Hepatitis B Virus Transgenic Mice: Models of Viral Immunobiology and Pathogenesis

  • F. V. Chisari
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 206)

Abstract

The hepatitis B virus (HBV) is a noncytopathic, enveloped virus with a circular, double-stranded DNA genome that causes acute and chronic necroinflammatory liver disease and hepatocellular carcinoma (reviewed in CHISARI and FERRARI 1994). HBV infection acquired in adult life is often clinically inapparent and the vast majority of acutely infected adults recover completely from the disease and clear the virus. Rarely, however, the acute liver disease may be so severe that the patient can die from fulminant hepatitis. Approximately 5%–10% of acutely infected adults become persistently infected by the virus and develop chronic liver disease of varying severity. Neonatally transmitted HBV infection, however, is rarely cleared, and over 90% of such children become chronically infected. Because HBV is commonly spread from infected mother to newborn infant in highly populated areas of Africa and Asia, several hundred million people throughout the world are persistently infected by HBV for most of their lives and suffer varying degrees of chronic liver disease which greatly increases their risk of developing cirrhosis and hepatocellular carcinoma (HCC). Indeed, the risk of HCC is increased 100-fold in patients with chronic hepatitis, and the lifetime risk of HCC in males infected at birth approaches 40% (BEASLEY ET AL. 1981). Accordingly, a large fraction of the world’s population suffers and dies from these late complications of HBV infection.

Keywords

Hepatitis Codon Sarcoma Polypeptide Interferon 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alexander GJ, Eddieston AL (1986) Does maternal antibody to core antigen prevent recognition of transplacental transmission of hepatitis-B-virus infection2. Lancet 1: 296–297PubMedCrossRefGoogle Scholar
  2. Alter HJ (1988) Transfusion-associated non-A, non-B hepatitis: the first decade. In: Zuckerman AJ (ed) Viral hepatitis and liver disease. Liss, New York, pp 534–Google Scholar
  3. Ando K, Moriyama T, Guidotti LG, Wirth S, Schreiber RD, Schlicht HJ, Huang S, Chisari FV (1993) Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J Exp Med 178: 1541–1554PubMedCrossRefGoogle Scholar
  4. Ando K, Guidotti LG, Cerny A, Ishikawa T, Chisari FV (1994a) CTL access to tissue antigen is restricted in vivo. J Immunol 153: 482–488PubMedGoogle Scholar
  5. Ando K, Guidotti LG, Wirth S, Ishikawa T, Missale G, Moriyama T, Schreiber RD, Schlicht HJ, Huang S, Chisari FV (1994b) Class I restricted cytotoxic T lymphocytes are directly cytopathic for their target cells in vivo. J Immunol 152: 3245–3253PubMedGoogle Scholar
  6. Araki K, Miyazaki J-I, Hino O, Tomita N, Chisaka O, Matsubara K, Yamamura K-I (1989) Expression and replication of hepatitis B virus genome in transgenic mice. Proc Natl Acad Sci USA 86: 207–211PubMedCrossRefGoogle Scholar
  7. Babinet C, Farza H, Morello D, Hadchouel M, Pourcel C (1985) Specific expression of hepatitis B surface antigen (HBsAg) in transgenic mice. Science 230: 1160–1163PubMedCrossRefGoogle Scholar
  8. Bartenschlager R, Junker-Niepmann M, Schaller H (1990) The P gene product of hepatitis B virus is required as a structural component for genomic RNA encapsidation. J Virol 64: 5324–5332PubMedGoogle Scholar
  9. Bavand MR, Laub O (1988) Two proteins with reverse transcriptase activities associated with hepatitis B virus-like particles. J Virol 62: 626–628PubMedGoogle Scholar
  10. Bavand Mr, Feitelson M, Laub O (1989) The hepatitis B virus-associated reverse transcriptase is encoded by the viral pol gene. J Virol 63: 1019–1021PubMedGoogle Scholar
  11. Beasley RP, Lin C-C, Hwang LY, Chen C-S (1981) Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22, 707 men in Taiwan. Lancet 2: 1129–1133PubMedCrossRefGoogle Scholar
  12. Blum HE, Zhang Z-S, Galun E, von Weizsäcker F, Garner B, Liang TJ, Wands JR (1992) Hepatitis B virus X protein is not central to the viral life cycle in vitro. J Virol 66: 1223–1227PubMedGoogle Scholar
  13. Bosch V, Bartenschlager R, Radziwill G, Schaller H (1988) The duck hepatitis B virus P-gene codes for protein strongly associated with the 5’-end of the viral DNA minus strand. Virology 166Google Scholar
  14. Burk RD, DeLoia JA, ElAwady MK, Gearhart JD (1988) Tissue preferential expression of the hepatitis B virus (HBV) surface antigen gene in two lines of HBV transgenic mice. J Virol 62: 649–654PubMedGoogle Scholar
  15. Carlson J, Eriksson S (1985) Chronic “cryptogenic” liver disease and malignant hepatoma in intermediate alpha-1-antitrypsin deficiency identified by a pi 2-specific monoclonal antibody. Scand J Gastroenterol 20: 835–841PubMedCrossRefGoogle Scholar
  16. Chemin I, Baginski I, Vermot-Desroches C, Hantz O, Jacquet C, Rigal D, Trepo C (1992) Demonstration of woodchuck hepatitis virus infection of peripheral blood mononuclear cells by flow cytometry and polymerase chain reaction. J Gen Virol 73: 123–129PubMedCrossRefGoogle Scholar
  17. Chen HS, Knew MC, Hornbuckle WE, Tenant BC, Cote PJ, Gerin JL, Purcell RH, Miller RH (1992) The precore gene of the woodchuck hepatitis virus genome is not essential for viral replication in the natural host. J Virol 66: 5682–5684PubMedGoogle Scholar
  18. Chen HS, Kaneko S, Girones R, Anderson RW, Hornbuckle WE, Tenant BC, Cote PJ, Gerin JL, Purcell RH, Miller RH (1993) The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks. J Virol 67: 1218–1226PubMedGoogle Scholar
  19. Chen HS, Kaneko S, Girones R, Anderson RW, Hornbuckle WE, Tennant BC, Cote PJ, Gerin JL, Purcell RH, Miller RH (1994) The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks. J Virol 67: 1218–1226Google Scholar
  20. Chisari FV (1991) Analysis of hepadnavirus gene expression, biology and pathogenesis in the transgenic mouse. Curr Top Microbiol Immunol 168: 85–101PubMedGoogle Scholar
  21. Chisari FV, Ferrari C (1994) Immunobiologyand pathogenesis of viral hepatitis. In: Nathenson N Ahmed R, Gonzatez-Scarano F, Griffin D, Holmes K, Murphy FA, Robinson H (eds) Viral pathogenesis. Raven New York, (in press)Google Scholar
  22. Chisari FV, Pinkert CA, Milich DR, Filippi P, McLachlan A, Palmiter RD, Brinster RL (1985) A transgenic mouse model of the chronic hepatitis B surface antigen carrier state. Science 230: 1157–1160PubMedCrossRefGoogle Scholar
  23. Chisari FV, Filippi P, McLachlan A, Milich DR, Riggs M, Lee S, Palimiter RD, Pinker CA, Brinster RL (1986) Expression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic mice. J Virol 60: 880–887PubMedGoogle Scholar
  24. Chisari FV, Filippi P, Buras J, MclLlachlan A, Popper H, Pinkert CA, Palmiter RD, Brinstaer RL (1987) Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. Proc Natl Acad Sci USA 84: 6909–6913PubMedCrossRefGoogle Scholar
  25. 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: 1145–1156PubMedCrossRefGoogle Scholar
  26. Colgrove R, Simon G, Ganem D (1989) Transcriptional activation of homologous and heterologous genes by the hepatitis B virus X gene product in cells permissive for viral replication. J Virol 63: 4019–4026PubMedGoogle Scholar
  27. Condreay LD, Aldrich CE, Coates L, Mason WS, Wu T-T (1990) Efficient duck hepatitis B virus production by an avian liver tumor cell line. J Virol 64: 3249–3258PubMedGoogle Scholar
  28. 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: 3138–3144PubMedGoogle Scholar
  29. DeLoia JA, Burk RD, Gearhart JD (1989) Developmental regulation of hepatitis B surface antigen expression in two lines of hepatitis B virus transgenic mice. J Virol 63: 4069–4073Google Scholar
  30. Dunsford HA, Sell S, Chisari FV (1990) Hepatocarcinogenesis due to chronic liver cell injury in hepatitis B virus transgenic mice. Cancer Res 50: 3400–3407PubMedGoogle Scholar
  31. Dycaico MJ, Grant SG, Felts K, Nichols WS, Geller SA, Hager JH, Pollard AJ, Kohler SW, Short HP, Jirik FR et al. (1988) Neonatal hepatitis induced by alpha 1-antitrypsin: a transgenic mouse model. Science 242: 1409–1412PubMedCrossRefGoogle Scholar
  32. Eble BE, Lingappa VR, Ganem D (1986) Hepatitis B surface antigen: an unusual secreted protein initially synthesized as a transmembrane polypeptide. Model Cell Biol 6: 1454–1463Google Scholar
  33. Eble BE, MacRae DR, Lingappa VR, Ganem D (1987) Multiple topogenic sequences determine the transmembrane orientation of hepatitis B surface antigen. Mol Cell Biol 7: 3591–3601PubMedGoogle Scholar
  34. Eckhardt SG, Milich DR, McLachlan A (1991) Hepatitis B virus core antigen has two nuclear localization sequences in the arginine-rich carboxyl terminus. J Virol 65: 575–582PubMedGoogle Scholar
  35. Eriksson S, Carlson J, Velez RN (1986) Risk of cirrhosis and primary liver cancer in alpha-1-antrypsin deficiency. N Engl J Med 314: 736–740PubMedCrossRefGoogle Scholar
  36. Etiemble J, Degott C, Renard CA, Fourel G, Shamoon B, Vitvitski-Trepo L, Hsu TY, Tiollais P, Babinet C, Buendia MA (1994) Liver-specific expression and high oncogenic efficiency of a c-myc transgene activated by woodchuck hepatitis virus insertion. Oncogene 9: 727–737PubMedGoogle Scholar
  37. Farza H, Salmon AM, Hadchouel M, Moreau, Babinet C, Tiollais P, Pourcel C (1987) Hepatitis B surface antigen gene expression is regulated by sex steroids and glucocorticoids in transgenic mice. Proc Natl Acad Sci USA 84: 1187–1191PubMedCrossRefGoogle Scholar
  38. Farza H, Hadchouel M, Scotto J, Tiollais P, Babinet C, Pourcel C (1988) Replication and gene expression of hepatitis B virus in a transgenic mouse that contains the complete viral genome. J Virol 62: 4144–4152PubMedGoogle Scholar
  39. Filippi P, Buras J, McLachlan A, Popper H, Pinkert CA, Palmiter RD, Brinster RL, Chisari FV (1988) Overproduction of hepatitis B virus large envelope polypeptide causes filament storage, ground glass cell formation, hepatocellular injury and nodular hyperplasia in transgenic mice, In: Zucker-man AJ (ed) Viral hepatitis and liver disease. Liss, New York, PP 632–Google Scholar
  40. Franco A, Paroli M, Testa U, Benvenuto R, Peschle CM, Balsano F, Bamaba V (1992) Transferrin receptor mediates uptake and presentation of hepatitis B envelope antigen by T lymphocytes. J Exp Med 175: 1195–1205PubMedCrossRefGoogle Scholar
  41. Fukuda R, Okinaga S, Akagi S, Hidaka M, Ono N, Fukumoto S, Shimada Y (1988) Alteration of infection pattern of duck hepatitis B virus by immunomodulatory drugs. J Med Virol 26: 387–396PubMedCrossRefGoogle Scholar
  42. Gerber MA, Hadziyannis S, Vissoulis C, Schaffner F, Paronetto F, Popper H (1974a) Hepatitis B antigen: nature and distribution of cytoplasmic antigen in hepatocytes of carriers (37912). Proc Soc Exp Biol Med 145: 863–867PubMedGoogle Scholar
  43. Gerber MA, Hadziyannis S, Vissoulis C, Schaffner F, Paronetto F, Popper H (1974b) Electron microscopy and immunoelectron microscopy of cytoplasmic hepatitis B antigen in hepatocytes. Am J pathol 175: 489–502Google Scholar
  44. Gilles PN, Fey G, Chisari FV (1992a) Tumor necrosis factor-alpha negatively regulates hepatitis B virus gene expression in transgenic mice. J Virol 66: 3955–3960PubMedGoogle Scholar
  45. Gilles PN, Guerrette DL, Ulevitch RJ, Schreiber RD, Chisari FV (1992b) Hepatitis B surface antigen retention sensitizes the hepatocyte to injury by physiologic concentrations of gamma interferon. Hepatology 16: 655–663PubMedCrossRefGoogle Scholar
  46. Guidotti LG, Ando K, Hobbs MV, Ishikawa T, Runkel RD, Schreiber RD, Chisari FV (1994a) Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgeneic mice. Proc Natl Acad Sci USA 91: 3764–3768PubMedCrossRefGoogle Scholar
  47. Guidotti LG, Guilhot S, Chisari FV (1994b) Interleukin 2 and interferon alpha/beta downregulate hepatitis B virus gene expression in vivo by tumor necrosis factor dependent and independent pathways. J Virol 68: 1265–1270PubMedGoogle Scholar
  48. Guidotti LG, Martinez V, Loh YT, Rogler CE, Chisari FV (1994c) Hepatitis B virus nucleocapsid particles do not cross the hepatocyte nuclear membrane in transgenic mice. J Virol 68: 5469–5475PubMedGoogle Scholar
  49. Guilhot S, Guidotti LG, Chisari FV (1993) lnterleukin-2 downregulates hepatitis B virus gene expression in transgenic mice by a post-transcriptional mechanism. J Virol 67: 7444–7449PubMedGoogle Scholar
  50. Guilhot S, Huang S, Xia YP, LaMonica N, Lai MMC, Chisari FV (1994) Expression of the hepatitis delta virus and small antigens in transgenic mice. J Virol 68: 1052–1058PubMedGoogle Scholar
  51. Hagen TM, Wehr C, Huang SN, Fowler P, Martine ZV, Curnutte J, Anes BN, Chisari FV (1994) Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. Proc Natl Acad Sci USA 97: 12808–12812CrossRefGoogle Scholar
  52. Haritanin H, Uchida T, Okuda Y, Shikata T (1989) Effect of 3′-azido-3-deoxythmidine on replication of duck B virus in vivo and in vitro. J Med Virol 29: 244–248CrossRefGoogle Scholar
  53. Hertogs K, Lenders WPJ, Depla E, DeBruin WCC, Meheus L, Raymackers J, Moshage H, Yap SH (1993) Endonexin II, present on human liver plasma membranes, is a specific binding protein of small hepatitis B virus envelope protein. Virology 197: 549–557PubMedCrossRefGoogle Scholar
  54. Hino O, Nomura K, Ohtake K, Kawaguchi T, Sugano H, Kitagawa T (1989) Instability of integrated hepatitis B virus DNA with inverted repeat structure in a transgenic mouse. Cancer Genet Cytogenet 37: 273–278PubMedCrossRefGoogle Scholar
  55. Hirsch RC, Lavine JE, Chang L, Varmus HE, Ganem D (1990) Polymerase gene products of hepatitis B viruses are required for genomic RNA packaging as well as for reverse transcription. Nature 344: 552–555PubMedCrossRefGoogle Scholar
  56. Höhne M, Schaefer S, Seifer M, Feitelson MA, Paul D, Gerlich WH (1990) Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA. EMBO J 9: 1137–1145PubMedGoogle Scholar
  57. Homburger F, Russfield AB, Weisburger JH, Lim S, Chak SP, Weisburger EK (1975) Aging changes in CD1 HaM/ICR mice reared under standard laboratory conditions. J Natl Cancer Inst 55: 37–45PubMedGoogle Scholar
  58. Jean-Jean O, Weimer T, De Recondo AM, Will H, Rossignol JM (1989) Internal entry of ribosomes and ribosomal scanning involved in hepatitis B virus P gene expression. J Virol 63: 5451–5454PubMedGoogle Scholar
  59. Jilbert AR, Wu T-T, England JM, De La M, Hall P, Carp NZ, O’Connell AP, Mason WS (1992) Rapid resolution of duck hepatitis B virus infections occurs after massive hepatocellular involvement. J Virol 66: 1377–1388PubMedGoogle Scholar
  60. Junker-Niepmann M, Bartechlager R, Schaller H (1990) A short cis-acting sequence is required for hepatitis B virus progenome encapsidation and sufficient for packaging of foreign RNA. EMBO J 9: 3389–3396PubMedGoogle Scholar
  61. Kawamoto S, Yamamoto S, Ueda K, Nagahata T, Chisaka O, Matsubara K, (1990) Translation of hepatitis B virus DNA polymerase from the internal AUG codon, not from the upstream AUG codon for the core protein. Biochem Biophys Res Commun 171: 1130–1136PubMedCrossRefGoogle Scholar
  62. Kim C-M, Koike K, Saito I, Miyamura T, Jay G (1991) HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351: 317–320PubMedCrossRefGoogle Scholar
  63. Koike K, Moriya K, lino S, Yotsuyanagi H, Endo Y, Miyammura T, Hurokawa K (1994) High level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice. Hepatology. 19: 810–819PubMedCrossRefGoogle Scholar
  64. Korba BE, Wells F, Tennant BC, Yoakum GH, Purcell RH, Gerin JL (1986) Hepadnavirus infection of peripheral blood lymphocytes in vivo: woodchuck and chimpanzee models of viral hepatitis. J Virol 58: 1–8PubMedGoogle Scholar
  65. Korba BE, Wells F, Tennant BC, Cote PJ, Gerin JL (1987) Lymphoid cells in the spleens of woodchuck hepatitis virus-infected woodchucks are a site of active viral replication. J Virol 61: 1318–1324PubMedGoogle Scholar
  66. Korba BE, Cote PJ, Wells FV, Baldwin B, Popper H, Purcell RH, Tennant BC, Gerin JI (1989) Natural history of woodchuk hepatitis virus infections during the course of experimental viral infection: molecular virologie features of the liver and lymphoid tissues. J Virol 63: 1360–1370PubMedGoogle Scholar
  67. Korba BE, Brown TL, Wells FV, Baldwin B, Cote PJ, Steinberg H, Tennant BC, Gerin JL (1990) Natural history of experimental woodchuck hepatitis virus infection: molecular virologie features of the pancreas, kidney, ovary, and testis. J Virol 64: 4499–4506PubMedGoogle Scholar
  68. Kuo MT, Zou J-Y, Teeter LD, Ikeguchi M, Chisari FV (1992) Activation of multidrug resistance (P-glycoptotein) mdr3/mdrla gene during the development of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell Growth Differ 3: 531–540PubMedGoogle Scholar
  69. Lavine J, Hirsch R (1989) A system for studying the selective encapsidation of hepadnavirus FNA. J Virol 63: 4257–4263PubMedGoogle Scholar
  70. Lee T-H, Finegold MJ, Shen R-F, DeMayo JL, Woo SL, Butel JS (1990) Hepatitis B virus transactivator X protein is not tumorigenic in transgenic mice. J Virol 64: 5939–5947PubMedGoogle Scholar
  71. Lieber CS, Garro A, Leo MA, Mak KM, Worner T (1986) Alcohol and cancer. Hepatology 6: 1005–1019PubMedCrossRefGoogle Scholar
  72. Lien J-M, Aldrich CE, Mason WS (1986) Evidence that a capped oligoribonucleotide is the primer for duck hepatitis B virus plus-strand DNA synthesis. J Virol 57: 229–236PubMedGoogle Scholar
  73. Limmer J, Fleig WE, Leupold D, Bittner R, Ditscheunest H, Berger H-G (1988) Hepatocellular carcinoma in type 1 glycogen storage disease. Hepatology 8: 531–537PubMedCrossRefGoogle Scholar
  74. Machida A, Kishimoto S, Ohnuma H, Miyamoto H, Baba K, Oda K, Nakamura T, Miyakawa Y, Mayumi M (1983) A hepatitis B surface antigen polypeptide (P31) with the receptor for polymerized human as well as chimpanzee albumins. Gastroenterology 85: 268–274PubMedGoogle Scholar
  75. Mack DH, Bloch W, Nath N, Sninsky JJ (1988) Hepatitis B virus particles contain a polypeptide encoded by the largest open reading frame: a putative reverse transcriptase. J Virol 62: 4768–4790Google Scholar
  76. Maguire HF, Hoeffler JP, Siddiqui A (1991) HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science 252: 842–844PubMedCrossRefGoogle Scholar
  77. Mancini M, Hadchouel M, Tiollais P, Pourcel C, Michel ML (1993) Induction of anti-hepatitis B surface antigen (HBsAg) antibodies in HBsAg producing transgenic mice: a possible way of circumventing “nonresponse” to HBsAg. J Med Virol 39: 67–74PubMedCrossRefGoogle Scholar
  78. Marion PL, Oshiro LS, Regnery DC, Scullard GH, Robinson WS (1980) A virus in Beechey ground squirrels which is related to hepatitis B virus of man. Proc Natl Acad Sci USA 77: 2941–2945PubMedCrossRefGoogle Scholar
  79. 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: 4543–4546PubMedCrossRefGoogle Scholar
  80. Mason WS, Seal S, Summers J (1980) Virus of Pekin ducks with structural and biological relatedness to human hepatitis B virus. J Virol 36: 829–836PubMedGoogle Scholar
  81. Mason WS, Aldrich C, Summers J et al. (1982) Asymmetric replication of duck hepatitis B virus DNA in liver cells (free minus-strand DNA). Proc Natl Acad Sci USA 79: 3997–4001PubMedCrossRefGoogle Scholar
  82. Mason WS, Halpern MS, England JM, Seal G, Egan J, Coates L, Aldrich C, Summers J (1983) Experimental transmission of duck hepatitis B virus. Virology 131: 375–384PubMedCrossRefGoogle Scholar
  83. McLachlan A, Milich DR, Raney AK, Riggs MG, Hughes JL, Sorage J, Chisari FV (1987) Expression of hepatitis B virus surface and core antigens: influences of pre-S and precore sequences. J Virol 61: 683–780PubMedGoogle Scholar
  84. Mehdi H, Kaplan MJ, Anlar FY, Yang X, Bayer R, Sutherland K, Peeples ME (1994) Hepatitis B virus surface antigen binds to apolipoprotein H. J Virol 68: 2415–2424PubMedGoogle Scholar
  85. Melia WM, Wilkinson ML, Portmann BC, Johnson PJ, Williams R (1984) Hepatocellular carcinoma in the non-cirrhotic liver: a comparison with that complicating cirrhosis. Q J Med 53: 391–400PubMedGoogle Scholar
  86. Milich DR, Jones JE, Hughes JL, Price J, Raney AK, McLachlan A (1990) Is a funtion of the secreted hepatitis B antigen to induce immunologie tolerance in utero? Proc Natl Acad Sci USA 87: 6599–6603PubMedCrossRefGoogle Scholar
  87. Milich DR, Jones JE, Hughes JL, Maruyama T, Price J, Melhado I, Jirik F (1994) Extrathymic expression of the intracellular hepatitis B core antigen results in T cell tolerance in transgenic mice. J Immunol 152: 455–466PubMedGoogle Scholar
  88. Miller RH, Marion PL, Robinson WS (1984a) Hepatitis B viral DNA-RNA hybrid molecules in particles from infected liver are converted to viral DNA molecules during an endogenous DNA polymerase reaction. Virology 139: 64–72PubMedCrossRefGoogle Scholar
  89. Miller RH, Tran C-T, Robinson WS (1984b) Hepatitis B virus particles of plasma and liver contain viral DNA-RNA hybrid molecules. Virology 139: 53–63PubMedCrossRefGoogle Scholar
  90. Molnar-Kimber KL, Summers JW, Mason WS (1984) Mapping of the cohesive overlap of duck hepatitis B virus DNA and of the site of initiation of reverse transcription. J Virol 51: 181–191PubMedGoogle Scholar
  91. Molnar-Kimber KL, Jarocki-Witek V, Dheer SK, Vernon SK, Conley AJ, Davis AR, Hung PP (1988) Distinctive properties of the hepatitis B virus envelope proteins. J Virol 62: 407–416PubMedGoogle Scholar
  92. 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: 361–364PubMedCrossRefGoogle Scholar
  93. Nassal M (1992) The arginine-rich domain of the hepatitis B virus core protein is required for pregenome encapsidation and productive viral positive-strand DNA synthesis but not for virus assembly. J Virol 66: 4107–4116PubMedGoogle Scholar
  94. Negro F, Korba BE, Forzani B, Baroudy BM, Brown TL, Gerin JL, Ponzetto A (1989) Hepatitis delta virus (HDV) and woodchuck hepatitis virus (WHV) nucleic acids in tissues of HDV-infected chronic WHV carrier woodchucks. J Virol 63: 1612–1618PubMedGoogle Scholar
  95. Neurath AR, Kent SB, Strick N, Parker K (1986) Identification and chemical synthesis of a host cell receptor binding site on hepatitis B virus. Cell 46: 429–436PubMedCrossRefGoogle Scholar
  96. Neurath AR, Strick N, Sproul P (1992) Search for hepatitis B virus cell receptors reveals binding sites for interleukin 6 on the virus envelope protein. J Exp Med 175: 461–469PubMedCrossRefGoogle Scholar
  97. Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G (1985) Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 313: 1256–1262PubMedCrossRefGoogle Scholar
  98. Niu J, Wang Y, Qiao M, Gowans E, Edwards P, Thyagarajan SP, Gust I, Locamini S (1990) Effect of Phyllanthus amarus on duck hepatitis B virus replication in vivo. J med Virol 32: 212–218PubMedCrossRefGoogle Scholar
  99. Ou J-H, Rutter WJ (1987) Regulation of secretion of the hepatitis B virus major surface antigen by the preS-1 protein. J Vitrol 61: 782–786Google Scholar
  100. Ou J-H, Yeh CT, Yen TSB (1989) Transport of hepatitis B virus precore protein in to the nucleus after cleavage of its signal peptide. J Virol 63: 5238–5243PubMedGoogle Scholar
  101. Pasquinelli C, Bhavani K, Chisari FV (1992) Multiple oncogenes and tumor suppressor genes are structurally and functionally intact during hepatocarcinogenesis in hepatitis B virus transgenic mice. Cancer Res 52: 2823–2829PubMedGoogle Scholar
  102. Patzer EJ, Nakamura GR, Yaffe A (1984) Intracellular transport and secretion of hepatitis B surface antigen in mammalian cells. J Virol 51: 346–353PubMedGoogle Scholar
  103. Patzer EJ, Nakamura GR, Simonsen CC, Levinson AD, Brands R (1986) Intracellular assembly and packaging of hepatitis B surface antigen particles occur in the endoplasmic reticulum. J Virol 58: 884–892PubMedGoogle Scholar
  104. Petcu DJ, Aldrich CE, Coates L, Taylor JM, Mason WS (1988) Suramin inhibits in vitro infection by duck hepatitis B virus, Rous sarcoma virus, and hepatitis delta virus. Virology 167: 385–392PubMedGoogle Scholar
  105. Popper H, Roth L, Purcell RH, Tennant BC, Gerin JL (1987) Hepatocarcinogenicity of the woodchuck hepatitis virus. Proc Natl Acad Sci USA 84: 866–870PubMedCrossRefGoogle Scholar
  106. Potts RC, Sherif MM, Robesrton AJ, Gibbs JH, Brown RA, Beck JS (1981) Serum inhibitory factor in lepromatous leprosy: its effect on the pre-S-phase cell-cycle kinetics of mitogen-stimulated normal human lymphocytes. Scand J Immunol 14: 269–280PubMedCrossRefGoogle Scholar
  107. Robinson WS, Miller RH, Marion PL (1987) Hepadnaviruses and retroviruses share genome homology and features of replication. Hepatology 7: 64S–73SPubMedCrossRefGoogle Scholar
  108. Rosenthal N, Kress M, Gruss P et al. (1983) BK, viral enhancer element and a human cellular homology. Science 222: 749–755Google Scholar
  109. Schirmacher P, Held WA, Chisari FV, Yang D, Rogler CE (1992) Reactivation of insulin-like growth factor II during hepatocarcinogenesis in transgenic mice suggests a role in malignant growth. Cancer Res 52: 2549–2556PubMedGoogle Scholar
  110. Schlicht HJ, Schaller H (1989) The secretory core protein of human hepatitis B virus is expressed on the cell surface. J Virol 63: 5399–5404PubMedGoogle Scholar
  111. Schlicht HJ, Radziwill G, Schaller H (1989) Synthesis and encapsidation of duck hepatitis B virus reverse transcriptase do not require formation of core-polymerase fusion proteins. Cell 56: 85–92PubMedCrossRefGoogle Scholar
  112. Seeger C, Ganem D, Varmus HE (1986) Biochemical and genetic evidence for the hepatitis B virus replication strategy. Science 232: 477–484PubMedCrossRefGoogle Scholar
  113. Seifer M, Zhou S, Standring DN (1993) A micromolar pool of antigenically distinct precursors is required to initiate cooperative assembly of hepatitis B virus capsids in Xenopus oocytes. J Virol 67: 249–257PubMedGoogle Scholar
  114. Sell S, Hunt JM, Dunsford HA, Chisari FV (1991) Synergy between hepatitis B virus expression and chemical hepatocarcinogens in transgenic in mice. Cancer Res 51: 1278–1285PubMedGoogle Scholar
  115. Seto E, Yen TSB, Peterlin BM, Ou J-H (1988) Trans-activation of the human immunodeficiency virus long terminal repeat by the hepatitis B virus X protein. Proc Natl Acad Sci USA 85: 8286–8290PubMedCrossRefGoogle Scholar
  116. Siddiqui A, Gaynor R, Srinivasan A, Mapoles J, Farr RW (1989) Transactivation of viral enhancers including long terminal repeat of the human immunodeficiency virus by the hepatitis B virus X protein. Virology 173: 764–766CrossRefGoogle Scholar
  117. Snyder RL, Summers J (1980) Woodchuck hepatitis virus and hepatocellular carcinoma. Cold Spring Harbor Conf Cell Proliferation 7: 447–458Google Scholar
  118. Spandau DF, Lee CH (1988) Transactivation of viral enhancers by the hepatitis B virus X protein. J Virol 62: 427–434PubMedGoogle Scholar
  119. Standring DN, Ou J-H, Rutter WJ (1986) Assembly of viral particles in Xenopus oocytes: pre-surface-antigens regulate secretion of the hepatitis B viral surface envelope particle. Proc Natl Acad Sci USA 83: 9338–9342PubMedCrossRefGoogle Scholar
  120. Standring DN, Ou J-H, Masiarz FR, Rutter WJ (1989) A signal peptide encoded within the precore region of hepatitis B virus directs the secretion of a heterogeneous population of e antigens in Xenopus oocytes. Proc Natl Acad Sci USA 85: 8405–8409CrossRefGoogle Scholar
  121. Summers J (1988) The replication cycle of hepatitis B viruses. Cancer 61: 1957–1962PubMedCrossRefGoogle Scholar
  122. Summers J, Mason WS (1982) Replication of the genome of a hepatitis B—like virus by reverse transcription of an RNA intermediate. Cell 29: 403–415PubMedCrossRefGoogle Scholar
  123. Tuttleman J, Pourcel C, Summers J (1986) Formation of the pool of covalently closed circular viral DNA in hepadnavirus infected cells. Cell 47: 451–460PubMedCrossRefGoogle Scholar
  124. Tuttlemen J, Pugh J, Summers J (1986) In vitro experimental infection of primary duck hepatocyte cultures with duck hepatitis B virus. J Virol 58: 17–25Google Scholar
  125. Twu JS, Schloemer RH (1987) Transcriptional trans-activating function of hepatitis B virus. J virol 61: 3448–3453PubMedGoogle Scholar
  126. Twu JS, Chu K, Robinson WS (1989) Hepatitis B virus X gene activated kB-like enhancer sequences in the long terminal repeat of human immunodeficiency virus 1. Proc Natl Aead Sci USA 86: 5168–5172CrossRefGoogle Scholar
  127. Unger T, Shaul Y (1990) The X protein of the hepatitis B virus acts as a transcription factor when targeted to its responsive element. EMBO J 9: 1889–1895PubMedGoogle Scholar
  128. Wang GH, Seeger C (1992) The reverse transcriptase of hepatitis B virus acts as a protein primer for viral DNA synthesis. Cell 71: 663–670PubMedCrossRefGoogle Scholar
  129. Wang GH, Seeger C (1993) Novel mechanism for reverse transcription in hepatitis B viruses. J Virol 67: 6506–6512Google Scholar
  130. Wang XW, Forrester K, Yeh H, Feitelson MA, Gu J-R, Harris CC (1994) Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity and associated with transcription factor ERCC3. Proc Natl Acad Sci USA 91: 2230–2234PubMedCrossRefGoogle Scholar
  131. Will H (1991) The X-protein of hepatitis B virus. Facts and fiction. J Hepatol 13 Suppl 4: S56–S57CrossRefGoogle Scholar
  132. Will H, Reiser W, Weimer T, Pfaff E, Buscher M, Sprengel R, Cattaneo R, Schaller H (1987) Replication strategy of human hepatitis B virus. J Virol 61: 904–911PubMedGoogle Scholar
  133. Wollersheim M, Debelka U, Hofschneider PH (1988) A transactivating function encoded in the hepatitis B virus X gene is conserved in the integrated state. Oncogene 3: 545–552PubMedGoogle Scholar
  134. Yamamura K, Tsurimoto T, Ebihara T, Kamino K, Fujiyama A, Ochiya T, Matsubara K (1987) Methylation of hepatitis B virus DNA and liver-specific suppression of RNA production in transgenic mouse. Jpn J Cancer Res 78: 681–688PubMedGoogle Scholar
  135. Yeh C-T, Liaw Y-F, Ou J-H (1990) The arginine-rich domain of hepatitis B virus precore and core proteins contains a signal for nuclear transport. J Virol 64: 6141–6147PubMedGoogle Scholar
  136. Yokota T, Konno K, Chonan E, Mochizuki S, Kojima K, Shigeta S, De Clercq E (1990) Comparative activates of several nucleoside analogs against duck hepatitis B virus in vitro. Antimicrob Agents Chemother 34: 1326–1330PubMedGoogle Scholar
  137. Zhou S, Standring DN (1991) Production of hepatitis B virus nucleocapsid like core particles in Xenopus oocytes: assembly occurs mainly in the cytoplasm and does not require the nucleus. J Virol 65: 5457–5464PubMedGoogle Scholar
  138. Zhou S, Standring DN (1992) Hepatitis B virus capsid particles are assembled from core-protein dimer precursors. Proc Natl Acad Sci USA 89: 10046–10050PubMedCrossRefGoogle Scholar
  139. Zhou S, Yang SQ, Standring DN (1992) Characterization of hepatitis B virus capsid particle assembly in Xenopus oocytes. J Virol 66: 3086–3092PubMedGoogle Scholar
  140. Zoulim F, Saputelli J, Seeger C (1994) Woodchuck hepatitis virus X protein is required for viral infection in vivo. J Virol 68: 2026–2030PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • F. V. Chisari
    • 1
  1. 1.Department of Molecular and Experimental MedicineThe Scripps Research InstituteLa JollaUSA

Personalised recommendations