1887

Abstract

Co-infection and superinfection of hepatitis B virus (HBV) with hepatitis delta virus (HDV) leads to suppression of HBV replication both in patients and in animal and cellular models. The mechanisms behind this inhibition have not previously been explored fully. HBV replication is governed by four promoters and two enhancers, Enh1 and Enh2. Repression of these enhancers has been reported to be one of the main mechanisms of HBV inhibition. Moreover, in a previous study, it has been demonstrated that alpha interferon (IFN-)-inducible MxA protein inhibits HBV replication. HDV encodes two proteins, p24 and p27. p27 was shown to activate several heterologous promoters, including HBV promoters. In an attempt to analyse the mechanisms of HBV inhibition by HDV, the question was raised whether HDV proteins could act directly by repressing HBV enhancers, and/or indirectly by activating the MxA gene. This issue was addressed in a co-transfection model in Huh-7 cells, using p24- or p27-expressing plasmids along with Enh1, Enh2, HBV and MxA promoter–luciferase constructs. Enh1 and Enh2 were strongly repressed, by 60 and 80 % and 40 and 60 %, by p24 and p27, respectively. In addition, p27 was responsible for threefold activation of the MxA promoter and potentiation of IFN- on this promoter. MxA mRNA quantification and a virus yield reduction assay confirmed these results. In conclusion, this study shows that HDV proteins inhibit HBV replication by -repressing its enhancers and by -activating the IFN--inducible MxA gene.

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2009-11-01
2024-03-28
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References

  1. Arribas J. R., Gonzalez-Garcia J. J., Lorenzo A., Montero D., Ladron de Guevara C., Montes M., Hernandez S., Pacheco R., Pena J. M., Vazquez J. J. 2005; Single (B or C), dual (BC or BD) and triple (BCD) viral hepatitis in HIV-infected patients in Madrid, Spain. . AIDS 19, 1361–1365 [CrossRef]
    [Google Scholar]
  2. 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. J Leukoc Biol 55:299–309
    [Google Scholar]
  3. Bock C. T., Malek N. P., Tillmann H. L., Manns M. P., Trautwein C. 2000; The enhancer I core region contributes to the replication level of hepatitis B virus in vivo and in vitro . J Virol 74:2193–2202 [CrossRef]
    [Google Scholar]
  4. Chen C. W., Tsay Y. G., Wu H. L., Lee C. H., Chen D. S., Chen P. J. 2002; The double-stranded RNA-activated kinase, PKR, can phosphorylate hepatitis D virus small delta antigen at functional serine and threonine residues. J Biol Chem 277:33058–33067 [CrossRef]
    [Google Scholar]
  5. Colombo P., Di Blasi F., Magrin S., Fabiano C., Di Marco V., D'Amelio L., Lojacono F., Spinelli G., Craxi A. 1991; Smouldering hepatitis B virus replication in patients with chronic liver disease and hepatitis delta virus superinfection. J Hepatol 12:64–69 [CrossRef]
    [Google Scholar]
  6. Doitsh G., Shaul Y. 2004; Enhancer I predominance in hepatitis B virus gene expression. Mol Cell Biol 24:1799–1808 [CrossRef]
    [Google Scholar]
  7. George C. X., Samuel C. E. 1999; Characterization of the 5′-flanking region of the human RNA-specific adenosine deaminase ADAR1 gene and identification of an interferon-inducible ADAR1 promoter. Gene 229:203–213 [CrossRef]
    [Google Scholar]
  8. Gordien E., Rosmorduc O., Peltekian C., Garreau F., Brechot C., Kremsdorf D. 2001; Inhibition of hepatitis B virus replication by the interferon-inducible MxA protein. J Virol 75:2684–2691 [CrossRef]
    [Google Scholar]
  9. Goto T., Kato N., Ono-Nita S. K., Yoshida H., Otsuka M., Shiratori Y., Omata M. 2000; Large isoform of hepatitis delta antigen activates serum response factor-associated transcription. J Biol Chem 275:37311–37316 [CrossRef]
    [Google Scholar]
  10. Goto T., Kato N., Yoshida H., Otsuka M., Moriyama M., Shiratori Y., Koike K., Matsumura M., Omata M. 2003; Synergistic activation of the serum response element-dependent pathway by hepatitis B virus X protein and large-isoform hepatitis delta antigen. J Infect Dis 187:820–828 [CrossRef]
    [Google Scholar]
  11. Govindarajan S. 1990; Inhibition of HBV replication during coinfection with HBV and HDV: inhibition of the inhibition by coinfection with HIV. Hepatology 11:703–704 [CrossRef]
    [Google Scholar]
  12. Guidotti L. G., Matzke B., Schaller H., Chisari F. V. 1995; High-level hepatitis B virus replication in transgenic mice. J Virol 69:6158–6169
    [Google Scholar]
  13. Hartwig D., Schutte C., Warnecke J., Dorn I., Hennig H., Kirchner H., Schlenke P. 2006; The large form of ADAR 1 is responsible for enhanced hepatitis delta virus RNA editing in interferon- α -stimulated host cells. J Viral Hepat 13:150–157 [CrossRef]
    [Google Scholar]
  14. Ishida H., Ueda K., Ohkawa K., Kanazawa Y., Hosui A., Nakanishi F., Mita E., Kasahara A., Sasaki Y. other authors 2000; Identification of multiple transcription factors, HLF, FTF, and E4BP4, controlling hepatitis B virus enhancer II. J Virol 74:1241–1251 [CrossRef]
    [Google Scholar]
  15. Jardi R., Rodriguez F., Buti M., Costa X., Cotrina M., Galimany R., Esteban R., Guardia J. 2001; Role of hepatitis B, C, and D viruses in dual and triple infection: influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference. Hepatology 34:404–410 [CrossRef]
    [Google Scholar]
  16. Kosovsky M. J., Huan B., Siddiqui A. 1996; Purification and properties of rat liver nuclear proteins that interact with the hepatitis B virus enhancer 1. J Biol Chem 271:21859–21869 [CrossRef]
    [Google Scholar]
  17. Lai M. M. 2005; RNA replication without RNA-dependent RNA polymerase: surprises from hepatitis delta virus. J Virol 79:7951–7958 [CrossRef]
    [Google Scholar]
  18. Lai C. K., Ting L. P. 1999; Transcriptional repression of human hepatitis B virus genes by a bZIP family member, E4BP4. J Virol 73:3197–3209
    [Google Scholar]
  19. Lee S. D., Wang J. Y., Wu J. C., Tsai Y. T., Lo K. J., Lai K. H., Tsay S. H., Govindarajan S. 1987; Hepatitis D virus (delta agent) superinfection in an endemic area of hepatitis B infection: immunopathologic and serologic findings. Scand J Infect Dis 19:173–177 [CrossRef]
    [Google Scholar]
  20. Leong P. L., Andrews G. A., Johnson D. E., Dyer K. F., Xi S., Mai J. C., Robbins P. D., Gadiparthi S., Burke N. A. other authors 2003; Targeted inhibition of STAT3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci U S A 100:4138–4143 [CrossRef]
    [Google Scholar]
  21. Lo W. Y., Ting L. P. 1994; Repression of enhancer II activity by a negative regulatory element in the hepatitis B virus genome. J Virol 68:1758–1764
    [Google Scholar]
  22. Moolla N., Kew M., Arbuthnot P. 2002; Regulatory elements of hepatitis B virus transcription. J Viral Hepat 9:323–331 [CrossRef]
    [Google Scholar]
  23. Negro F., Korba B. E., Forzani B., Baroudy B. M., Brown T. L., Gerin J. L., 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 63:1612–1618
    [Google Scholar]
  24. Ott M., Thyagarajan S. P., Gupta S. 1997; Phyllanthus amarus suppresses hepatitis B virus by interrupting interactions between HBV enhancer I and cellular transcription factors. Eur J Clin Invest 27:908–915 [CrossRef]
    [Google Scholar]
  25. Park G. T., Yi Y. W., Choi C. Y., Rho H. M. 1997; A negative regulatory element and its binding protein in the upstream of enhancer II of hepatitis B virus. DNA Cell Biol 16:1459–1465 [CrossRef]
    [Google Scholar]
  26. Pastore G., Monno L., Santantonio T., Angarano G., Milella M., Giannelli A., Fiore J. R. 1990; Hepatitis B virus clearance from serum and liver after acute hepatitis delta virus superinfection in chronic HBsAg carriers. J Med Virol 31:284–290 [CrossRef]
    [Google Scholar]
  27. Patterson J. B., Samuel C. E. 1995; Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Mol Cell Biol 15:5376–5388
    [Google Scholar]
  28. Peltekian C., Gordien E., Garreau F., Meas-Yedid V., Soussan P., Willams V., Chaix M. L., Olivo-Marin J. C., Brechot C., Kremsdorf D. 2005; Human MxA protein participates to the interferon-related inhibition of hepatitis B virus replication in female transgenic mice. J Hepatol 43:965–972 [CrossRef]
    [Google Scholar]
  29. Raney A. K., Milich D. R., Easton A. J., McLachlan A. 1990; Differentiation-specific transcriptional regulation of the hepatitis B virus large surface antigen gene in human hepatoma cell lines. J Virol 64:2360–2368
    [Google Scholar]
  30. Rosmorduc O., Sirma H., Soussan P., Gordien E., Lebon P., Horisberger M., Brechot C., Kremsdorf D. 1999; Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein. J Gen Virol 80:1253–1262
    [Google Scholar]
  31. Schuttler C. G., Fiedler N., Schmidt K., Repp R., Gerlich W. H., Schaefer S. 2002; Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein. J Hepatol 37:855–862 [CrossRef]
    [Google Scholar]
  32. Shih C. M., Lo S. J., Miyamura T., Chen S. Y., Lee Y. H. 1993; Suppression of hepatitis B virus expression and replication by hepatitis C virus core protein in Huh-7 cells. J Virol 67:5823–5832
    [Google Scholar]
  33. Taylor J. M. 2006; Hepatitis delta virus. Virology 344:71–76 [CrossRef]
    [Google Scholar]
  34. Tur-Kaspa R., Teicher L., Laub O., Itin A., Dagan D., Bloom B. R., Shafritz D. A. 1990; Alpha interferon suppresses hepatitis B virus enhancer activity and reduces viral gene transcription. J Virol 64:1821–1824
    [Google Scholar]
  35. Waris G., Siddiqui A. 2002; Interaction between STAT-3 and HNF-3 leads to the activation of liver-specific hepatitis B virus enhancer 1 function. J Virol 76:2721–2729 [CrossRef]
    [Google Scholar]
  36. Wei Y., Ganem D. 1998; Activation of heterologous gene expression by the large isoform of hepatitis delta antigen. J Virol 72:2089–2096
    [Google Scholar]
  37. Wong S. K., Lazinski D. W. 2002; Replicating hepatitis delta virus RNA is edited in the nucleus by the small form of ADAR1. Proc Natl Acad Sci U S A 99:15118–15123 [CrossRef]
    [Google Scholar]
  38. Wu J. C., Chen P. J., Kuo M. Y., Lee S. D., Chen D. S., Ting L. P. 1991; Production of hepatitis delta virus and suppression of helper hepatitis B virus in a human hepatoma cell line. J Virol 65:1099–1104
    [Google Scholar]
  39. Yuh C. H., Ting L. P. 1990; The genome of hepatitis B virus contains a second enhancer: cooperation of two elements within this enhancer is required for its function. J Virol 64:4281–4287
    [Google Scholar]
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