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. 1993 Dec;67(12):7032–7040. doi: 10.1128/jvi.67.12.7032-7040.1993

Dysregulated surface gene expression from disrupted hepatitis B virus genomes.

Z M Huang 1, T S Yen 1
PMCID: PMC238164  PMID: 8230428

Abstract

During chronic infection by hepatitis B virus, the viral genome frequently integrates into the host chromosome, causing gross disruption and rearrangement of the viral DNA. We have obtained data showing that viral genomic disruptions which delete the enhancers from the transcribed region of the viral surface gene can lead to dysregulation of surface gene expression at the transcriptional level. Specifically, in cells transfected with such disrupted genomes, there is a decreased amount of transcripts coding for the major form of the surface protein but little change in the amount of transcripts coding for the large surface protein. In these cells, secretion of the surface proteins is blocked in the endoplasmic reticulum-Golgi intermediate compartment, consistent with previous work from other groups showing that relative overexpression of the large surface protein can block secretion of all forms of the surface protein. Our findings suggest that viral genomic rearrangements during integration may be a contributing factor in the pathogenesis of ground-glass hepatocytes, which contain large amounts of intracellular surface proteins as a result of a block in secretion and are frequently seen in the livers of patients with chronic hepatitis B.

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Selected References

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

  1. Caselmann W. H., Meyer M., Kekulé A. S., Lauer U., Hofschneider P. H., Koshy R. A trans-activator function is generated by integration of hepatitis B virus preS/S sequences in human hepatocellular carcinoma DNA. Proc Natl Acad Sci U S A. 1990 Apr;87(8):2970–2974. doi: 10.1073/pnas.87.8.2970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cheng K. C., Smith G. L., Moss B. Hepatitis B virus large surface protein is not secreted but is immunogenic when selectively expressed by recombinant vaccinia virus. J Virol. 1986 Nov;60(2):337–344. doi: 10.1128/jvi.60.2.337-344.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chisari F. V., Filippi P., McLachlan A., Milich D. R., Riggs M., Lee S., Palmiter R. D., Pinkert C. A., Brinster R. L. Expression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic mice. J Virol. 1986 Dec;60(3):880–887. doi: 10.1128/jvi.60.3.880-887.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chisari F. V., Klopchin K., Moriyama T., Pasquinelli C., Dunsford H. A., Sell S., Pinkert C. A., Brinster R. L., Palmiter R. D. Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell. 1989 Dec 22;59(6):1145–1156. doi: 10.1016/0092-8674(89)90770-8. [DOI] [PubMed] [Google Scholar]
  5. Dienes H. P., Gerlich W. H., Wörsdörfer M., Gerken G., Bianchi L., Hess G., Meyer zum Büschenfelde K. H. Hepatic expression patterns of the large and middle hepatitis B virus surface proteins in viremic and nonviremic chronic hepatitis B. Gastroenterology. 1990 Apr;98(4):1017–1023. doi: 10.1016/0016-5085(90)90028-y. [DOI] [PubMed] [Google Scholar]
  6. Eble B. E., Lingappa V. R., Ganem D. Hepatitis B surface antigen: an unusual secreted protein initially synthesized as a transmembrane polypeptide. Mol Cell Biol. 1986 May;6(5):1454–1463. doi: 10.1128/mcb.6.5.1454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fridovich-Keil J. L., Gudas J. M., Bryan I. B., Pardee A. B. Improved expression vectors for eukaryotic promoter/enhancer studies. Biotechniques. 1991 Nov;11(5):572–579. [PubMed] [Google Scholar]
  8. Ganem D., Varmus H. E. The molecular biology of the hepatitis B viruses. Annu Rev Biochem. 1987;56:651–693. doi: 10.1146/annurev.bi.56.070187.003251. [DOI] [PubMed] [Google Scholar]
  9. Gerber M. A., Thung S. N. Molecular and cellular pathology of hepatitis B. Lab Invest. 1985 Jun;52(6):572–590. [PubMed] [Google Scholar]
  10. 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]
  11. Hobman T. C., Woodward L., Farquhar M. G. The rubella virus E1 glycoprotein is arrested in a novel post-ER, pre-Golgi compartment. J Cell Biol. 1992 Aug;118(4):795–811. doi: 10.1083/jcb.118.4.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Huovila A. P., Eder A. M., Fuller S. D. Hepatitis B surface antigen assembles in a post-ER, pre-Golgi compartment. J Cell Biol. 1992 Sep;118(6):1305–1320. doi: 10.1083/jcb.118.6.1305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Klausner R. D., Sitia R. Protein degradation in the endoplasmic reticulum. Cell. 1990 Aug 24;62(4):611–614. doi: 10.1016/0092-8674(90)90104-m. [DOI] [PubMed] [Google Scholar]
  14. Lau J. Y., Bain V. G., Davies S. E., O'Grady J. G., Alberti A., Alexander G. J., Williams R. High-level expression of hepatitis B viral antigens in fibrosing cholestatic hepatitis. Gastroenterology. 1992 Mar;102(3):956–962. doi: 10.1016/0016-5085(92)90182-x. [DOI] [PubMed] [Google Scholar]
  15. Nagaya T., Nakamura T., Tokino T., Tsurimoto T., Imai M., Mayumi T., Kamino K., Yamamura K., Matsubara K. The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma. Genes Dev. 1987 Oct;1(8):773–782. doi: 10.1101/gad.1.8.773. [DOI] [PubMed] [Google Scholar]
  16. Nakabayashi H., Taketa K., Miyano K., Yamane T., Sato J. Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Cancer Res. 1982 Sep;42(9):3858–3863. [PubMed] [Google Scholar]
  17. Ou J. H., Rutter W. J. Regulation of secretion of the hepatitis B virus major surface antigen by the preS-1 protein. J Virol. 1987 Mar;61(3):782–786. doi: 10.1128/jvi.61.3.782-786.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Persing D. H., Varmus H. E., Ganem D. Inhibition of secretion of hepatitis B surface antigen by a related presurface polypeptide. Science. 1986 Dec 12;234(4782):1388–1391. doi: 10.1126/science.3787251. [DOI] [PubMed] [Google Scholar]
  19. Raimondo G., Burk R. D., Lieberman H. M., Muschel J., Hadziyannis S. J., Will H., Kew M. C., Dusheiko G. M., Shafritz D. A. Interrupted replication of hepatitis B virus in liver tissue of HBsAg carriers with hepatocellular carcinoma. Virology. 1988 Sep;166(1):103–112. doi: 10.1016/0042-6822(88)90151-1. [DOI] [PubMed] [Google Scholar]
  20. Schweizer A., Matter K., Ketcham C. M., Hauri H. P. The isolated ER-Golgi intermediate compartment exhibits properties that are different from ER and cis-Golgi. J Cell Biol. 1991 Apr;113(1):45–54. doi: 10.1083/jcb.113.1.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Standring D. N., Ou J. H., Rutter W. J. Assembly of viral particles in Xenopus oocytes: pre-surface-antigens regulate secretion of the hepatitis B viral surface envelope particle. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9338–9342. doi: 10.1073/pnas.83.24.9338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Vannice J. L., Levinson A. D. Properties of the human hepatitis B virus enhancer: position effects and cell-type nonspecificity. J Virol. 1988 Apr;62(4):1305–1313. doi: 10.1128/jvi.62.4.1305-1313.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wands J. R., Liang T. J., Blum H. E., Shafritz D. A. Molecular pathogenesis of liver disease during persistent hepatitis B virus infection. Semin Liver Dis. 1992 Aug;12(3):252–264. doi: 10.1055/s-2007-1007397. [DOI] [PubMed] [Google Scholar]
  24. Zhou D. X., Yen T. S. Differential regulation of the hepatitis B virus surface gene promoters by a second viral enhancer. J Biol Chem. 1990 Dec 5;265(34):20731–20734. [PubMed] [Google Scholar]
  25. Zhou D. X., Yen T. S. The hepatitis B virus S promoter comprises A CCAAT motif and two initiation regions. J Biol Chem. 1991 Dec 5;266(34):23416–23421. [PubMed] [Google Scholar]
  26. Zhou D. X., Yen T. S. The ubiquitous transcription factor Oct-1 and the liver-specific factor HNF-1 are both required to activate transcription of a hepatitis B virus promoter. Mol Cell Biol. 1991 Mar;11(3):1353–1359. doi: 10.1128/mcb.11.3.1353. [DOI] [PMC free article] [PubMed] [Google Scholar]

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