Skip to main content
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1998 Feb;89(2):150–158. doi: 10.1111/j.1349-7006.1998.tb00543.x

Transgenic Mouse Expressing a Full‐length Hepatitis C Virus cDNA

Jun‐ichi Matsuda 1, Misao Suzuki 2, Chikateru Nozaki 1, Noriko Shinya 1, Kayo Tashiro 1, Kyousuke Mizuno 1, Youichi Uchinuno 1, Ken‐ichi Yamamura 2
PMCID: PMC5921765  PMID: 9548442

Abstract

Hepatitis C virus (HCV), a major causative agent of post transfusion non‐A, non‐B hepatitis (NANBH), can only infect humans and chimpanzees. We produced nine transgenic mouse lines carrying a full‐length HCV cDNA with the human serum amyloid P component (hSAP) promoter that can direct liver‐specific expression. In one of these lines HCV mRNA and HCV core protein were detected in the liver of the transgenic mouse, although the levels of expression were very low. In addition, HCV‐related antibody was detected in the serum.

Keywords: promoter, Hepatitis C virus, Transgenic mouse, Human serum amyloid P component (hSAP)

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

REFERENCES

  • 1. ) Saito , I. , Miyamura , T. , Ohbayashi , A. , Harada , H. , Katayama , T. , Kikuchi , S. , Watanabe , Y. , Koi , S. , Onji , M. , Ohta , Y. , Choo , Q.‐L. , Houghton , M. and Kuo , G.Hepatitis C virus infection is associated with the development of hepatocellular carcinoma . Proc. Natl. Acad. Sci. USA , 87 , 6547 – 6549 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. ) Kato , N. , Hijikata , M. , Ootsuyama , Y. , Nakagawa , M. , Ohkoshi , S. , Sugimura , T. and Shimotohno , K.Molecular cloning of the human hepatitis C virus genome from Japanese patients with non‐A, non‐B hepatitis . Proc. Natl. Acad. Sci. USA , 87 , 9524 – 9528 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. ) Choo , Q.‐L. , Richman , K. H. , Han , J. H. , Berger , K. , Lee , C. , Dong , C. , Gallegos , C. , Coit , D. , Medina‐Selby , A. , Barr , P. J. , Weiner , A. J. , Bradley , D. W. , Kuo , G. and Houghton , M.Genetic organization and diversity of the hepatitis C virus . Proc. Natl. Acad. Sci. USA , 88 , 2451 – 2455 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. ) Takamizawa , A. , Mori , C. , Fuke , I. , Manabe , S. , Murakami , S. , Fujita , J. , Onishi , E. , Andoh , T. , Yoshida , I. and Okayama , H.Structure and organization of hepatitis C virus genome isolated from human carriers . J. Virol. , 65 , 1105 – 1113 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. ) Spaete , R. R. , Alexander , D. , Rugroden , M. E. , Choo , Q.‐L. , Berger , K. , Crawford , K. , Kuo , C. , Leng , S. , Lee , C. , Ralston , R. , Thudium , K. , Tung , J. W. , Kuo , G. and Houghton , M.Characterization of the hepatitis C virus E2/NS1 gene product expressed in mammalian cells . Virology , 188 , 819 – 830 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Hijikata , M. , Kato , N. , Ootsuyama , Y. , Nakagawa , M. and Shimotohno , K.Gene mapping of the putative structural region of the hepatitis C virus genome by in vitro processing analysis . Proc. Natl. Acad. Sci. USA , 88 , 5547 – 5551 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Selby , M. J. , Choo , Q.‐L. , Berger , K. , Kuo , G. , Glazer , E. , Eckart , M. , Lee , C. , Chien , D. , Kuo , C. and Houghton , M.Expression, identification and subcellular localization of the proteins encoded by the hepatitis C viral genome . J. Gen. Virol. , 74 , 1103 – 1113 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Eckart , M. R. , Selby , M. , Masiarz , F. , Lee , C. , Berger , K. , Crawford , K. , Kuo , C. , Kuo , G. , Houghton , M. and Choo , Q.‐L.The hepatitis C virus encodes a serine protease involved in processing of the putative nonstructural proteins from the viral polyprotein precursor . Biochem. Biophys. Res. Commun. , 192 , 399 – 406 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Grakoui , A. , Wychowski , C. , Lin , C. , Feinstone , S. M. and Rice , C. M.Expression and identification of hepatitis C virus polyprotein . J. Virol. , 67 , 1385 – 1395 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. ) Grakoui , A. , McCourt , D. W. , Wychowski , C. , Feinstone , S. M. and Rice , C. M.Characterization of the hepatitis C virus‐encoded serine proteinase: determination of proteinase‐dependent polyprotein cleavage site . J. Virol. , 67 , 2832 – 2843 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. ) Shimizu , Y. K. , Purcell , R. H. and Yoshikura , H.Correlation between the infectivity of hepatitis C virus in vivo and its infectivity in vitro . Proc. Natl. Acad. Sci. USA , 90 , 6037 – 6041 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Ikeda , M. , Kato , N. , Mizutani , T. , Sugiyama , K. , Tanaka , K. and Shimotohno , K.Analysis of the cell tropism of HCV by using in vitro HCV‐infected human lymphocytes and hepatocytes . J. Hepatol. , 27 , 445 – 454 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Hijikata , M. , Mizuno , K. , Rikihisa , T. , Shimizu , Y. K. , Iwamoto , A. , Nakajima , N. and Yoshikura , H.Selective transmission of hepatitis C virus in vivo and in vitro . Jpn. Arch. Virol. , 140 , 1623 – 1628 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Kato , N. , Nakazawa , T. , Mizutani , T. and Shimotohno , K.Susceptibility of human T‐lymphotropic virus type I infected cell line MT‐2 to hepatitis C virus infection . Biochem. Biophys. Res. Commun. , 206 , 863 – 869 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Mizutani , T. , Kato , N. , Hirota , M. , Sugiyama , K. , Murakami , A. and Shimotohno , K.Inhibition of hepatitis C virus replication by antisense oligonucleotide in culture cells . Biochem. Biophys. Res. Commun. , 212 , 906 – 911 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Mizutani , T. , Kato , N. , Ikeda , M. , Sugiyama , K. and Shimotohno , K.Long‐term human T‐cell culture system supporting hepatitis C virus replication . Biochem. Biophys. Res. Commun. , 227 , 822 – 826 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Serafino , A. , Valli , M. B. , Alessandrini , A. , Ponzetto , A. , Carloni , G. and Bertolini , L.Ultrastructural observations of viral particles within hepatitis C virus‐infected human B lymphoblastoid cell line . Res. Virol. , 148 , 153 – 159 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Shimizu , Y. K. , Feinstone , S. M. , Kohara , M. , Purcell , R. H. and Yoshikura , H.Hepatitis C virus: detection of intra‐cellular virus particles by electron microscopy . Hepatology , 23 , 205 – 209 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Sugiyama , K. , Kato , N. , Mizutani , T. , Ikeda , M. , Tanaka , T. and Shimotohno , K.Genetic analysis of the hepatitis C virus (HCV) genome from HCV‐infected human T cells . J. Gen. Virol. , 78 , 329 – 336 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Zibert , A. , Schreier , E. and Roggendorf , M.Antibodies in human sera specific to hypervariable region 1 of hepatitis C virus can block viral attachment . Virology , 208 , 653 – 661 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Crbier , B. , Schmitt , C. , Bingen , A. , Kirn , A. and Keller , F.In vitro infection of peripheral blood mononuclear cells by hepatitis C virus . J. Gen. Virol. , 76 , 2485 – 2491 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Kato , N. , Ikeda , M. , Mizutani , T. , Sugiyama , K. , Noguchi , M. , Hirohashi , S. and Shimotohno , K.Replication of hepatitis C virus in cultured non‐neoplastic human hepatocytes . Jpn. J. Cancer Res. , 87 , 787 – 792 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. ) Dash , S. , Halim , A. B. , Tsuji , H. , Hiramatsu , N. and Gerber , M. A.Transfection of HepG2 cells with infectious hepatitis C virus genome . Am. J. Pathol. , 151 , 363 – 373 ( 1997. ). [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Lanford , R. E. , Sureau , C. , Jacob , J. R. , White , R. and Fuerst , T. R.Demonstration of in vitro infection of chimpanzee hepatocytes with hepatitis C virus using strand‐specific RT/PCR . Virology , 202 , 606 – 614 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Liu , Q. , Tackey , C. , Bhat , R. A. , Prince , A. M. and Zhang , P.Regulated processing of hepatitis C virus core protein is linked to subcellular localization . J. Virol. , 71 , 657 – 662 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. ) Barba , G. , Haraper , F. , Harada , T. , Kohara , M. , Goulinet , S. , Matsuura , Y. , Eder , G. , Schaff , Zs. , Chapman , M. J. , Miyamura , T. and Brechot , C.Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets . Proc. Natl. Acad. Sci. USA , 94 , 1200 – 1205 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. ) Ide , Y. , Zhang , L. , Chen , M. , Inchauspe , G. , Bahl , C. , Sasaguri , Y. and Padmanabhan , R.Characterization of the nuclear localization signal and subcellular distribution of hepatitis C virus nonstructural protein NS5A . Gene , 182 , 203 – 211 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Eithan , G. , Tatjana , B. , Mali , K. , Ido , L. , Elias , S. , Yuval , K. , Ahmed , E. , Yaron , I. , Avraham , R. , Galina , P. , Daniel , S. and Yair , R.Hepatitis C virus viremia in SCID‐BNX mouse chimera . J. Infect. Dis. , 172 , 25 – 30 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Yamamoto , M. , Hayashi , N. , Miyamoto , Y. , Takehara , T. , Mita , E. , Seki , M. , Fusamoto , H. and Kamada , T.In vivo transfection of hepatitis C virus complementary DNA into rodent liver by asialoglycoprotein receptor mediated gene delivery . Hepatology , 22 , 847 – 855 ( 1995. ). [PubMed] [Google Scholar]
  • 30. ) Takehara , T. , Hayashi , N. , Miyamoto , Y. , Yamamoto , M. , Mita , E. , Fusamoto , H. and Kamada , T.Expression of the hepatitis C virus genome in rat liver after cationic liposome‐mediated in vivo gene transfer . Hepatology , 21 , 746 – 751 ( 1995. ). [PubMed] [Google Scholar]
  • 31. ) Chisari , F. V. , Pinkert , C. A. , Milich , D. P. , Filippi , P. , McLachlan , A. , Palmiter , R. D. and Brinster , R. L.A transgenic mouse model of the chronic hepatitis B surface antigen carrier state . Science , 230 , 1157 – 1160 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Araki , K. , Miyazaki , J. , Hino , O. , Tomita , N. , Chisaka , O. , Matsubara , K. and Yamamura , K.Expression and replication of hepatitis B virus genome in transgenic mice . Proc. Natl. Acad. Sci. USA , 86 , 207 – 211 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. ) Koike , K. , Moriya , K. , Ishibashi , K. , Matsuura , Y. , Suzuki , T. , Saito , I. , Iino , S. , Kurokawa , K. and Miyamura , T.Expression of hepatitis C virus envelope proteins in transgenic mice . J. Gen. Virol. , 76 , 3031 – 3038 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Koike , K. , Moriya , K. , Ishibashi , K. , Yotsuyanagi , H. , Shintani , Y. , Fujie , H. , Kurokawa , K. , Matsuura , Y. and Miyamura , T.Sialadenitis histologically resembling Sjögren syndrome in mice transgenic for hepatitis C virus envelope genes . Proc. Natl. Acad. Sci. USA , 94 , 233 – 236 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. ) Pasquinelli , C. , Shoenberger , J. M. , Chung , J. , Chang , K. , Guidotti , L. G. , Selby , M. , Berger , K. , Lesniewski , R. , Hougton , M. and Chisari , F. V.Hepatitis C virus core and E2 protein expression in transgenic mice . Hepatology , 25 , 719 – 727 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 36. ) Kawamura , T. , Furusaka , A. , Koziel , M. J. , Chung , R. T. , Wang , T. C. , Schmida , E. V. and Liang , T. J.Transgenic expression of hepatitis C virus structural proteins in the mouse . Hepatology , 25 , 1014 – 1021 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 37. ) Moriya , K. , Yotsuyanagi , H. , Shintani , Y. , Fujie , H. , Ishibashi , K. , Matsuura , Y. , Miyamura , T. and Koike , K.Hepatitis C virus core protein induces hepatic steatosis in transgenic mice . J. Gen. Virol. , 78 , 1527 – 1531 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 38. ) Zhao , X. , Araki , K. , Jun‐ichi , M. and Yamamura , K.Developmental and liver‐specific expression directed by the serum amyloid P component promoter in transgenic mice . J. Biochem. , 111 , 736 – 738 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 39. ) Hayashi , N. , Higashi , H. , Kaminaka , K. , Sugimoto , H. , Esumi , M. , Komatsu , K. , Hayashi , K. , Sugitani , M. , Suzuki , K. , Okano , T. , Nozaki , C. , Mizuno , K. and Shikata , T.Molecular cloning and heterogeneity of the human hepatitis C virus genome . J. Hepatol. , 17 , 94 – 107 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 40. ) Ohnishi , S. , Maeda , S. , Shimada , K. and Arao , T.Isolation and characterization of the complete complementary and genomic DNA sequences of human serum amyloid P component . J. Biochem. , 100 , 849 – 858 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 41. ) Gordon , J. W. , Scangos , G. A. , Plotkin , D. J. , Barbosa , J. A. and Ruddle , F. H.Genetic transformation of mouse embryos by microinjection of purified DNA . Proc. Natl. Acad. Sci. USA , 77 , 7380 – 7384 ( 1980. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. ) Yamamura , K. , Kikutani , H. , Takahashi , N. , Taga , T. , Araki , S. , Kawai , K. , Fukuchi , K. , Kumahara , Y. , Honjo , T. and Kishimoto , T.Introduction of human gamma 1 immunoglobulin genes into fertilized mouse eggs . J. Biochem. , 96 , 357 – 363 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 43. ) Sambrook , J. , Fritsch , E. F. and Maniatis , T.Molecular cloning . In“A Laboratory Manual ,” 2nd Ed. , Vol. 7 , pp. 71 – 78 ( 1989. ). Cold Spring Harbor Laboratory Press; , New York . [Google Scholar]
  • 44. ) Kayhan , T. , Aria , N. , Sallie , R. , Sanger , D. , Graeme , J. , Alexander , M. , Smith , H. , Byrne , J. , Portmann , B. , Adrian , L. W. , Eddleston , F. and Williams , R.Detection of genomic and intermediate replicative strands of hepatitis C virus in liver tissue by in situ hybridization . J. Clin. Invest. , 91 , 2226 – 2234 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. ) Takashima , H. , Araki , K. , Miyazaki , J. , Yamamura , K. and Kimoto , M.Characterization of T‐cell tolerance to hepatitis B virus (HBV) antigen in transgenic mice . Immunology , 75 , 398 – 405 ( 1992. ). [PMC free article] [PubMed] [Google Scholar]
  • 46. ) Araki , K. , Hino , O. , Miyazaki , J. and Yamamura , K.Development of two types of hepatocellular carcinoma in transgenic mice carrying the SV40 large T‐antigen gene . Carcinogenesis , 12 , 2059 – 2062 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 47. ) Nakane , P. K. , Yamada , G. , Nishimoto , H. , Endou , H. , Doi , T. , Takahashi , M. , Tsuji , T. , Yoshizawa , H. , Nozawa , M. and Koji , T.Localization of hepatitis C viral RNA and capsid protein in human liver . Dig. Dis. Sci. , 38 , 882 – 887 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 48. ) Araki , K. , Akagi , K. , Miyazaki , J. , Matsubara , K. and Yamamura , K.Correlation of tissue‐specific methylation with gene inactivity in hepatitis B virus transgenic mice . Jpn. J. Cancer Res. , 81 , 1265 – 1271 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. ) Kato , T. , Ahmed , M. , Yamamoto , T. , Takahashi , H. , Dohara , M. , Ikeda , T. , Aida , Y. , Katsuki , M. , Arakawa , Y. , Shikata , T. and Esumi , M.Inactivation of hepatitis C virus cDNA transgene by hypermethylation in transgenic mice . Arch. Virol. , 141 , 951 – 958 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 50. ) Di Biscceglie , A. M. , Goodman , Z. D. , Ishak , K. G. , Hoofnagle , J. H. , Melpolder , J. J. and Alter , H.Long‐term clinical and histopathological follow‐up of chronic post‐transfusion hepatitis . Hepatology , 14 , 969 – 974 ( 1991. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES