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. 1981 Jun;78(6):3906–3910. doi: 10.1073/pnas.78.6.3906

State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and -negative liver diseases.

C Bréchot, M Hadchouel, J Scotto, M Fonck, F Potet, G N Vyas, P Tiollais
PMCID: PMC319682  PMID: 6267609

Abstract

Using the Southern blot technique and cloned hepatitis B virus (HBV) DNA as a probe, we studied the state of HBV DNA in the liver of 13 patients with hepatocellular carcinoma, 17 patients with chronic hepatitis, and 2 patients with acute hepatitis. The hybridization results were compared with the serological and immunohistological data. Integration of HBV DNA in cellular DNA of the liver from patients with hepatocellular carcinoma was demonstrated. In two patients from which tumorous and nontumorous liver tissue samples were available the integration patterns were different. In one patient with hepatitis B e antigen (HBeAg)-positive early hepatocellular carcinoma, free viral DNA was present in the liver. In some patients with HBeAg-negative chronic hepatitis, without tumor, integration of HBV DNA in cellular DNA was also demonstrated. This suggests that HBV is not the only factor involved in the development of a tumor. In patients with HBeAg-positive chronic hepatitis, free viral DNA was detected in the liver. In the two acute hepatitis patients analyzed, the restriction endonuclease patterns strongly suggested HBV DNA integration. Therefore, viral DNA integration seems to occur early in infection. Whatever the form of the disease, discrete bands were observed, suggesting the existence of limited and specific integration sites in host cellular DNA. The presence of integrated or free DNA sequences has implications for antiviral therapy. In addition, detection of HBV DNA in the liver is another sensitive viral marker that could be useful for diagnostic purposes.

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Selected References

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

  1. Brechot C., Pourcel C., Louise A., Rain B., Tiollais P. Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature. 1980 Jul 31;286(5772):533–535. doi: 10.1038/286533a0. [DOI] [PubMed] [Google Scholar]
  2. Brechot C., Trepo C., Ninova-Bradistilova D., Goudeau A., Degott C., Maupas P., Potet F., Benhamou J. P. Hepatitis B core antigen in hepatocytes of patients with chronic active hepatitis. Dig Dis Sci. 1980 Aug;25(8):593–596. doi: 10.1007/BF01318872. [DOI] [PubMed] [Google Scholar]
  3. Chakraborty P. R., Ruiz-Opazo N., Shouval D., Shafritz D. A. Identification of integrated hepatitis B virus DNA and expression of viral RNA in an HBsAg-producing human hepatocellular carcinoma cell line. Nature. 1980 Jul 31;286(5772):531–533. doi: 10.1038/286531a0. [DOI] [PubMed] [Google Scholar]
  4. Charnay P., Pourcel C., Louise A., Fritsch A., Tiollais P. Cloning in Escherichia coli and physical structure of hepatitis B virion DNA. Proc Natl Acad Sci U S A. 1979 May;76(5):2222–2226. doi: 10.1073/pnas.76.5.2222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chenciner N., Meneguzzi G., Corallini A., Grossi M. P., Grassi P., Barbanti-Brodano G., Milanesi G. Integrated and free viral DNA in hamster tumors induced by BK virus. Proc Natl Acad Sci U S A. 1980 Feb;77(2):975–979. doi: 10.1073/pnas.77.2.975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Edman J. C., Gray P., Valenzuela P., Rall L. B., Rutter W. J. Integration of hepatitis B virus sequences and their expression in a human hepatoma cell. Nature. 1980 Jul 31;286(5772):535–538. doi: 10.1038/286535a0. [DOI] [PubMed] [Google Scholar]
  7. Hirschman S. Z. Integrator enzyme hypothesis for replication of hepatitis-B virus. Lancet. 1975 Sep 6;2(7932):436–438. doi: 10.1016/s0140-6736(75)90847-8. [DOI] [PubMed] [Google Scholar]
  8. Kojima M., Udo K., Takahashi Y., Yoshizawa H., Tsuda F., Itoh Y., Miyakawa Y., Mayumi M. Correlation between titer of antibody to hepatitis B core antigen and presence of viral antigens in the liver. Gastroenterology. 1977 Oct;73(4 Pt 1):664–667. [PubMed] [Google Scholar]
  9. Lutwick L. I., Robinson W. S. DNA synthesized in the hepatitis B Dane particle DNA polymerase reaction. J Virol. 1977 Jan;21(1):96–104. doi: 10.1128/jvi.21.1.96-104.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Marion P. L., Salazar F. H., Alexander J. J., Robinson W. S. State of hepatitis B viral DNA in a human hepatoma cell line. J Virol. 1980 Feb;33(2):795–806. doi: 10.1128/jvi.33.2.795-806.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Obata H., Hayashi N., Motoike Y., Hisamitsu T., Okuda H., Kobayashi S., Nishioka K. A prospective study on the development of hepatocellular carcinoma from liver cirrhosis with persistent hepatitis B virus infection. Int J Cancer. 1980 Jun 15;25(6):741–747. doi: 10.1002/ijc.2910250609. [DOI] [PubMed] [Google Scholar]
  12. Omata M., Afroudakis A., Liew C. T., Ashcavai M., Peters R. L. Comparison of serum hepatitis B surface antigen (HBsAg) and serum anticore with tissue HBsAg and hepatitis B core antigen (HBcAg). Gastroenterology. 1978 Dec;75(6):1003–1009. [PubMed] [Google Scholar]
  13. Ray M. B., Desmet V. J., Bradburne A. F., Desmyter J., Fevery J., De Groote J. Differential distribution of hepatitis B surface antigen and hepatitis B core antigen in the liver of hepatitis B patients. Gastroenterology. 1976 Sep;71(3):462–469. [PubMed] [Google Scholar]
  14. Shouval D., Chakraborty P. R., Ruiz-Opazo N., Baum S., Spigland I., Muchmore E., Gerber M. A., Thung S. N., Popper H., Shafritz D. A. Chronic hepatitis in chimpanzee carriers of hepatitis B virus: morphologic, immunologic, and viral DNA studies. Proc Natl Acad Sci U S A. 1980 Oct;77(10):6147–6151. doi: 10.1073/pnas.77.10.6147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Sninsky J. J., Siddiqui A., Robinson W. S., Cohen S. N. Cloning and endonuclease mapping of the hepatitis B viral genome. Nature. 1979 May 24;279(5711):346–348. doi: 10.1038/279346a0. [DOI] [PubMed] [Google Scholar]
  16. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  17. Spero J. A., Lewis J. H., Van Theil D. H., Hasiba U., Rabin B. S. Asymptomatic structural liver disease in hemophilia. N Engl J Med. 1978 Jun 22;298(25):1373–1378. doi: 10.1056/NEJM197806222982501. [DOI] [PubMed] [Google Scholar]
  18. Szmuness W. Hepatocellular carcinoma and the hepatitis B virus: evidence for a causal association. Prog Med Virol. 1978;24:40–69. [PubMed] [Google Scholar]
  19. Thomas H. C., Bassendine M. F. Immunological and anti-viral therapy of chronic hepatitis B virus infection. Clin Gastroenterol. 1980 Jan;9(1):85–95. [PubMed] [Google Scholar]
  20. Trepo C., Vitvitski L., Hantz O., Grimaud J. A. Virus de l'hépatite non A non B: démonstration d'une double parenté antigénique et structurale avec le virus de l'hépatite B. C R Seances Acad Sci D. 1980 Jan 28;290(4):343–346. [PubMed] [Google Scholar]
  21. Valenzuela P., Gray P., Quiroga M., Zaldivar J., Goodman H. M., Rutter W. J. Nucleotide sequence of the gene coding for the major protein of hepatitis B virus surface antigen. Nature. 1979 Aug 30;280(5725):815–819. doi: 10.1038/280815a0. [DOI] [PubMed] [Google Scholar]
  22. Wahl G. M., Stern M., Stark G. R. Efficient transfer of large DNA fragments from agarose gels to diazobenzyloxymethyl-paper and rapid hybridization by using dextran sulfate. Proc Natl Acad Sci U S A. 1979 Aug;76(8):3683–3687. doi: 10.1073/pnas.76.8.3683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Weinberg R. A. Integrated genomes of animal viruses. Annu Rev Biochem. 1980;49:197–226. doi: 10.1146/annurev.bi.49.070180.001213. [DOI] [PubMed] [Google Scholar]
  24. Wright R. Type B hepatitis: progression to chronic hepatitis. Clin Gastroenterol. 1980 Jan;9(1):97–115. [PubMed] [Google Scholar]

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