1887

Abstract

Chronic hepatitis B treatment has been significantly improved by interferon (IFN) treatment. However, some studies have suggested that hepatitis B virus (HBV) might have a direct effect on the resistance to IFN. Defective particles, generated by spliced HBV RNA and associated with chronic hepatitis B, have been previously characterized; expression of these particles leads to cytoplasmic accumulation of the capsid protein. The aim of this study was to investigate the role of these defective genomes in IFN resistance. The global antiviral activity of IFN was studied by virus yield reduction assays, the expression of three IFN-induced antiviral proteins was analysed by Western blotting and confocal microscopy, and the regulation of MxA gene expression was studied by Northern blotting and the luciferase assay, in Huh7 cells transfected with a complete or the defective HBV genome. Results showed that the expression of the defective genome reduces the antiviral activity of IFN and that this modulation involves a selective inhibition of MxA protein induction by the HBV capsid protein. Our results also show the trans-suppressive effect of the HBV capsid on the MxA promoter, which might participate in this phenomenon. In conclusion, this study shows a direct interplay between the IFN-sensitive pathway and the capsid protein and might implicate this defective HBV genome in virus persistence.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-80-5-1253
1999-05-01
2023-02-05
Loading full text...

Full text loading...

/deliver/fulltext/jgv/80/5/0801253a.html?itemId=/content/journal/jgv/10.1099/0022-1317-80-5-1253&mimeType=html&fmt=ahah

References

  1. Baca L. M., Genis P., Kalvakolanu D., Sen G., Meltzer M. S., Zhou A., Silverman R., Gendelman H. E. 1994; Regulation of interferon-α-inducible cellular genes in human immunodeficiency virus-infected monocytes. Journal of Leukocyte Biology 55:299–309
    [Google Scholar]
  2. Beasley R. P. 1988; Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 61:1942–1956
    [Google Scholar]
  3. Blum H. E., Haase A. T., Vyas G. N. 1984; Molecular pathogenesis of hepatitis B virus infection: simultaneous detection of viral DNA and antigens in paraffin-embedded liver sections. Lancet ii:771–774
    [Google Scholar]
  4. Bréchot C. 1997; Molecular mechanisms of hepatitis B and C viruses related liver carcinogenesis. In Viral Hepatitis and Liver Disease pp 490–508 Edited by Rizzetto M., Purcell R. H., Gerin J. L., Verme G. Roma: Edizioni Minerva Medica;
    [Google Scholar]
  5. Burleson F. G., Chambers T. M., Wiedbrauk D. L. 1991; Plaque assays. In Virology A Laboratory Manual pp 74–84 New York: Academic Press;
    [Google Scholar]
  6. Chang C., Jeng K. S., Hu C. P., Lo K. J., Su T. S., Ting L. P., Chong C. K., Han S. H., Pfaff E., Salfeld J., Schaller H. 1987; Production of hepatitis B virus in vitro by transient expression of cloned HBV DNA in hepatoma cell line. EMBO Journal 6:675–680
    [Google Scholar]
  7. Chebath J. P., Benech P., Revel M., Vigneron M. 1987; Constitutive expression of 2, 5-oligo A synthetase confers resistance to picornavirus infection. Nature 330:587–588
    [Google Scholar]
  8. Chomczynski P., Sacchi N. 1987; Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analytical Biochemistry 162:156–159
    [Google Scholar]
  9. Fernandez M., Quiroga J., Martin J., Cotonat T., Pardo M., Horisberger M., Carreno V. 1997; Impaired interferon induction of human MxA protein in chronic hepatitis B virus infection. Journal of Medical Virology 51:332–337
    [Google Scholar]
  10. Foster G. R., Ackrill A. M., Goldin R. D., Kerr P. M., Thomas H. C., Stark G. R. 1991; Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons alpha and gamma and double stranded RNA. Proceedings of the National Academy of Sciences, USA 88:2888–2892
    [Google Scholar]
  11. Foster G. R., Goldin R. D., Hay A., McGarvey M. J., Stark G. R., Thomas H. C. 1993; Expression of the terminal protein of hepatitis B virus is associated with failure to respond to interferon therapy. Hepatology 17:757–762
    [Google Scholar]
  12. Foster G. R., Ackrill A. M., Goldin R. D., Kerr P. M., Thomas H. C., Stark G. R. 1995; Correction. Proceedings of the National Academy of Sciences, USA 92:3632
    [Google Scholar]
  13. Frese M., Kochs G., Meier-Dieter U., Siebler J., Haller O. 1995; Human MxA protein inhibits tick-borne Thogoto virus but not Dhori virus. Journal of Virology 69:3904–3909
    [Google Scholar]
  14. Gerken G., Kremsdorf D., Capel F., Petit M.-A., Dauguet C., Manns M. P., Meyer Zum Buschenfelde K. H., Brechot C. 1991; Hepatitis B defective virus with rearrangements in the PreS gene during chronic HBV infection. Virology 183:555–565
    [Google Scholar]
  15. Guidotti L. G., Martinez V., Loh Y. -T., Rogler C. E., Chisari F. V. 1994; Hepatitis B virus nucleocapsid particles do not cross the hepatocyte nuclear membrane in transgenic mice. Journal of Virology 68:5469–5475
    [Google Scholar]
  16. Holland J. J. 1990; Defective viral genomes. In Fields Virology 2nd edn, pp 151–165 Edited by Fields B. N., Knipe D. M. New York: Raven Press;
    [Google Scholar]
  17. Horisberger M. A. 1992; Interferon-induced human protein MxA is a GTPase which binds transiently to cellular proteins. Journal of Virology 66:4705–4709
    [Google Scholar]
  18. Horisberger M. A., McMaster G. K., Zeller H., Wathelet M. G., Dellis J., Content J. 1990; Cloning and sequence analysis of cDNAs for interferon- and virus-induced human Mx proteins reveal that they contain putative guanine nucleotide-binding sites: functional study of the corresponding gene promoter. Journal of Virology 64:1171–1181
    [Google Scholar]
  19. Huang T., Pavlovic J., Staeheli P., Krystal M. 1992; Overexpression of the influenza virus polymerase can titrate out inhibition by the murine Mx1 protein. Journal of Virology 66:4154–4160
    [Google Scholar]
  20. Ikeda T., Lever A. M. L., Thomas H. C. 1986; Evidence for deficiency of interferon-α production in patients with chronic HBV infection acquired in adult life. Hepatology 6:962–965
    [Google Scholar]
  21. Jakschies D., Zachoval R., Muller R., Manns M., Nolte K.-U., Hochkeppel H. K., Horisberger M.-A., Deicher H., Von Wussow P. 1993; Strong transient expression of the type I interferon-induced MxA protein in hepatitis A but not in acute hepatitis B and C. Hepatology 19:857–865
    [Google Scholar]
  22. Nakabayashi H., Takeda K., Takoshy Y., Sato J. 1982; Growth of human hepatoma cell lines with differentiated functions in chemically defined medium. Cancer Research 42:3858–3863
    [Google Scholar]
  23. Nishiguchi S., Kuroki T., Otani S., Takeda T., Hirota S., Shimizu Y., Nakajima S., Saito S., Shiomi S., Kobayashi K. 1989; Relationship of the effects of interferon on chronic hepatitis B and the induction of 2′, 5′-oligoadenylate synthetase. Hepatology 10:29–33
    [Google Scholar]
  24. Onji M., Lever A. M. L., Saito I., Thomas H. C. 1989; Defective response to interferon in cells transfected with the hepatitis B virus genome. Hepatology 9:92–96
    [Google Scholar]
  25. Pavlovic J., Zurcher T., Haller O., Staeheli P. 1990; Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. Journal of Virology 64:3370–3375
    [Google Scholar]
  26. Pavlovic J., Haller O., Staeheli P. 1992; Human and mouse Mx proteins inhibit different steps of the influenza virus multiplication cycle. Journal of Virology 66:2564–2569
    [Google Scholar]
  27. Pavlovic J., Arzet H. A., Hefti H. P., Frese M., Rost D., Ernst B., Kolb E., Staeheli P., Haller O. 1995; Enhanced virus resistance of transgenic mice expressing the human MxA protein. Journal of Virology 69:4506–4510
    [Google Scholar]
  28. Perrillo R. P., Schiff E. R., Davis G. L., Bodenheimer H. C. Jr, Lindsay K., Payne J., Dienstag J. L., O’Brien C., Tamburro C., Jacobson I. M., Sampliner R., Feit D., Lefkowitch J., Meschievitz C., Sanghvi B., Albrecht J., Gibas A. & the Hepatitis Interventional Therapy Group 1990; A randomized controlled trial of interferon alpha 2b alone and after prednisolone withdrawal in the treatment of chronic hepatitis B. New England Journal of Medicine 323:295–301
    [Google Scholar]
  29. Pestka S., Langer J. A., Zoon K. C., Samuel C. E. 1987; Interferon and their actions. Annual Review of Biochemistry 56:727–777
    [Google Scholar]
  30. Pitossi F., Blank A., Schroder A., Schwarz A., Hussi P., Schwemmle M., Pavlovic J., Staeheli P. 1993; A functional GTP-binding motif is necessary for antiviral activity of Mx proteins. Journal of Virology 67:6726–6732
    [Google Scholar]
  31. Poitrine A., Chousterman S., Chousterman M., Naveau S., Thang M. N., Chaput J. C. 1985; Lack of in vivo activation of interferon system in HBsAg-positive chronic active hepatitis. Hepatology 5:171–174
    [Google Scholar]
  32. Porter A. C. G., Chernajovsky Y., Dale T. C., Gilbert C. S., Stark G. R., Kerr I. M. 1988; Interferon response element of the human 6-16 gene. EMBO Journal 7:85–92
    [Google Scholar]
  33. Roingeard P., Romet-Lemonne J. L., Leturq D., Goudeau A., Essex M. 1990; Hepatitis B virus core antigene accumulation in an HBV non producer clone of HepG2 transfected cells is associated with cytopathic effect. Virology 179:113–120
    [Google Scholar]
  34. Rosmorduc O., Petit M. A., Pol S., Capel F., Bortolotti F., Berthelot P., Brechot C., Kremsdorf D. 1995; In vivo and in vitro expression of the defective HBV particles generated by the 2.2 kb singly spliced RNAs. Hepatology 22:10–19
    [Google Scholar]
  35. Rothman J. H., Raymond C. K., Gilbert T., O’Hara P. J., Stevens T. H. 1990; A putative GTP binding protein homologous to interferon-inducible Mx proteins performs an essential function in yeast protein sorting. Cell 61:1063–1074
    [Google Scholar]
  36. Schuster A., Johnston I., Das T., Banerjee A., Pavlovic J., ter Meulen V., Schneider-Schaulies S. 1996; Expression of the human MxA protein is associated with hyperphosphorylation of VSV P protein in human neural cells. Virology 220:241–245
    [Google Scholar]
  37. Sen G. C., Ransohoff R. M. 1993; Interferon-induced antiviral actions and their regulation. Advances in Virus Research 42:57–102
    [Google Scholar]
  38. Staeheli P., Pitossi F., Pavlovic J. 1993; Mx proteins: GTPases with antiviral activity. Trends in Cell Biology 3:268–272
    [Google Scholar]
  39. Terre S., Petit M. A., Brechot C. 1991; Defective hepatitis B virus particles are generated by packaging and reverse transcription of spliced viral RNAs in vivo. Journal of Virology 65:5539–5543
    [Google Scholar]
  40. Tran A., Kremsdorf D., Capel F., Housset C., Petit M. A., Dauguet C., Brechot C. 1991; Emergence of and takeover by hepatitis B virus (HBV) with rearrangements in the PreS/S and PreC/C genes during chronic HBV infection. Journal of Virology 65:3566–3574
    [Google Scholar]
  41. Whitten T. M., Quets A. T., Schloemer R. H. 1991; Identification of the hepatitis B virus factor that inhibits expression of the beta interferon gene. Journal of Virology 65:4699–4704
    [Google Scholar]
  42. Witt P. L., Marie I., Irizarry A., Borden E. C., Hovanessian A. G. 1993; Isoforms p69 and p100 of 2′, 5-oligoadenylate synthetase induced differentially by interferons in vivo and in vitro. Journal of Interferon Research 13:17–23
    [Google Scholar]
  43. Yeh C. -T., Wong S. W., Ou J. -H. 1993; Cell cycle regulation of nuclear localization of hepatitis B virus core protein. Proceedings of the National Academy of Sciences, USA 90:6459–6463
    [Google Scholar]
  44. Yeh C. -T., Ou J. -H., Chu C. -M., Liaw Y. -F. 1994; Alteration of the subcellular localization of the hepatitis B virus core protein by large but not small surface proteins. Biochemical and Biophysical Research Communications 203:1348–1354
    [Google Scholar]
  45. Zurcher T., Pavlovic J., Staeheli P. 1992; Mechanism of human MxA protein action: variants with changed antiviral properties. EMBO Journal 11:1657–1661
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-80-5-1253
Loading
/content/journal/jgv/10.1099/0022-1317-80-5-1253
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error