1887

Abstract

In an attempt to establish a model for hepatitis C virus (HCV) infection, we produced mice transgenic for the HCV envelope genes, E1 and E2, under the control of a regulatory element from hepatitis B virus. F-generation mice from the established founders demonstrated expression of both E1 and E2 proteins as glycosylated forms in their organs including the liver. Immunostaining revealed the localization of envelope proteins principally in the cytoplasm of hepatocytes around the hepatic central veins. Furthermore, E1 and E2 proteins were shown by immunoprecipitation to be associated with each other in the mouse liver. There was no evidence of tissue pathology in the mouse liver up to 16 months of age, suggesting that E1 and E2 proteins may not have direct pathogenic effects. Our results demonstrate the first successful expression of HCV gene products in the mouse liver and the association of expressed HCV envelope proteins. This transgenic mouse would be a good model to study the virus-cell interactions of HCV such as intracellular transport and assembly of envelope proteins. Also it may be a good model system to determine the role of these proteins in the pathogenesis of hepatitis or extra-hepatic manifestations in HCV infection by the introduction of cytotoxic T lymphocytes specific for the envelope proteins.

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1995-12-01
2021-10-25
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References

  1. Agnello V., Chung R. T., Kaplan L. M. 1992; A role for hepatitis C virus infection in type II cryoglobulinemia. New England Journal of Medicine 321:1490–1495
    [Google Scholar]
  2. Alter H. J., Purcell R. H., Shih J. H., Melpolder J. C., Houghton M., Choo Q.-L., Kuo G. 1989; Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. New England Journal of Medicine 321:1494–1500
    [Google Scholar]
  3. Araki K., Miyazaki J., Hino O., Tomita O., Chisaka O., Matsubara K. 1989; Expression and replication of hepatitis B virus genome in transgenic mice. Proceedings of the National Academy of Sciences, USA 86:207–211
    [Google Scholar]
  4. Chiba J., Ohba H., Matsuura Y., Watanabe Y., Katayama T., Kikuchi S., Saito I., Miyamura T. 1991; Serodiagnosis of hepatitis C virus (HCV) infection with an HCV core protein molecularly expressed by a recombinant baculovirus. Proceedings of the National Academy of Sciences, USA 88:4641–1645
    [Google Scholar]
  5. Chisari F. V., Filippi P., McLachlan A., Milich D. R., Riggs M., Lees S., Palmiter R. D., Pinkert C. A., Brinster R. L. 1986; Expression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic mice. Journal of Virology 60:880–887
    [Google Scholar]
  6. Chisari F. V., Klopchin K., Moriyama T., Pasquinelli C., Dunsford H. A., Sell S., Pinkert C. A., Brinster R. L., Palmiter R. D. 1989; Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell 59:1145–1156
    [Google Scholar]
  7. Choo Q.-L., Kuo G., Weiner A. J., Overby L. R., Brady D. W., Houghton M. 1989; Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362
    [Google Scholar]
  8. Choo Q.-L., Kuo G., Ralston R., Weiner A., Chen D., van Nest G., Han J., Berger K., Thudium K., Kuo C., Houghton M. 1994; Vaccination of chimpanzees against infection by the hepatitis C virus. Proceedings of the National Academy of Sciences, USA 91:1294–1298
    [Google Scholar]
  9. Dubuisson J., Hsu H. H., Cheung R. C., Greenberg H. B., Russell D. G., Rice C. M. 1994; Formation and intracellular localization of hepatitis C virus envelope glycoprotein complexes expressed by recombinant vaccinia and Sindbis viruses. Journal of Virology 68:6147–6160
    [Google Scholar]
  10. Esteban J. I., Gonzalez A., Hernadez J. M., Viladomiu L., Sanchez C., Lopez-Talavera J. C., Lucea D., Martin-Vega C., Vidal X., Esteban R., Guardia J. 1990; Evaluation of antibodies to hepatitis C virus in a study of transfusion-associated hepatitis. New England Journal of Medicine 323:1107–1112
    [Google Scholar]
  11. Farza H., Hadchouel M., Scotto J., Tiollais P., Babinet C., Pourcel D. 1988; Replication and gene expression of hepatitis B virus in a transgenic mouse that contains the complete viral genome. Journal of Virology 62:4144–4152
    [Google Scholar]
  12. Grakoui A., Wynchowski C., Lin C., Feinstone S. M., Rice C. M. 1993; Expression and identification of hepatitis C virus polyprotein cleavage products. Journal of Virology 67:1385–1395
    [Google Scholar]
  13. Guilhot S., Huang S. N., Xia Y. P., La Monica N., Lai M. M. C., Chisari F. V. 1994; Expression of the hepatitis delta virus large and small antigens in transgenic mice. Journal of Virology 68:1052–1058
    [Google Scholar]
  14. Haddad J., Deny P., Munz-Gotheil C., Ambrosini J. C., Trinchet J. C., Pateron D., Mal F., Callard P., Beaugrand M. 1992; Lymphocytic sialadenitis of Sjogren’s syndrome associated with chronic hepatitis C virus liver disease. Lancet 339:321–323
    [Google Scholar]
  15. Harada S., Watanabe Y., Takeuchi K., Suzuki T., Katayama T., Takebe Y., Saito I., Miyamura T. 1991; Expression of processed core protein of hepatitis C virus in mammalian cells. Journal of Virology 65:3015–3021
    [Google Scholar]
  16. Hijikata M., Kato N., Ootsuyama Y., Nakagawa M., Shimotohno K. 1991; Gene mapping of the putative structural region of the hepatitis C virus genome by in vitro processing analysis. Proceedings of the National Academy of Sciences, USA 88:5547–5551
    [Google Scholar]
  17. Houghton M., Weiner A., Han J., Kuo G., Choo Q. L. 1991; Molecular biology of the hepatitis C viruses: implications for diagnosis, development and control of viral disease. Hepatology 14:381–388
    [Google Scholar]
  18. Johnson R. J., Gretch D. R., Yamabe H., Hart J., Bacchi C. E., Hartwell P., Couser W. G. 1993; Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. New England Journal of Medicine 328:465–470
    [Google Scholar]
  19. Kato N., Sekiya H., Ootsuyama Y., Nakazawa T., Hijikata M., Ohkoshi S., Shimotohno K. 1993; Humoral immune response to hypervariable region 1 of the putative envelope glycoprotein (gp70) of hepatitis C virus. Journal of Virology 67:3923–3930
    [Google Scholar]
  20. Kim C.-M., Koike K., Saito I., Miyamura T., Jay G. 1989; HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351:317–320
    [Google Scholar]
  21. Kohara M., Tsukiyama-Kohara K., Maki N., Asano K., Yamaguchi K., Miki K., Tanaka S., Hattori N., Matsuura Y., Saito I., Miyamura T., Nomoto A. 1992; Expression and characterization of glycoprotein gp35 of hepatitis C virus using recombinant vaccinia virus. Journal of General Virology 73:2313–2318
    [Google Scholar]
  22. Koike K., Hinrichs S. H., Isselbacher K. J., Jay G. 1989; Transgenic mouse model for human gastric cancer. Proceedings of the National Academy of Sciences, USA 86:5615–5619
    [Google Scholar]
  23. Koike K., Moriya K., Iino S., Yotsuyanagi H., Endo Y., Miyamura T., Kurokawa K. 1994a; High-level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice. Hepatology 19:810–819
    [Google Scholar]
  24. Koike K., Moriya K., Yotsuyanagi H., Iino S., Kurokawa K. 1994b; Induction of cell cycle progression by hepatitis B virus HBx gene expression in quiescent mouse fibroblasts. Journal of Clinical Investigation 94:44–49
    [Google Scholar]
  25. Lanford R. E., Notvall L., Chavez D., White R., Frenzel G., Simonsen C., Kim J. 1993; Analysis of hepatitis C virus capsid, El, and E2/NS1 proteins expressed in insect cells. Virology 197:225–235
    [Google Scholar]
  26. Lin C., Lindenbach B. D., Pragai B. M., McCourt D. W., Rice C. M. 1994; Processing in the hepatitis C virus E2-NS2 region: Identification of p7 and two distinct E2-specific products with different C termini. Journal of Virology 68:5063–5073
    [Google Scholar]
  27. Matsuura Y., Miyamura T. 1993; The molecular biology of hepatitis C virus. Seminars in Virology 4:297–304
    [Google Scholar]
  28. Matsuura Y., Harada S., Suzuki R., Watanabe Y., Inoue Y., Saito I., Miyamura T. 1992; Expression of processed envelope protein of hepatitis C virus expressed in mammalian and insect cells. Journal of Virology 66:1425–1431
    [Google Scholar]
  29. Matsuura Y., Suzuki T., Suzuki R., Sato M., Aizaki H., Saito I., Miyamura T. 1994; Processing of El and E2 glycoprotein of hepatitis C virus expressed in mammalian cells and insect cells. Virology 205:141–150
    [Google Scholar]
  30. Mizushima H., Hijikata M., Asabe S. L., Hirota M., Kimura K., Shimotohno K. 1994; Two hepatitis C virus glycoprotein E2 products with different C termini. Journal of Virology 68:6215–6222
    [Google Scholar]
  31. Muraiso K., Hijikata M., Ohkoshi S., Cho M. J., Kikuchi M., Kato N., Shimotohno K. 1990; A structural protein of hepatitis C virus expressed in E. coli facilitates accurate detection of hepatitis C virus. Biochemical and Biophysical Research Communications 172:511–516
    [Google Scholar]
  32. Ou J. H., Rutter W. J. 1987; Regulation of secretion of the hepatitis B virus major surface antigen by the preS-1 protein. Journal of Virology 61:782–786
    [Google Scholar]
  33. Ralston R., Thudium K., Berger K., Kuo C., Gervase B., Hall J., Selby M., Kuo G., Houghton M., Choo Q. L. 1993; Characterization of hepatitis C virus envelope glycoprotein complexes expressed by recombinant vaccinia virus. Journal of Virology 67:6753–6761
    [Google Scholar]
  34. 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., Kuo G. 1990; Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proceedings of the National Academy of Sciences, USA 87:6547–6549
    [Google Scholar]
  35. Selby M. J., Choo Q.-L., Berger K., Kuo G., Glazer E., Eckart M., Lee C., Chien D., Kuo C., Houghton M. 1993; Expression, identification and subcellular localization of the proteins encoded by the hepatitis C viral genome. Journal of General Virology 74:1103–1113
    [Google Scholar]
  36. Shimizu Y. K., Iwamoto A., Hijikata M., Purcell R. H., Yoshikura H. 1992; Evidence for in vitro replication of hepatitis C virus genome in a human T cell line. Proceedings of the National Academy of Sciences, USA 89:5477–5481
    [Google Scholar]
  37. Spaete R. R., Alexander D., Rugroden M. E., Choo Q.-L., Berger K., Crawford K., Kuo G., Leng S., Lee C., Ralston R., Thudium K., Tung J. W., Kuo G., Houghton M. 1992; Characterization of the hepatitis C virus E2/NS1 gene product expressed in mammalian cells. Virology 188:819–830
    [Google Scholar]
  38. Takehara T., Hayashi N., Miyamoto Y., Yamamoto M., Mita E., Fusamoto H., Kamada T. 1995; Expression of the hepatitis C virus genome in rat liver after cationic liposome-mediated in vivo gene transfer. Hepatology 21:746–751
    [Google Scholar]
  39. Taniguchi S., Okamoto H., Sakamoto M., Kojima M., Tsuda F., Tanaka T., Munekata E., Muchmore E. E., Peterson D. A., Mishiro S. 1993; A structurally flexible and antigenically variable N-terminal domain of the hepatitis C virus E2/NS1 protein: implication for an escape from antibody. Virology 195:297–301
    [Google Scholar]
  40. Tomei L., Faira C., Santolini E., Francesco R. D., La Monica N. 1993; NS3 is a serine protease required for processing of hepatitis C virus polyprotein. Journal of Virology 67:4017–4026
    [Google Scholar]
  41. Weiner A. J., Kuo G., Bradley D. W., Bonino F., Saraco G., Lee C., Rosenblatt J., Choo Q.-L., Houghton M. 1990; Detection of hepatitis C viral sequences in non-A, non-B hepatitis. Lancet 335:1–3
    [Google Scholar]
  42. Yoshioka K., Kakumu S., Wakita T., Ishikawa T., Itoh Y., Takayanagi M., Hihashi Y., Shibata M., Morishita T. 1992; Detection of hepatitis C virus by polymerase chain reaction and response to interferon-a therapy: relationship to genotypes of hepatitis C virus. Hepatology 16:293–299
    [Google Scholar]
  43. Yotsuyanagi H., Iino S., Koike K., Yasuda K., Hino K., Kurokawa K. 1993; Duration of viremia in human hepatitis A viral infection as determined by polymerase chain reaction. Journal of Medical Virology 40:35–38
    [Google Scholar]
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