann C, Sandig V, Jennings G, Rudolph M, Schlag P, Strauss M. Efficient gene transfer into human hepatocytes by baculovirus vectors.  Proc Natl Acad Sci U S A. 1995;  92 10099-10103
• 66 Hofmann C, Strauss M. Baculovirus-mediated gene transfer in the presence of human serum or blood facilitated by inhibition of the complement system.  Gene Ther. 1998;  5 531-536
• 67 Isogawa M, Kakimi K, Kamamoto H, Protzer U, Chisari F V. Differential dynamics of the peripheral and intrahepatic cytotoxic T lymphocyte response to hepatitis B surface antigen.  Virology. 2005;  333 293-300
• 68 Feitelson M A, DeTolla L J, Zhou X D. A chronic carrierlike state is established in nude mice injected with cloned hepatitis B virus DNA.  J Virol. 1988;  62 1408-1415
• 69 Liu F, Song Y, Liu D. Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA.  Gene Ther. 1999;  6 1258-1266
• 70 Yang P L, Althage A, Chung J, Chisari F V. Hydrodynamic injection of viral DNA: a mouse model of acute hepatitis B virus infection.  Proc Natl Acad Sci U S A. 2002;  99 13825-13830
• 71 Klein C, Bock C T, Wedemeyer H et al.. Inhibition of hepatitis B virus replication in vivo by nucleoside analogues and siRNA.  Gastroenterology. 2003;  125 9-18
• 72 McCaffrey A P, Nakai H, Pandey K et al.. Inhibition of hepatitis B virus in mice by RNA interference.  Nat Biotechnol. 2003;  21 639-644
• 73 Giladi H, Ketzinel-Gilad M, Rivkin L, Felig Y, Nussbaum O, Galun E. Small interfering RNA inhibits hepatitis B virus replication in mice.  Mol Ther. 2003;  8 769-776
• 74 Morrissey D V, Lockridge J A, Shaw L et al.. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs.  Nat Biotechnol. 2005;  23 1002-1007
• 75 Ilan E, Burakova T, Dagan S et al.. The hepatitis B virus-trimera mouse: a model for human HBV infection and evaluation of anti-HBV therapeutic agents.  Hepatology. 1999;  29 553-562
• 76 Eren R, Ilan E, Nussbaum O et al.. Preclinical evaluation of two human anti-hepatitis B virus (HBV) monoclonal antibodies in the HBV-trimera mouse model and in HBV chronic carrier chimpanzees.  Hepatology. 2000;  32 588-596
• 77 Bocher W O, Galun E, Marcus H et al.. Reduced hepatitis B virus surface antigen-specific Th1 helper cell frequency of chronic HBV carriers is associated with a failure to produce antigen-specific antibodies in the trimera mouse.  Hepatology. 2000;  31 480-487
• 78 Bocher W O, Dekel B, Schwerin W et al.. Induction of strong hepatitis B virus (HBV) specific T helper cell and cytotoxic T lymphocyte responses by therapeutic vaccination in the trimera mouse model of chronic HBV infection.  Eur J Immunol. 2001;  31 2071-2079
• 79 Ohashi K, Marion P L, Nakai H et al.. Sustained survival of human hepatocytes in mice: a model for in vivo infection with human hepatitis B and hepatitis delta viruses.  Nat Med. 2000;  6 327-331
• 80 Brown J J, Parashar B, Moshage H et al.. A long-term hepatitis B viremia model generated by transplanting nontumorigenic immortalized human hepatocytes in Rag-2-deficient mice.  Hepatology. 2000;  31 173-181
• 81 Gupta S, Bhargava K K, Novikoff P M. Mechanisms of cell engraftment during liver repopulation with hepatocyte transplantation.  Semin Liver Dis. 1999;  19 15-26
• 82 Sandgren E P, Palmiter R D, Heckel J L, Daugherty C C, Brinster R L, Degen J L. Complete hepatic regeneration after somatic deletion of an albumin- plasminogen activator transgene.  Cell. 1991;  66 245-256
• 83 Rhim J A, Sandgren E P, Degen J L, Palmiter R D, Brinster R L. Replacement of diseased mouse liver by hepatic cell transplantation.  Science. 1994;  263 1149-1152
• 84 Overturf K, Al-Dhalimy M, Tanguay R et al.. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I.  Nat Genet. 1996;  12 266-273
• 85 Mignon A, Guidotti J E, Mitchell C et al.. Selective repopulation of normal mouse liver by Fas/CD95-resistant hepatocytes.  Nat Med. 1998;  4 1185-1188
• 86 Shinkai Y, Rathbun G, Lam K P et al.. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement.  Cell. 1992;  68 855-867
• 87 Petersen J, Dandri M, Gupta S, Rogler C E. Liver repopulation with xenogenic hepatocytes in B and T cell-deficient mice leads to chronic hepadnavirus infection and clonal growth of hepatocellular carcinoma.  Proc Natl Acad Sci U S A. 1998;  95 310-315
• 88 Dandri M, Burda M R, Torok E et al.. Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus.  Hepatology. 2001;  33 981-988
• 89 Meuleman P, Libbrecht L, De Vos R et al.. Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera.  Hepatology. 2005;  41 847-856
• 90 Mercer D F, Schiller D E, Elliott J F et al.. Hepatitis C virus replication in mice with chimeric human livers.  Nat Med. 2001;  7 927-933
• 91 Tateno C, Yoshizane Y, Saito N et al.. Near completely humanized liver in mice shows human-type metabolic responses to drugs.  Am J Pathol. 2004;  165 901-912
• 92 Tsuge M, Hiraga N, Takaishi H et al.. Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis B virus.  Hepatology. 2005;  42 1046-1054
• 93 Dandri M, Burda M R, Zuckerman D M et al.. Chronic infection with hepatitis B viruses and antiviral drug evaluation in uPA mice after liver repopulation with tupaia hepatocytes.  J Hepatol. 2005;  42 54-60