Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1994 Feb;68(2):1052–1058. doi: 10.1128/jvi.68.2.1052-1058.1994

Expression of the hepatitis delta virus large and small antigens in transgenic mice.

S Guilhot 1, S N Huang 1, Y P Xia 1, N La Monica 1, M M Lai 1, F V Chisari 1
PMCID: PMC236543  PMID: 8289334

Abstract

Simultaneous infection with hepatitis delta virus (HDV) and hepatitis B virus (HBV) in humans is often associated with severe viral liver disease including fulminant hepatitis. Since HBV is thought to be noncytopathic to the hepatocyte, the enhanced disease severity observed during dual infection has been attributed to either simultaneous immune responses against the two viruses or direct cytotoxic effects of HDV products on the hepatocyte or both. To examine these alternate possibilities, we produced transgenic mice that express the small and large delta antigens (HDAg) in hepatocyte nuclei at levels equal to those observed during natural HDV infection. No biological or histopathological evidence of liver disease was detectable during 18 months of observation, suggesting that neither the large nor small form of HDAg is directly cytopathic to the hepatocyte in vivo.

Full text

PDF
1058

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bergmann K. F., Gerin J. L. Antigens of hepatitis delta virus in the liver and serum of humans and animals. J Infect Dis. 1986 Oct;154(4):702–706. doi: 10.1093/infdis/154.4.702. [DOI] [PubMed] [Google Scholar]
  2. Buitrago B., Popper H., Hadler S. C., Thung S. N., Gerber M. A., Purcell R. H., Maynard J. E. Specific histologic features of Santa Marta hepatitis: a severe form of hepatitis delta-virus infection in northern South America. Hepatology. 1986 Nov-Dec;6(6):1285–1291. doi: 10.1002/hep.1840060610. [DOI] [PubMed] [Google Scholar]
  3. Casey J. L., Bergmann K. F., Brown T. L., Gerin J. L. Structural requirements for RNA editing in hepatitis delta virus: evidence for a uridine-to-cytidine editing mechanism. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7149–7153. doi: 10.1073/pnas.89.15.7149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chang M. F., Baker S. C., Soe L. H., Kamahora T., Keck J. G., Makino S., Govindarajan S., Lai M. M. Human hepatitis delta antigen is a nuclear phosphoprotein with RNA-binding activity. J Virol. 1988 Jul;62(7):2403–2410. doi: 10.1128/jvi.62.7.2403-2410.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chao M., Hsieh S. Y., Taylor J. Role of two forms of hepatitis delta virus antigen: evidence for a mechanism of self-limiting genome replication. J Virol. 1990 Oct;64(10):5066–5069. doi: 10.1128/jvi.64.10.5066-5069.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen P. J., Kuo M. Y., Chen M. L., Tu S. J., Chiu M. N., Wu H. L., Hsu H. C., Chen D. S. Continuous expression and replication of the hepatitis delta virus genome in Hep G2 hepatoblastoma cells transfected with cloned viral DNA. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5253–5257. doi: 10.1073/pnas.87.14.5253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chisari F. V., Filippi P., Buras J., McLachlan A., Popper H., Pinkert C. A., Palmiter R. D., Brinster R. L. Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6909–6913. doi: 10.1073/pnas.84.19.6909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cole S. M., Gowans E. J., Macnaughton T. B., Hall P. D., Burrell C. J. Direct evidence for cytotoxicity associated with expression of hepatitis delta virus antigen. Hepatology. 1991 May;13(5):845–851. [PubMed] [Google Scholar]
  9. Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gilles P. N., Fey G., Chisari F. V. Tumor necrosis factor alpha negatively regulates hepatitis B virus gene expression in transgenic mice. J Virol. 1992 Jun;66(6):3955–3960. doi: 10.1128/jvi.66.6.3955-3960.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gilles P. N., Guerrette D. L., Ulevitch R. J., Schreiber R. D., Chisari F. V. HBsAg retention sensitizes the hepatocyte to injury by physiological concentrations of interferon-gamma. Hepatology. 1992 Sep;16(3):655–663. doi: 10.1002/hep.1840160308. [DOI] [PubMed] [Google Scholar]
  12. Guilhot S., Fowler P., Portillo G., Margolskee R. F., Ferrari C., Bertoletti A., Chisari F. V. Hepatitis B virus (HBV)-specific cytotoxic T-cell response in humans: production of target cells by stable expression of HBV-encoded proteins in immortalized human B-cell lines. J Virol. 1992 May;66(5):2670–2678. doi: 10.1128/jvi.66.5.2670-2678.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hadziyannis S. J., Sherman M., Lieberman H. M., Shafritz D. A. Liver disease activity and hepatitis B virus replication in chronic delta antigen-positive hepatitis B virus carriers. Hepatology. 1985 Jul-Aug;5(4):544–547. doi: 10.1002/hep.1840050404. [DOI] [PubMed] [Google Scholar]
  14. Heckel J. L., Sandgren E. P., Degen J. L., Palmiter R. D., Brinster R. L. Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator. Cell. 1990 Aug 10;62(3):447–456. doi: 10.1016/0092-8674(90)90010-c. [DOI] [PubMed] [Google Scholar]
  15. Hoofnagle J. H. Type D (delta) hepatitis. JAMA. 1989 Mar 3;261(9):1321–1325. [PubMed] [Google Scholar]
  16. Hsieh S. Y., Chao M., Coates L., Taylor J. Hepatitis delta virus genome replication: a polyadenylated mRNA for delta antigen. J Virol. 1990 Jul;64(7):3192–3198. doi: 10.1128/jvi.64.7.3192-3198.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hwang S. B., Lee C. Z., Lai M. M. Hepatitis delta antigen expressed by recombinant baculoviruses: comparison of biochemical properties and post-translational modifications between the large and small forms. Virology. 1992 Sep;190(1):413–422. doi: 10.1016/0042-6822(92)91227-l. [DOI] [PubMed] [Google Scholar]
  18. Kojima T., Callea F., Desmyter J., Desmet V. J. Immune electron microscopy of hepatitis delta-antigen in hepatocytes. Lab Invest. 1986 Aug;55(2):217–225. [PubMed] [Google Scholar]
  19. Krogsgaard K., Kryger P., Aldershvile J., Andersson P., Sørensen T. I., Nielsen J. O. Delta-infection and suppression of hepatitis B virus replication in chronic HBsAg carriers. Hepatology. 1987 Jan-Feb;7(1):42–45. doi: 10.1002/hep.1840070110. [DOI] [PubMed] [Google Scholar]
  20. Kuo M. Y., Chao M., Taylor J. Initiation of replication of the human hepatitis delta virus genome from cloned DNA: role of delta antigen. J Virol. 1989 May;63(5):1945–1950. doi: 10.1128/jvi.63.5.1945-1950.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Luo G. X., Chao M., Hsieh S. Y., Sureau C., Nishikura K., Taylor J. A specific base transition occurs on replicating hepatitis delta virus RNA. J Virol. 1990 Mar;64(3):1021–1027. doi: 10.1128/jvi.64.3.1021-1027.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Macnaughton T. B., Gowans E. J., Jilbert A. R., Burrell C. J. Hepatitis delta virus RNA, protein synthesis and associated cytotoxicity in a stably transfected cell line. Virology. 1990 Aug;177(2):692–698. doi: 10.1016/0042-6822(90)90535-y. [DOI] [PubMed] [Google Scholar]
  23. Makino S., Chang M. F., Shieh C. K., Kamahora T., Vannier D. M., Govindarajan S., Lai M. M. Molecular cloning and sequencing of a human hepatitis delta (delta) virus RNA. Nature. 1987 Sep 24;329(6137):343–346. doi: 10.1038/329343a0. [DOI] [PubMed] [Google Scholar]
  24. Negro F., Bergmann K. F., Baroudy B. M., Satterfield W. C., Popper H., Purcell R. H., Gerin J. L. Chronic hepatitis D virus (HDV) infection in hepatitis B virus carrier chimpanzees experimentally superinfected with HDV. J Infect Dis. 1988 Jul;158(1):151–159. doi: 10.1093/infdis/158.1.151. [DOI] [PubMed] [Google Scholar]
  25. Negro F., Korba B. E., Forzani B., Baroudy B. M., Brown T. L., Gerin J. L., Ponzetto A. Hepatitis delta virus (HDV) and woodchuck hepatitis virus (WHV) nucleic acids in tissues of HDV-infected chronic WHV carrier woodchucks. J Virol. 1989 Apr;63(4):1612–1618. doi: 10.1128/jvi.63.4.1612-1618.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pinkert C. A., Ornitz D. M., Brinster R. L., Palmiter R. D. An albumin enhancer located 10 kb upstream functions along with its promoter to direct efficient, liver-specific expression in transgenic mice. Genes Dev. 1987 May;1(3):268–276. doi: 10.1101/gad.1.3.268. [DOI] [PubMed] [Google Scholar]
  27. Ponzetto A., Cote P. J., Popper H., Hoyer B. H., London W. T., Ford E. C., Bonino F., Purcell R. H., Gerin J. L. Transmission of the hepatitis B virus-associated delta agent to the eastern woodchuck. Proc Natl Acad Sci U S A. 1984 Apr;81(7):2208–2212. doi: 10.1073/pnas.81.7.2208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rizzetto M., Canese M. G., Gerin J. L., London W. T., Sly D. L., Purcell R. H. Transmission of the hepatitis B virus-associated delta antigen to chimpanzees. J Infect Dis. 1980 May;141(5):590–602. doi: 10.1093/infdis/141.5.590. [DOI] [PubMed] [Google Scholar]
  29. Rizzetto M. The delta agent. Hepatology. 1983 Sep-Oct;3(5):729–737. doi: 10.1002/hep.1840030518. [DOI] [PubMed] [Google Scholar]
  30. Ruta M., Wolford R., Dhar R., Defeo-Jones D., Ellis R. W., Scolnick E. M. Nucleotide sequence of the two rat cellular rasH genes. Mol Cell Biol. 1986 May;6(5):1706–1710. doi: 10.1128/mcb.6.5.1706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Ryu W. S., Bayer M., Taylor J. Assembly of hepatitis delta virus particles. J Virol. 1992 Apr;66(4):2310–2315. doi: 10.1128/jvi.66.4.2310-2315.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Schibler U., Hagenbüchle O., Wellauer P. K., Pittet A. C. Two promoters of different strengths control the transcription of the mouse alpha-amylase gene Amy-1a in the parotid gland and the liver. Cell. 1983 Jun;33(2):501–508. doi: 10.1016/0092-8674(83)90431-2. [DOI] [PubMed] [Google Scholar]
  33. Slot J. W., Geuze H. J. A new method of preparing gold probes for multiple-labeling cytochemistry. Eur J Cell Biol. 1985 Jul;38(1):87–93. [PubMed] [Google Scholar]
  34. Slot J. W., Geuze H. J. Sizing of protein A-colloidal gold probes for immunoelectron microscopy. J Cell Biol. 1981 Aug;90(2):533–536. doi: 10.1083/jcb.90.2.533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sureau C., Guerra B., Lanford R. E. Role of the large hepatitis B virus envelope protein in infectivity of the hepatitis delta virion. J Virol. 1993 Jan;67(1):366–372. doi: 10.1128/jvi.67.1.366-372.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sureau C., Jacob J. R., Eichberg J. W., Lanford R. E. Tissue culture system for infection with human hepatitis delta virus. J Virol. 1991 Jul;65(7):3443–3450. doi: 10.1128/jvi.65.7.3443-3450.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sureau C., Taylor J., Chao M., Eichberg J. W., Lanford R. E. Cloned hepatitis delta virus cDNA is infectious in the chimpanzee. J Virol. 1989 Oct;63(10):4292–4297. doi: 10.1128/jvi.63.10.4292-4297.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Taylor J., Mason W., Summers J., Goldberg J., Aldrich C., Coates L., Gerin J., Gowans E. Replication of human hepatitis delta virus in primary cultures of woodchuck hepatocytes. J Virol. 1987 Sep;61(9):2891–2895. doi: 10.1128/jvi.61.9.2891-2895.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wang K. S., Choo Q. L., Weiner A. J., Ou J. H., Najarian R. C., Thayer R. M., Mullenbach G. T., Denniston K. J., Gerin J. L., Houghton M. Structure, sequence and expression of the hepatitis delta (delta) viral genome. Nature. 1986 Oct 9;323(6088):508–514. doi: 10.1038/323508a0. [DOI] [PubMed] [Google Scholar]
  40. Xia Y. P., Yeh C. T., Ou J. H., Lai M. M. Characterization of nuclear targeting signal of hepatitis delta antigen: nuclear transport as a protein complex. J Virol. 1992 Feb;66(2):914–921. doi: 10.1128/jvi.66.2.914-921.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zheng H., Fu T. B., Lazinski D., Taylor J. Editing on the genomic RNA of human hepatitis delta virus. J Virol. 1992 Aug;66(8):4693–4697. doi: 10.1128/jvi.66.8.4693-4697.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES