Skip to main content
SpringerLink
Log in

The woodchuck model of hepadnavirus infection

  • Chapter
Book cover Comparative Hepatitis

Part of the book series: Birkhäuser Advances in Infectious Diseases ((BAID))

Abstract

Since discovery of the hepatitis B virus (HBV),closely related viruses have been described in several animal species. The first of these was the woodchuck hepatitis virus (WHV),identified in woodchucks (Marmota monax)that were maintained at the Philadelphia Zoological Garden and which had experienced a high prevalence of chronic hepatitis and hepatocellular carcinoma (HCC). On the basis of morphological and molecular analyses,it was concluded that WHV was closely related to HBV. Since description of WHV,infection with viruses that belong to the family Hepadnaviridae have been described in the California ground squirrel (Spermophilus beecheyi)and the Arctic ground squirrel (Spermophilus parryi), two species closely related phylogenetical- ly to woodchucks,and in six avian species. A total of four well characterized,mammalian hepadnaviruses now have been associated with development of HCC. These observations on naturally acquired hepadnavirus infections combined with the development of HCC in woodchucks following experimental infection with WHV or with the California ground squirrel virus (GSHV)provides,by analogy,convincing comparative medical evidence for the hepatocarcinogenicity of HBV. The woodchuck has become useful as an experimental animal model for research on the pathogenesis of HBV infection and for investigation of the molecular mechanisms of hepatocarcinogenesis. The woodchuck also has been useful in the discovery and preclinical development of antiviral drugs for treatment of HBV infection and for testing new forms of immunotherapy using cytokines and therapeutic vaccination. In particular, the woodchuck has been valuable for determining the impact of long-term antiviral treatment on the outcome of chronic hepadnavirus infection in placebo controlled,lifetime survival studies which have been predictive of the results of subsequent clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Summers J, Smolec JM, Snyder R (1978) A virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woodchucks.Proc Natl Acad Sci USA 75:4533–4537

    PubMed  CAS  Google Scholar 

  2. Tyler GV, Summers J, Snyder R (1981) Woodchuck hepatitis virus in natural woodchuck population.J Wildlife Dis 17:297–301

    CAS  Google Scholar 

  3. Wong DC, Shih JWK, Purcell RH, Gerin JL, London WT (1982) Natural and experimental infection of woodchucks with woodchuck hepatitis virus,as measured by new,specific assays for woodchuck surface antigen and antibody (Marmota monax).J Clin Microbiol 15:484–490

    PubMed  CAS  Google Scholar 

  4. Lutwick LI, Hebert MB, Sywassink JM (1982) Cross-reactions between the hepatitis B and woodchuck hepatitis viruses.In:W Szmuness, HJ Alter, JE Maynard (eds) In:Viral hepatitis.Franklin Institute Press, Philadelphia,711

    Google Scholar 

  5. Summers J (1981) Three recently described animal virus models for human hepatitis B virus .Hepatology 1:179–183

    PubMed  CAS  Google Scholar 

  6. Young RA, Sims EAH (1979) The woodchuck,Marmota monax,as a laboratory animal.Lab Anim Sci 29:770–780

    PubMed  CAS  Google Scholar 

  7. Fox H (1912) Observations upon neoplasms in wild animals in the Philadelphia Zoological Garden.J Pathol Bacteriol 17:217–231

    Google Scholar 

  8. Ratcliffe HL (1933) Incidence and nature of tumors in captive mammals and birds.Am J Cancer 17:116–135

    Google Scholar 

  9. Habermann RT, Williams FP, Eyestone WH (1954) Spontaneous hepatomas in two woodchucks and a carcinoma of the testis in a badger.J Am Vet Med Assoc 125:295

    PubMed  CAS  Google Scholar 

  10. Bond E (1970) Hepatoma and arteriosclerosis in a woodchuck.J Wildlife Dis 6: 418–421

    CAS  Google Scholar 

  11. Long GG, Terrell TG, Stockey JL (1975) Hepatomas in a group of captured woodchucks.J Am Vet Med Assoc 167:589

    PubMed  CAS  Google Scholar 

  12. Snyder RL (1968) Hepatomas of captive woodchucks.Am J Path 52:32

    Google Scholar 

  13. Snyder RL, Ratcliffe HL (1969) Marmota monax:A model for studies of cardiovascular,cerebrovascular and neoplastic disease.Acta Zool Pathol Antverp 48:265–273

    PubMed  CAS  Google Scholar 

  14. Snyder RL, Summers J(1980) Woodchuck hepatitis virus and hepatocellular carcinoma.In:M Essex, G Todaro, H zur Hausen (eds) In:Viruses in naturally occurring cancers,Book A.Cold Spring Harbor Conferences on Cell Proliferation,Cold Spring Harbor Laboratory,447–457

    Google Scholar 

  15. Snyder RL, Tyler G, Summers J (1982) Chronic hepatitis and hepatocellular carcinoma associated with woodchuck hepatitis virus.Am J Pathol 107:422–425

    PubMed  CAS  Google Scholar 

  16. Popper H, Shih JWK, Gerin JL, Wong DC, Hoyer BH, London WT, Sly DL, Purcell RH (1981) Woodchuck hepatitis and hepatocellular carcinoma: Correlation of histologic with virologic observations. Hepatology 1:91–98

    PubMed  CAS  Google Scholar 

  17. Roth L, King JM, Hornbuckle WE, Harvey HJ, Tennant BC (1985) Chronic hepatitis and hepatocellular carcinoma associated with persistent woodchuck hepatitis virus infection.Vet Pathol 22:238–343

    Google Scholar 

  18. Ganem D, Varmus HE (1987) The molecular biology of the hepatitis B viruses. Annu Rev Biochem 56:651–693

    PubMed  CAS  Google Scholar 

  19. Summers J, Smolec JM, Werner BG, Kelly TJ, Tyler GV, Snyder RL (1980) Hepatitis B virus and woodchuck hepatitis virus are members of a novel class of DNA viruses.In:M Essex, G Todaro, H zur Hausen (eds) In:Viruses in naturally occurring cancers,Book A.Cold Spring Harbor Conferences on Cell Proliferation,Cold Spring Harbor Laboratory 459-470

    Google Scholar 

  20. Tiollais P, Pource C, Dejean A (1985) The hepatitis B virus. Nature 317:489–495

    PubMed  CAS  Google Scholar 

  21. Marion PL, Oshiro LS, Regnery DC, Scullard GH, Robinson WS (1980) A virus in Beechey ground squirrels that is related to hepatitis B virus of humans.Proc Natl Acad Sci USA 77:2941–2945

    PubMed  CAS  Google Scholar 

  22. Weiser B, Ganem D, Seeger C, Varmus HE (1983) Closed circular viral DNA and asymmetrical heterogeneous forms in livers from animals infected with ground squirrel hepatitis virus (woodchucks,ducks).Microbiology 48:1–9

    CAS  Google Scholar 

  23. Kodama K, Ogasawara N, Yoshikawa H, Murakami S (1985) Nucleotide sequence of a cloned woodchuck hepatitis virus genome:Evolutional relationship between hepadnaviruses.J Virol 56:978–986

    PubMed  CAS  Google Scholar 

  24. Marion PL, Knight SS, Salazar FH, Popper H, Robinson WS (1983) Ground squirrel hepatitis virus infection. Hepatology 3:519–527

    PubMed  CAS  Google Scholar 

  25. Marion PL, Van Davelaar MJ, Knight SS, Salazar FH, Garcia G, Popper H, Robinson WS (1986) Hepatocellular carcinoma in ground squirrels persistently infected with ground squirrel hepatitis virus.Proc Natl Acad Sci USA 83: 4543–4546

    PubMed  CAS  Google Scholar 

  26. Cullen JM, Marion PL (1996) Non-neoplastic liver disease associated with chronic ground squirrel hepatitis virus infection. Hepatology 23:1324–1329

    PubMed  CAS  Google Scholar 

  27. Testut P, Renard CA, Terradillos O, Vitvitski TL, Tekaia F, Degott C, Blake J, Boyer B, Buendia MA (1996) A new hepadnavirus endemic in arctic ground squirrels in Alaska.J Virol 70:4210–4219

    PubMed  CAS  Google Scholar 

  28. Feitelson MA, Millman I, Blumberg BS (1986) Tree squirrel hepatitis B virus: antigenic and structural characterization.Proc Natl Acad Sci USA 83:2994–2997

    PubMed  CAS  Google Scholar 

  29. Minuk GY, Shaffer EA, Hoar DI, Kelly J (1986) Ground squirrel hepatitis virus (GSHV) infection and hepatocellular carcinoma in the Canadian Richardson ground squirrel. (Spermophilus richardsonii).Liver 6:350–356

    PubMed  CAS  Google Scholar 

  30. Tennant BC, Mrosovsky N, McLean K, Cote PJ, Korba BE, Engle RE, Gerin JL, Wright J, Michener GR, Uhl E et al (1991) Hepatocellular carcinoma in Richardson’ s ground squirrels (Spermophilus richardsonii):Evidence for association with hepatitis B-like virus infection. Hepatology 13:1215–1221

    PubMed  CAS  Google Scholar 

  31. Mason WS, Seal G, Summers J (1980) Virus of Pekin ducks with structural and biological relatedness to human hepatitis B virus.J Virol 36:829–836

    PubMed  CAS  Google Scholar 

  32. Omata M, Uchiumi K, Ito Y, Yokosuka O, Mori J, Terao K, Wei-Fa Y, O’Connell AP, London WT, Okuda K (1983) Duck hepatitis B virus and liver diseases. Gastroenterology 85:260–267

    PubMed  CAS  Google Scholar 

  33. Marion PL, Cullen JM, Azcarraga RR, van Davelaar MJ, Robinson WS (1987) Experimental transmission of duck hepatitis B virus to Pekin ducks and to domestic geese. Hepatology 7:724–731

    PubMed  CAS  Google Scholar 

  34. Sprengel R, Kaleta EF, Will H (1988) Isolation and characterization of a hepatitis B virus endemic in herons.J Virol 62:3832–3839

    PubMed  CAS  Google Scholar 

  35. Chang S-F, Netter HJ, Bruns M, Schneider R, Frölich K, Will H (1999) A new avian hepadnavirus infecting snow geese (Anser caerulescens) produces a significant fraction of virions containing single-stranded DNA. Virology 262: 39–54

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  37. Cohn DL, Erb HN, Georgi JR, Tennant BC (1986) Parasites of the laboratory woodchuck (Marmota monax).Lab Anim Sci 36:298–302

    PubMed  CAS  Google Scholar 

  38. Millman I, Southam L, Halbherr T, Simmons H, Kang CM (1984) Woodchuck hepatitis virus:Experimental infection and natural occurrence. Hepatology 4: 817–823

    PubMed  CAS  Google Scholar 

  39. Tyler GV, Snyder RL, Summers J (1986) Experimental infection of the woodchuck (Marmota monax monax) with woodchuck hepatitis virus. Lab Invest 55: 51–55

    PubMed  CAS  Google Scholar 

  40. Kajino K, Jilbert AR, Saputelli J, Aldrich CE, Cullen J, Mason WS (1994) Woodchuck hepatitis virus infections:Very rapid recovery following a prolonged viremia and infection of virtually every hepatocyte.J Virol 68:5792–5803

    PubMed  CAS  Google Scholar 

  41. Guo JT, Zhou H, Liu C, Aldrich C, Saputelli J, Whitaker T, Barrasa MI, Mason WS, Seeger C (2000) Apoptosis and regeneration of hepatocytes during recovery from transient hepadnavirus infections.J Virol 74:1495–1505

    PubMed  CAS  Google Scholar 

  42. Menne S, Maschke J, Tolle TK, Lu M, Roggendorf M (1997) Characterization of T-cell response to woodchuck hepatitis virus core protein and protection of woodchucks from infection by immunization with peptides containing a T-cell epitope.J Virol 71:65–74

    PubMed  CAS  Google Scholar 

  43. Shanmuganathan S, Waters JA, Karayiannis P, Thursz M, Thomas HC (1997) Mapping of the cellular immune responses to woodchuck hepatitis core antigen epitopes in chronically infected woodchucks.J Med Virol 52:128–135

    PubMed  CAS  Google Scholar 

  44. Cote PJ, Korba BE, Steinberg H, Ramirez-Mejia C, Baldwin B, Hornbuckle WE, Tennant BC, Gerin JL (1991) Cyclosporin A modulates the course of woodchuck hepatitis virus infection and induces chronicity.J Immunol 146: 3138–3144

    PubMed  CAS  Google Scholar 

  45. Cote PJ, Korba BE, Baldwin B, Hornbuckle WE, Tennant BC, Gerin JL (1992) Immunosuppression with cyclosporine during the incubation period of experimental woodchuck hepatitis virus infection increases the frequency of chronic infection in adult woodchucks.J Infect Dis 166:628–631

    PubMed  CAS  Google Scholar 

  46. Seeff LB, Beebe GW, Hoofnagle JH, Norman JE, Buskell-Bales Z, Waggoner JG, Kaplowitz N, Koff RS, Petrini JL Jr, Schiff ER et al (1987) A serologic follow-up of the 1942 epidemic of post-vaccination hepatitis in the United States Army.New Engl J Med 316:965–970

    PubMed  CAS  Google Scholar 

  47. Tassopoulos NC, Papaevangelou GJ, Sjogren MH, Roumeliotou-Karayannis A, Gerin JL, Purcell RH (1987) Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults. Gastroenterology 92:1844–1850

    PubMed  CAS  Google Scholar 

  48. Blumberg BS, London WT (1982) Hepatitis B virus:Pathogenesis and prevention of primary cancer of the liver.Cancer 50:2657–2665

    PubMed  CAS  Google Scholar 

  49. Cote PJ, Korba BE, Miller RH, Jacob JR, Baldwin BH, Hornbuckle WE, Purcell RH, Tennant BC, Gerin JL (2000) Effects of age and viral determinants on chronicity as an outcome of experimental woodchuck hepatitis virus infection. Hepatology 31:190–200

    PubMed  CAS  Google Scholar 

  50. Cote PJ, Toshkov I, Bellezza C, Ascenzi M, Roneker C, Graham LA, Baldwin BH, Gaye K, Nakamura I, Korba BE et al (2000) Temporal pathogenesis of experimental neonatal woodchuck hepatitis virus infection:Increased initial viral load and decreased severity of acute hepatitis during the development of chronic viral infection. Hepatology 32:807–817

    PubMed  CAS  Google Scholar 

  51. Gerin JL, Cote PJ, Korba BE, Tennant BC (1989) Hepadnavirus-induced liver cancer in woodchucks.Cancer Detect Prev 14:227–229

    PubMed  CAS  Google Scholar 

  52. Popper H, Roth L, Purcell RH, Tennant BC, Gerin JL (1987) Hepatocarcinogenicity of the woodchuck hepatitis virus.Proc Natl Acad Sci USA 84:866–870

    PubMed  CAS  Google Scholar 

  53. Cote PJ, Roneker C, Cass K, Schödel F, Peterson D, Tennant B, de Noronha F, Gerin J (1993) New enzyme immunoassays for the serologic detection of woodchuck hepatitis virus infection. Viral Immunol 6:161–169

    PubMed  CAS  Google Scholar 

  54. Tennant BC, Toshkov IA, Peek SF, Jacob JR, Menne S, Hornbuckle WE, Schinazi RD, Korba BE, Cote PJ, Gerin JL (2004) Hepatocellular carcinoma in the woodchuck model of hepatitis B virus infection. Gastroenterology 127: S283–293 Review

    PubMed  Google Scholar 

  55. Abe K, Kurata T, Shikata T, Tennant BC (1988) Enzyme-altered liver cell foci in woodchucks infected with woodchuck hepatitis virus.Jpn J Cancer Res 79: 466–472

    PubMed  CAS  Google Scholar 

  56. Toshkov I, Hacker HJ, Roggendorf M, Bannasch P (1990) Phenotypic patterns of preneoplastic and neoplastic hepatic lesions in woodchucks infected with woodchuck hepatitis virus.J Cancer Res Clin Oncol 116:581–590

    PubMed  CAS  Google Scholar 

  57. Mi L-J, Patil J, Hornbuckle WE, Cote PJ, Gerin JL, Tennant BC, Paronetto F (1994) DNA ploidy analysis of hepatic preneoplastic and neoplastic lesions in woodchucks experimentally infected with woodchuck hepatitis virus. Hepatology 20:21–29

    PubMed  CAS  Google Scholar 

  58. Cullen JM, Linzey DW, Gebhard DH (1994) Nuclear ploidy of normal and neoplastic hepatocytes from woodchuck hepatitis virus-infected and uninfected woodchucks. Hepatology 19:1072–1078

    PubMed  CAS  Google Scholar 

  59. Wands J (2007) Hepatocellular carcinoma and sex.N Engl J Med 357:1974–1976

    PubMed  CAS  Google Scholar 

  60. Prieto J (2008) Inflammation,HCC and sex:IL-6 in the centre of the triangle. J Hepatol 48:380–381

    PubMed  CAS  Google Scholar 

  61. Nakatani T, Roy G, Fujimoto N, Asahara T, Ito A (2001) Sex hormone dependency of diethylnitrosamine-induced liver tumors in mice and chemoprevention by leuprorelin.Jpn J Cancer Res 92:249–256

    PubMed  CAS  Google Scholar 

  62. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121–124

    PubMed  CAS  Google Scholar 

  63. Baldwin BH, Tennant BC, Reimers TJ, Cowan RG, Concannon PW (1985) Circannual changes in serum testosterone concentrations of adult and yearling woodchucks (Marmota monax). Biol Reprod 32:804–812

    PubMed  CAS  Google Scholar 

  64. Peters DN, Steinberg H, Anderson WI, Hornbuckle WE, Cote PJ, Gerin JL, Lewis RM, Tennant BC (1992) Immunopathology of glomerulonephritis associated with chronic woodchuck hepatitis infection in woodchucks (Marmota monax).Am J Pathol 141:143–152

    PubMed  CAS  Google Scholar 

  65. Will H, Cattaneo R, Koch HG, Darai G, Schaller H, Schellekens H, vanErd PM, Deinhardt F (1982) Cloned HBV DNA causes hepatitis in chimpanzees. Nature 299:740

    PubMed  CAS  Google Scholar 

  66. Miller RH, Girones R, Cote PJ, Hornbuckle WE, Chestnut T, Baldwin BH, Korba BE, Tennant BC, Gerin JL, Purcell RH (1990) Evidence against a requisite role for defective virus in the establishment of persistent hepadnavirus infections.Proc Natl Acad Sci USA 87:9329–9332

    PubMed  CAS  Google Scholar 

  67. Sprengel R, Kuhn C, Manso C, Will H (1984) Cloned duck hepatitis B virus DNA is infectious in Pekin ducks.J Virol 52:932–937

    PubMed  CAS  Google Scholar 

  68. Seeger C, Ganem D, Varmus HE (1984) Nucleotide sequence of an infectious molecularly cloned genome of ground squirrel hepatitis virus.J Virol 51: 367–375

    PubMed  CAS  Google Scholar 

  69. Seeger C, Baldwin B, Hornbuckle WE, Yeager AE, Tennant BC, Cote P, Ferrell L, Ganem D, Varmus HE (1991) Woodchuck hepatitis virus is a more efficient oncogenic agent than ground squirrel hepatitis virus in a common host.J Virol 65:1673–1679

    PubMed  CAS  Google Scholar 

  70. Trueba D, Phelan M, Nelson J, Beck F, Pecha BS, Brown RJ, Varmus HE, Ganem D (1985) Transmission of ground squirrel hepatitis virus to homologous and heterologous hosts. Hepatology 5:435–439

    PubMed  CAS  Google Scholar 

  71. Seeger C, Baldwin B, Hornbuckle WE, Yeager AE, Tennant BC, Cote P, Ferrell L, Ganem D, Varmus HE (1991) Woodchuck hepatitis virus is a more efficient oncogenic agent than group hepatitis virus in a common host.J Virol 65:1673–1679

    PubMed  CAS  Google Scholar 

  72. Szmuness W (1978) Hepatocellular carcinoma and the hepatitis B virus: Evidence for a causal association.Prog Med Virol 24:40–69

    PubMed  CAS  Google Scholar 

  73. Maupas P, Werner B, Larouze B, Millman I, London WT, O’Connell A, Blumberg BS (1975) Antibody to hepatitis-B core antigen in patients with primary hepatic carcinoma. Lancet 2:9–11

    PubMed  CAS  Google Scholar 

  74. Blumberg BS, Larouze B, London WT, Werner B, Hesser JE, Millman I, Saimot G, Payet M (1975) The relation of infection with hepatitis B agent to primary hepatic carcinoma.Am J Path 81:669–682

    PubMed  CAS  Google Scholar 

  75. Prince AM, Szmuness W, Michon J, Demaille J, Diebolt G, Linhard J, Quenum C, Sankale M (1975) A case/control study of the association between primary liver cancer and hepatitis B infection in Senegal.Int J Cancer 16:376–383

    PubMed  CAS  Google Scholar 

  76. Asano M, Kato H, Yoshimoto K, Seyama S, Itakura H, Hamada T, Iijima S (1982) Primary liver carcinoma and liver cirrhosis in atomic bomb survivors, Hiroshima and Nagasaki,1961-75,with special reference to hepatitis B surface antigen.J Natl Cancer Inst 69:1221–1227

    PubMed  CAS  Google Scholar 

  77. Chien MC, Tong MJ, Lo KJ, Lee JK, Milich DR, Vyas GN, Murphy BL (1981) Hepatitis B viral markers in patients with primary hepatocellular carcinoma in Taiwan.J Natl Cancer Inst 66:475–479

    PubMed  CAS  Google Scholar 

  78. Hann HW, Kim CY, London WT, Whitford P, Blumberg BS (1982) Hepatitis B virus and primary hepatocellular carcinoma:Family studies in Korea.Int J Cancer 30:47–51

    PubMed  CAS  Google Scholar 

  79. Okuda K, Nakashima T, Sakamoto K, Ikari T, Hidaka H, Kubo Y, Sakuma K, Motoike Y, Okuda H, Obata H (1982) Hepatocellular carcinoma arising in noncirrhotic and highly cirrhotic livers:A comparative study of histopathology and frequency of hepatitis B markers.Cancer 49:450–455

    PubMed  CAS  Google Scholar 

  80. Omata M, Ashcavai M, Liew CT, Peters RL (1979) Hepatocellular carcinoma in the USA,etiologic considerations. Localization of hepatitis B antigens. Gastroenterology 76:279–287

    PubMed  CAS  Google Scholar 

  81. Tabor E, Gerety RS, Vogel CL, Byley AC, Anthony PP, Chan CH, Barker LF (1977) Hepatitis B virus infection and primary hepatocellular carcinoma.J Natl Cancer Inst 58:1197–1200

    PubMed  CAS  Google Scholar 

  82. Viola LA, Barrison IG, Coleman JC, Paradinas FJ, Fluker JL, Evans BA, Murray-Lyon IM (1981) Natural history of liver disease in chronic hepatitis B surface antigen carriers. Survey of 100 patients from Great Britain. Lancet 2: 1156–1159

    PubMed  CAS  Google Scholar 

  83. Beasley RP, Lin CC (1978) Hepatoma risk among hepatitis B surface antigen carriers.Am J Epidemiol 108:247

    Google Scholar 

  84. Beasley RP, Hwang LY, Lin CC, Chien CS (1981) Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan. Lancet 2: 1129–1133

    PubMed  CAS  Google Scholar 

  85. Beasley RP (1982) Hepatitis B virus as the etiologic agent in hepatocellular carcinoma-Epidemiologic considerations. Hepatology 2:21S–26S

    Google Scholar 

  86. Beasley RP (1988) Hepatitis B virus. The major etiology of hepatocellular carcinoma.Cancer 61:1942–1956

    PubMed  CAS  Google Scholar 

  87. Prince AM, Alcabes P (1982) The risk of development of hepatocellular carcinoma in hepatitis B virus carriers in New York:A preliminary estimate using death-records matching. Hepatology 2:15S–20S

    Google Scholar 

  88. Brechot C, Hadchouel M, Scotto J, Fonck M, Potet F, Vyas GN, Tiollais P (1981) State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and negative liver disease.Proc Natl Acad Sci USA 78: 3906–3910

    PubMed  CAS  Google Scholar 

  89. Chen DS, Hoyer BH, Nelson J, Purcell RH, Gerin JL (1982) Detection and properties of hepatitis B viral DNA in liver tissues from patients with hepatocellular carcinoma. Hepatology 2:42S–46S

    Google Scholar 

  90. Shafritz DA (1982) Hepatitis B virus DNA molecules in the liver of hepatitis B surface antigen carriers:Mechanistic considerations in the pathogenesis of hepatocellular carcinoma. Hepatology 2:35S–41S

    Google Scholar 

  91. Kremsdorf D, Soussan P, Paterlini-Brechot P, Bréchot C (2006) Hepatitis B virus-related hepatocellular carcinoma:paradigms for viral-related human carcinogenesis. Oncogene 25:3823–3833

    PubMed  CAS  Google Scholar 

  92. Murakami Y, Saigo K, Takashima H, Minami M, Okanoue T, Bréchot C, Paterlini-Bréchot P (2005) Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut 54:1162–1168

    PubMed  CAS  Google Scholar 

  93. Buendia MA (1994) Animal models for hepatitis B virus and liver cancer. In:C Bréchot (ed) In:Primary liver cancer:Etiological and progression factors.CRC Press, Boca Raton,Florida,211–224

    Google Scholar 

  94. Buendia MA, Pineu P (1995) The complex role of hepatitis B virus in human hepatocarcinogenesis.In:G Barbanti-Brodano, M Bendinelli, H Friedman (eds) In:DNA tumor viruses:Oncogenic mechanisms.Plenum Press, New York, 171–193

    Google Scholar 

  95. Farber E, Sarma DS (1987) Hepatocarcinogenesis:A dynamic cellular perspective.Lab Invest 56:4–22

    PubMed  CAS  Google Scholar 

  96. Pitot HC, Dragan YP (1991) Facts and theories concerning the mechanisms of carcinogenesis.FASEB J 5:2280–2286

    PubMed  CAS  Google Scholar 

  97. Korba BE, Wells FV, Baldwin B, Cote PJ, Tennant BC, Popper H, Gerin JL (1989) Hepatocellular carcinoma in woodchuck hepatitis-virus infected woodchucks. Presence of viral DNA in tumor tissue from chronic carriers and animals serologically recovered from acute infections. Hepatology 9:461–470

    PubMed  CAS  Google Scholar 

  98. Fuchs K, Heberger C, Weimer T, Roggendorf M (1989) Characterization of woodchuck hepatitis virus DNA and RNA in the hepatocellular carcinomas of woodchucks. Hepatology 10:215–220

    PubMed  CAS  Google Scholar 

  99. Kaneko S, Oshima T, Kodama K, Aoyama S, Yoshikawa H, Unoura M, Fukuoka K, Matsushita F, Morimoto H, Kobayashi K et al (1986) Stable integration of woodchuck hepatitis virus DNA in transplanted tumors and established tissue culture cells derived from a woodchuck primary hepatocellular carcinoma. Cancer Res 46:3608–3613

    PubMed  CAS  Google Scholar 

  100. Ogston CW, Jonak GJ, Rogler CE, Astrin SM, Summers J (1982) Cloning and structural analysis of integrated woodchuck hepatitis virus sequences from hepatocellular carcinomas of woodchucks. Cell 29:385–394

    PubMed  CAS  Google Scholar 

  101. Rogler CE, Summers J (1984) Cloning and structural analysis of integrated woodchuck hepatitis virus sequences from a chronically infected liver.J Virol 50:832–837

    PubMed  CAS  Google Scholar 

  102. Rogler CE, Hino O, Su CY (1987) Molecular aspects of persistent woodchuck hepatitis virus and hepatitis B virus infection and hepatocellular carcinoma. Hepatology 7:74S–78S

    PubMed  CAS  Google Scholar 

  103. Rogler CE(1991) Cellular and molecular mechanism of hepatocarcinogenesis associated with hepadnavirus infection.In:WS Mason,C Seeger (eds) In:Hepadna viruses:Molecular biology and pathogenesis (Current Topics in Microbiology and Immunology,Vol 168).Springer Verlag, New York,103–140

    Google Scholar 

  104. Yang D, Alt E, Rogler CE (1993) Coordinate expression of N-myc 2 and insulin-like growth factor II in pre-cancerous altered hepatic foci in woodchuck hepatitis virus carriers.Cancer Res 53:2020–2027

    PubMed  CAS  Google Scholar 

  105. Yang D, Faris R, Affigne S, Rogler CE (1996) Insulin-like growth factor II blocks apoptosis of N-myc2-expressing woodchuck liver epithelial cells.J Virol 70:6260–6268

    PubMed  CAS  Google Scholar 

  106. Yang W, Summers J (1999) Integration of hepadnavirus DNA in infected liver: Evidence for a linear precursor.J Virol 73:9710–9717

    PubMed  CAS  Google Scholar 

  107. Summers J, Jilbert AR, Yang W, Aldrich CE, Saputelli J, Litwin S, Toll E, Mason WS (2003) Hepatocyte turnover during resolution of a transient hepadnaviral infection.Proc Natl Acad Sci USA 100:11652–11659

    PubMed  CAS  Google Scholar 

  108. Mason SW, Jilbert AR, Summers J (2005) Clonal expansion of hepatocytes during chronic woodchuck hepatitis virus infection.Proc Natl Acad Sci USA 102: 1139–1144

    PubMed  CAS  Google Scholar 

  109. Summers J, Mason WS (2004) Residual integrated viral DNA after hepadnavirus clearance by nucleoside analog therapy.Natl Acad Sci USA 101:638–640

    CAS  Google Scholar 

  110. Moroy T, Marchio A, Etiemble J, Trepo C, Tiollais P, Buendia MA (1986) Rearrangement and enhanced expression of c-myc in hepatocellular carcinoma of hepatitis virus infected woodchucks. Nature 324:276–279

    PubMed  CAS  Google Scholar 

  111. Moroy T, Etiemble J, Bougueleret L, Hadchouel M, Tiollais P, Buendia MA (1989) Structure and expression of her,a locus rearranged with c-myc in a woodchuck hepatocellular carcinoma. Oncogene 4:59–65

    PubMed  CAS  Google Scholar 

  112. Hsu TY, Moroy T, Etiemble J, Louise A, Trepo C, Tiollais P, Buendia MA (1988) Activation of c-myc by woodchuck hepatitis virus insertion in hepatocellular carcinoma. Cell 55:627–635

    PubMed  CAS  Google Scholar 

  113. Dejean A, deThe H (1990) Hepatitis B virus as an insertional mutagene in a human hepatocellular carcinoma.Mol Biol Med 7:213–222

    PubMed  CAS  Google Scholar 

  114. Fourel G, Trepo C, Bougueleret L, Henglein B, Ponzetto A, Tiollais P, Buendia MA (1990) Frequent activation of N-myc genes by hepadnavirus insertion in woodchuck liver tumours. Nature 347:294–298

    PubMed  CAS  Google Scholar 

  115. Fourel G, Transy C, Tennant BC, Buendia MA (1992) Expression of the woodchuck N-myc2 retroposon in brain and in liver tumors is driven by a cryptic N-myc promoter.Mol Cell Biochem 12:5336–5344

    CAS  Google Scholar 

  116. Flajolet M, Gegonne A, Ghysdael J, Tiollais P, Buendia MA, Fourel G (1997) Cellular and viral trans-acting factors modulate N-myc2 promoter activity in woodchuck liver tumors. Oncogene 15:1103–1110

    PubMed  CAS  Google Scholar 

  117. Wei Y, Tennant B, Ganem D (1998) In vivo effects of mutations in woodchuck hepatitis virus enhancer II.J Virol 72:6608–6613

    PubMed  CAS  Google Scholar 

  118. Wei Y, Fourel G, Ponzetto A, Silvestro M, Tiollais P, Buendia MA (1992) Hepadnavirus integration:mechanisms of activation of the N-myc2 retrotransposon in woodchuck liver tumors.J Virol 66:5265–5276

    PubMed  CAS  Google Scholar 

  119. Fourel G, Ringeisen F, Flajolet M, Tronche F, Pontoglio M, Tiollais P, Buendia MA (1996) The HNF1/HNF4-dependent We2 element of woodchuck hepatitis virus controls viral replication and can activate the N-myc2 promoter.J Virol 70:8571–8583

    PubMed  CAS  Google Scholar 

  120. Fourel G, Couturier J, Wei Y, Apiou F, Tiollais P, Buendia MA (1994) Evidence for long-range oncogene activation by hepadnavirus insertion.EMBO J 13: 2526–2534

    PubMed  CAS  Google Scholar 

  121. Bruni R, Conti I, Villano U, Giuseppetti R, Palmieri G, Rapicetta M (2006) Lack of WHV integration nearby N-myc 2 and in the downstream b3n and win loci in a considerable fraction of liver tumors with activated N-myc 2 from naturally infected wild woodchucks. Virology 345:258–269

    PubMed  CAS  Google Scholar 

  122. Jacob JR, Sterczer A, Toshkov IA, Yeager AE, Korba BE, Cote PJ, Buendia MA, Gerin JL,Tennant BC (2004) Integration of woodchuck hepatitis and N-myc rearrangement determine size and histologic grade of hepatic tumors. Hepatology 39:1008–1016

    Google Scholar 

  123. Renard C-A, Fourel G, Bralet M-P, Degott C, de la Coste A, Perret C, Tiollais P, Buendia MA (2000) Hepatocellular carcinoma in WHV/N-myc 2 transgenic mice:Oncogenic mutations of ÿ-catenin and synergistic effect of p53 null alleles. Oncogene 19:2678–2686

    PubMed  CAS  Google Scholar 

  124. De La Coste A, Romagnolo B, Billuart P, Renard C-A, Buendia MA, Soubrane O, Fabre M, Jamel C, Beldjord C, Kahn Z et al (1998) Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 95:8847–8851

    Google Scholar 

  125. Quignon F, Renard CA, Tiollais P, Buendia MA, Transy C (1996) A functional N-myc2 retroposon in ground squirrels:Implications for hepadnavirus-associated carcinogenesis. Oncogene 12:2011–2017

    PubMed  CAS  Google Scholar 

  126. Transy C, Fourel G, Robinson WS, Tiollais P, Marion PL, Buendia MA (1992) Frequent amplification of c-myc in ground squirrel liver tumors associated with past or ongoing infection with a hepadnavirus.Proc Natl Acad Sci USA 89: 3874–3878

    PubMed  CAS  Google Scholar 

  127. Hansen LJ, Tennant BC, Seeger C, Ganem D (1993) Differential activation of myc gene family members in hepatic carcinogenesis by closely related hepatitis B viruses.Mol Cell Biochem 13:659–667

    CAS  Google Scholar 

  128. Hohne M, Schaefer S, Seifer M, Feitelson MA, Paul D, Gerlich WH (1990) Malignant transformation of immortalized transgenic hepatocytes following transfection with hepatitis B virus DNA.EMBO J 9:1137–1145

    PubMed  CAS  Google Scholar 

  129. Seifer M, Hohne M, Schaefer S, Gerlich WH (1991) In vitro tumorigenicity of hepatitis B virus DNA and HBx protein.J Hepatol 13:S61–S65

    PubMed  CAS  Google Scholar 

  130. Terradillos O, Billet O, Renard CA, Levy R, Molina T, Briand P, Buendia MA (1997) The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice. Oncogene 14:395–404

    PubMed  CAS  Google Scholar 

  131. Seeger C, Mason WS (2000) Hepatitis B virus biology.Microbiol Mol Biol Rev 64:51–68

    PubMed  CAS  Google Scholar 

  132. Feitelson MA, Lega L, Duan LX, Clayton M (1993) Characteristics of woodchuck hepatitis X-antigen in the livers and sera from infected animals.J Hepatol 17:S24–S34

    PubMed  CAS  Google Scholar 

  133. Jacob JR, Ascenzi MA, Roneker CA, Toshkov IA, Cote PJ, Gerin JL, Tennant BC (1997) Hepatic expression of the woodchuck hepatitis virus X-antigen during acute and chronic infection and detection of a woodchuck hepatitis virus X-antigen antibody response. Hepatology 26:1607–1615

    PubMed  CAS  Google Scholar 

  134. Feitelson MA, Ranganathan PN, Clayton MM, Zhang SM(1997) Partial characterization of the woodchuck tumor suppressor,p53,and its interaction with woodchuck hepatitis virus X antigen in hepatocarcinogenesis. Oncogene 15: 327–336

    PubMed  CAS  Google Scholar 

  135. Ghebranious N, Sell S (1998) The mouse equivalent of the human p53ser249 mutation p53ser246 enhances aflatoxin hepatocarcinogenesis in hepatitis B surface antigen transgenic and p53 heterozygous null mice. Hepatology 27: 967–973

    PubMed  CAS  Google Scholar 

  136. Ueda H, Ullrich SJ, Gangemi JD, Kappel CA, Ngo L, Feitelson MA, Jay G (1995) Functional inactivation but not structural mutation of p53 causes liver cancer.Nat Genet 9:41–47

    PubMed  CAS  Google Scholar 

  137. Hsia CC, Nakashima Y, Thorgeirsson SS, Harris CC, Minemura M, Momosake S, Wang NJ, Tabor E (2000) Correlation of immunohistochemical staining and mutations of p53 in human hepatocellular carcinoma.Oncol Reports 7: 353–356

    CAS  Google Scholar 

  138. Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436

    PubMed  CAS  Google Scholar 

  139. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    PubMed  CAS  Google Scholar 

  140. Kalayci C, Johnson PJ, Davies SE, Williams R (1991) Hepatitis B virus related hepatocellular carcinoma in the non-cirrhotic liver.J Hepatol 12:54–59

    PubMed  CAS  Google Scholar 

  141. El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576

    PubMed  CAS  Google Scholar 

  142. Schafer DF, Sorrell MF (1999) Hepatocellular carcinoma. Lancet 353:1253–1257

    PubMed  CAS  Google Scholar 

  143. Johnson PJ, Williams R (1987) Cirrhosis and the aetiology of hepatocellular carcinoma.J Hepatology 4:140–147

    CAS  Google Scholar 

  144. Chisari FV (2000) Viruses,immunity,and cancer:lessons from hepatitis B.Am J Pathol 156:1117–1132

    PubMed  CAS  Google Scholar 

  145. Chisari FV, Klopchin K, Moriyama T, Pasquinelli C, Dunsford HA, Sell S, Pinkert CA, Brinster RL, Palmiter RD (1989) Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice Cell 59:1145–1156

    PubMed  CAS  Google Scholar 

  146. Dunsford HA, Sell S, Chisari FV (1990) Hepatocarcinogenesis due to chronic liver cell injury in hepatitis B virus transgenic mice.Cancer Res 50:3400–3407

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  148. Sell S, Hunt JM, Dunsford HA, Chisari FV (1991) Synergy between hepatitis B virus expression and chemical hepatocarcinogens in transgenic mice.Cancer Res 51:1278–1285

    PubMed  CAS  Google Scholar 

  149. Bannasch P, Khoshkou NI, Hacker HJ, Radaeva S, Mrozek M, Zillmann U, Kopp-Schneider A, Haberkorn U, Elgas M, Tolle T et al (1995) Synergistic hepatocarcinogenic effect of hepadnaviral infection and dietary aflatoxin B1 in woodchucks.Cancer Res 55:3318–3330

    PubMed  CAS  Google Scholar 

  150. Faux SP, Francis JE, Smith AG, Chipman JK (1992) Induction of 8-hydroxy-deoxyguanosine in Ah-responsive mouse liver by iron and Aroclor 1254. Carcinogenesis 13:247–250

    PubMed  CAS  Google Scholar 

  151. Billiar TR, Curran RD, Harbrecht BC, Stadler J, Williams DL, Ochoa JB, DiSilvio M, Simmons RL, Murray SA (1992) Association between synthesis and release of cGMP and nitric oxide biosynthesis by hepatocytes.Am J Physiol 262:C1077–C1082

    PubMed  CAS  Google Scholar 

  152. Billiar TR, Hoffman RA, Curran RD, Langrehr JM, Simmons RL (1992) A role for inducible nitric oxide biosynthesis in the liver in inflammation and in the allogeneic immune response.J Lab Clin Med 120:192–197

    PubMed  CAS  Google Scholar 

  153. Curran RD, Billiar TR, Steuhr DJ, Ochoa JB, Harbrecht BG, Flint SG, Simmons RL (1990) Multiple cytokines are required to induce hepatocyte nitric oxide production and inhibit total protein synthesis.Ann Surg 212:462–469; Discussion 470-471

    PubMed  CAS  Google Scholar 

  154. Curran RD, Ferrari FK, Kispert PH, Stadler J, Steuhr DJ, Simmons RL, Billiar TR (1991) Nitric oxide and nitric oxide-generating compounds inhibit hepatocyte protein synthesis.FASEB J 5:2085–2092

    PubMed  CAS  Google Scholar 

  155. Geller DA, Nussler AK, Di Silvio M, Loenstein CJ, Shapiro RA, Wang SC, Simmons RL, Billiar TR (1993) Cytokines,endotoxin,and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes.Proc Natl Acad Sci USA 90:522–526

    PubMed  CAS  Google Scholar 

  156. Hortellano S, Genaro AM, Bosca L (1992) Phorbol esters induce nitric oxide synthase activity in rat hepatocytes.J Biol Chem 267:24937–24940

    Google Scholar 

  157. Knowles RG, Merrett M, Salter M, Moncada S (1990) Differential induction of brain,lung and liver nitric oxide synthase by endotoxins in the rat.Biochem J 270:833–836

    PubMed  CAS  Google Scholar 

  158. Wood ER, Berger H, Sherman PA, Lapetina EG (1993) Hepatocytes and macrophages express an identical cytokine inducible nitric oxide synthase gene. Biochem Biophys Res Comm 191:767–774

    PubMed  CAS  Google Scholar 

  159. Kilbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, Levi R, Lodato RF (1990) N G-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension:Implications for the involvement of nitric oxide.Proc Natl Acad Sci USA 87:3629–3632

    PubMed  CAS  Google Scholar 

  160. Liu RH, Baldwin B, Tennant BC, Hotchkiss JH (1991) Elevated formation of nitrate and N nitrosodimethylamine in woodchucks (Marmota monax) associated with chronic woodchuck hepatitis virus infection.Cancer Res 51: 3925–3929

    PubMed  CAS  Google Scholar 

  161. Nguyen T, Brunson D, Crespi CL, Penman BW, Wishnok JS, Tannenbaum SR (1992) DNA damage and mutation in human cells exposed to nitric oxide in vitro.Proc Natl Acad Sci USA 89:3030–3034

    PubMed  CAS  Google Scholar 

  162. Liu RH, Jacob JR, Tennant BC, Hotchkiss JH (1992) Nitrite and nitrosamine synthesis by hepatocytes isolated from normal woodchucks (Marmota monax) and woodchucks chronically infected with woodchuck hepatitis virus.Cancer Res 52:4139–4143

    PubMed  CAS  Google Scholar 

  163. Liu RH, Jacob JR, Hotchkiss JH, Tennant BC (1993) Synthesis of nitric oxide and nitrosamine by immortalized woodchuck hepatocytes.Carcinogenesis 14: 1609–1613

    PubMed  CAS  Google Scholar 

  164. Liu RH, Jacob JR, Hotchkiss JH, Cote PJ, Gerin JL, Tennant BC (1994) Woodchuck hepatitis virus surface antigen induces nitric oxide synthesis in hepatocytes:Possible role in hepatocarcinogenesis.Carcinogenesis 15:2875–2877

    PubMed  CAS  Google Scholar 

  165. Marletta M, Yoon PS, Iyengar R, Leaf CD, Wishnok JS(1988) Macrophage oxidation of L-arginine to nitrite and nitrate:Nitric oxide is an intermediate. Biochem 27:8706–8711

    CAS  Google Scholar 

  166. Archer MC (1989) Mechanisms of action of N-nitroso compounds.Cancer Surv 8:241–250

    PubMed  CAS  Google Scholar 

  167. Magee PN (1989) The experimental basis for the role of nitroso compounds in human cancer.Cancer Surv 8:207–239

    PubMed  CAS  Google Scholar 

  168. Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Bunams TM, Cebula TA, Koch WH, Andrews AW, Allen JS et al (1991) DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science 254: 1001–1003

    PubMed  CAS  Google Scholar 

  169. Rivkina M, Cote PJ, Robinson WS, Tennant BC, Marion PL (1996) Absence of mutations in the p53 tumor suppressor gene in woodchuck hepatocellular carcinomas associated with hepadnavirus infection and intake of aflatoxin B 1. Carcinogensis 17:2689–2694

    CAS  Google Scholar 

  170. Tennant BC, Hornbuckle WE, Yeager AE, Baldwin BH, Sherman WK, Anderson WI, Steinber H, Cote PH, Korba BE, Gerin JL (1991) Effects of aflatoxin B 1 on experimental woodchuck hepatitis virus infection and hepatocellular carcinoma.In: FB Hollinger, SM Lemon, H Margolis (eds) In: Viral hepatitis and liver disease. Williams & Wilkins, Baltimore, 599–6

    Google Scholar 

  171. Yan RQ, Su JJ, Huang DR, Gan YC, Yang C, Huang GH (1996) Human hepatitis B virus and hepatocellular carcinoma.II.Experimental induction of hepatocellular carcinoma in tree shrews exposed to hepatitis B virus and aflatoxin B1.J Cancer Res Clin Oncol 122:289–295

    PubMed  CAS  Google Scholar 

  172. Slagle BL, Lee TH, Medina D, Finegold MJ, Butel JS (1996) Increased sensitivity to the hepatocarcinogen diethylnitrosamine in transgenic mice carrying the hepatitis B virus X gene.Mol Carcinog 15:261–269

    PubMed  CAS  Google Scholar 

  173. Chu CK, Boudinot FD, Peek SF, Hong JH, Choi Y, Korba BE, Gerin JL, Cote PJ, Tennant BC, Cheng YC (1998) Preclinical investigation of L-FMAU as an anti-hepatitis B virus agent.Antiviral Ther 3:113–121

    CAS  Google Scholar 

  174. Hostetler KY, Beadle JR, Hornbuckle WE, Bellezza CA, Tochkov IA, Cote PJ, Gerin JL, Korba BE, Tennant BC (2000) Antiviral activities of oral 1-O-hexadecyl-propanediol-3-phospho-acyclovir and acyclovir in woodchucks with chronic woodchuck hepatitis virus infection.Antimicrob Agents Chemother 44: 1964–1969

    PubMed  CAS  Google Scholar 

  175. Korba BE, Cote P, Hornbuckle W, Schinazi R, Gangemi JD, Tennant BC, Gerin JL (2000) Enhanced antiviral benefit of combination therapy with lamivudine and alpha interferon against WHV replication in chronic carrier woodchucks. Antivir Ther 5:95–104

    PubMed  CAS  Google Scholar 

  176. Korba BE, Cote P, Hornbuckle W, Schinazi R, Gerin JL, Tennant BC (2000) Enhanced antiviral benefit of combination therapy with lamivudine and famciclovir against WHV replication in chronic WHV carrier woodchucks.Antiviral Res 45:19–32

    PubMed  CAS  Google Scholar 

  177. Korba BE, Cote P, Hornbuckle W, Tennant BC, Gerin JL (2000) Treatment of chronic woodchuck hepatitis virus infection in the Eastern woodchuck (Marmota monax) with nucleoside analogues is predictive of therapy for chronic hepatitis B virus infection in humans. Hepatology 31:1165–1175

    PubMed  CAS  Google Scholar 

  178. Gangemi JD, Korba B, Tennant B, Ueda H, Jay G (1996) Antiviral and anti-pro-liferative activities of interferons in experimental hepatitis B virus infections. Antiviral Therapy 1:64–70

    CAS  Google Scholar 

  179. Tennant BC, Baldwin BH, Hornbuckle WE, Korba BE, Cote PJ, Gerin JL (1996) Animal models in the preclinical assessment of therapy for viral hepatitis.Antivir Ther 1:47–52

    CAS  Google Scholar 

  180. Korba BE, Gerin JL (1992) Use of a standardized cell culture assay to assess activities of nucleoside analogs against hepatitis B virus replication.Antivir Res 19:55–70

    PubMed  CAS  Google Scholar 

  181. Enriquez PM, Jung C, Josephson L, Tennant BC (1995) Conjugation of adenine arabinoside 5’-monophosphate to arabinogalactan:Synthesis,characterization and antiviral activity.Bioconjugate Chem 6:195–202

    CAS  Google Scholar 

  182. Tennant BC, Baldwin BH, Graham LA, Ascenzi MA, Hornbuckle WE, Rowland PH, Tochkov IA, Yeager AE, Erb HN, Colacino JM et al (1998) Antiviral activity and toxicity of fialuridine in the woodchuck model of hepatitis B virus infection. Hepatology 28:179–191

    PubMed  CAS  Google Scholar 

  183. Peek SF, Cote PJ, Jacob JR, Toshkov IA, Hornbuckle WE, Baldwin BH, Wells FV, Chu CK, Gerin JL, Tennant BC et al (2000) Antiviral activity of L-FMAU (1-(2-fluoro-5-methyl-ץ,L-arabinofuranosyl) uracil) against WHV replication and gene expression in chronically infected woodchucks (M.monax). Hepatology 33:254–266

    Google Scholar 

  184. Rajagopalan P, Boudinot FD, Chu CK, Tennant BC, Baldwin BH, Schinazi RF (1996) Pharmacokinetics of (–)-2’-3’-dideoxy-3’-thiacytidine in woodchucks. Antimicrob Agents Chemother 40:642–645

    PubMed  CAS  Google Scholar 

  185. Moraleda G, Saputelli J, Aldrich CE, Averett D, Condreay L, Mason WS (1997) Lack of effect of antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus.J Virol 71:9392–9399

    PubMed  CAS  Google Scholar 

  186. Korba BE, Schinazi RF, Cote P, Tennant BC, Gerin JL (2000) Effect of oral administration of emtricitabine on woodchuck hepatitis virus replication in chronically infected woodchucks.Antimicrob Agents Chemother 44:1757–1760

    PubMed  CAS  Google Scholar 

  187. Peek SF, Toshkov IA, Erb HN, Schinazi RF, Korba BE, Cote PJ, Gerin JL, Tennant BC (1997) 3’-Thiacytidine (3TC) delays development of hepatocellular carcinoma (HCC) in woodchucks with experimentally induced chronic woodchuck hepatitis virus (WHV) infection:Preliminary results of a lifetime study Hepatology 26:368

    Google Scholar 

  188. Mason WS, Cullen J, Moraleda G, Saputelli J, Aldrich CE, Miller DS, Tennant B, Frick L, Averett D, Condreay LD et al (1998) Lamivudine therapy of WHV-infected woodchucks Virology 245:18–32

    PubMed  CAS  Google Scholar 

  189. Zhou T, Saputelli J, Aldrich CE, Deslauriers M, Condreay LD, Mason WS (1999) Emergence of drug-resistant populations of woodchuck hepatitis virus in woodchucks treated with the antiviral nucleoside lamivudine.Antimicrob Agents Chemother 43:1947–1954

    PubMed  CAS  Google Scholar 

  190. Tatti KM, Korba BE, Stang HL, Peek S, Gerin JL, Tennant BC, Schinazi RF (2002) Mutations in the conserved woodchuck hepatitis virus polymerase FLLA and YMDD regions conferring resistance to lamivudine.Antiviral Res 55:141–150

    PubMed  CAS  Google Scholar 

  191. Cullen JM, Li DH, Brown C, Eisenberg EJ, Cundy KC, Wolfe J, Toole J, Gibbs C (2001) Antiviral efficacy and pharmacokinetics of oral adefovir dipivoxil in chronically woodchuck hepatitis virus-infected woodchucks.Antimicrob Agents Chemother 45:2740–2745

    PubMed  CAS  Google Scholar 

  192. Jacob JR, Korba BE, Cote PJ, Toshkov I, Delaney WE 4th, Gerin JL, Tennant BC (2004) Suppression of lamivudine-resistant B-domain mutants by adefovir dipivoxil in the woodchuck hepatitis virus model.Antiviral Res 63:115–121

    PubMed  CAS  Google Scholar 

  193. Menne S, Cote PJ, Korba BE, Butler SD, George AL, Tochkov IA, Delaney WE 4th, Xiong S, Gerin JL, Tennant BC (2005) Antiviral effect of oral administration of tenofovir disoproxil fumarate in woodchucks with chronic woodchuck hepatitis virus infection.Antimicrob Agents Chemother 49:2720–2728

    PubMed  CAS  Google Scholar 

  194. Menne S, Asif G, Narayanasamy J, Butler SD, George AL, Hurwitz SJ, Schinazi RF, Chu CK, Cote PJ, Gerin JL et al (2007) Antiviral effect of orally administered (–)-beta-D-2-aminopurine dioxolane in woodchucks with chronic woodchuck hepatitis virus infection.Antimicrob Agents Chemother 51:3177–3184

    PubMed  CAS  Google Scholar 

  195. Colono RJ, Genovesi EV, Medina I, Lamb L, Durham SK, Huang ML, Corey L, Littlejohn M, Locamini S, Tennant BC et al (2001) Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection.J Infect Dis 184:1236–1245

    Google Scholar 

  196. Menne S, Roneker CA, Korba BE, Gerin JL, Tennant BC, Cote PJ (2002) Immunization with surface antigen vaccine alone and after treatment with 1-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)-uracil (L-FMAU) breaks humoral and cell-mediated immune tolerance in chronic woodchuck hepatitis virus infection.J Virol 76:5305–5314

    PubMed  CAS  Google Scholar 

  197. Liaw Y-F, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON et al (2004) Lamivudine for patients with chronic hepatitis B and advance liver disease.N Engl J Med 351:1521–1531

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Sciences, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA

    Bud C. Tennant & William E. Hornbuckle

  2. Department of Molecular Virology and Immunology, Georgetown University Medical School, Washington, DC, 20057, USA

    John L. Gerin

Authors
  1. Bud C. Tennant
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William E. Hornbuckle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John L. Gerin
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Bayer AG, 51368, Leverkusen, Germany

    Olaf Weber

  2. Institute of Virology, Technical University Munich/Helmholtz Center Munich, Trogerstr. 30, 81675, München, Germany

    Ulrike Protzer

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Birkhäuser Verlag Basel/Switzerland

About this chapter

Cite this chapter

Tennant, B.C., Hornbuckle, W.E., Gerin, J.L. (2008). The woodchuck model of hepadnavirus infection. In: Weber, O., Protzer, U. (eds) Comparative Hepatitis. Birkhäuser Advances in Infectious Diseases. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8558-3_13

Download citation

Publish with us

Policies and ethics

Search

Navigation