Clonal expansion of hepatocytes with a selective advantage occurs during all stages of chronic hepatitis B virus infection

T. Tu, W. S. Mason, A. D. Clouston, N. A. Shackel, G. W. McCaughan, M. M. Yeh, Eugene R Schiff, A. R. Ruszkiewicz, J. W. Chen, H. A J Harley, U. H. Stroeher, A. R. Jilbert

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Abstract

Summary Hepatocyte clone size was measured in liver samples of 21 patients in various stages of chronic hepatitis B virus (HBV) infection and from 21 to 76 years of age. Hepatocyte clones containing unique virus-cell DNA junctions formed by the integration of HBV DNA were detected using inverse nested PCR. The maximum hepatocyte clone size tended to increase with age, although there was considerable patient-to-patient variation in each age group. There was an upward trend in maximum clone size with increasing fibrosis, inflammatory activity and with seroconversion from HBV e-antigen (HBeAg)-positive to HBeAg-negative, but these differences did not reach statistical significance. Maximum hepatocyte clone size did not differ between patients with and without a coexisting hepatocellular carcinoma. Thus, large hepatocyte clones containing integrated HBV DNA were detected during all stages of chronic HBV infection. Using laser microdissection, no significant difference in clone size was observed between foci of HBV surface antigen (HBsAg)-positive and HBsAg-negative hepatocytes, suggesting that expression of HBsAg is not a significant factor in clonal expansion. Laser microdissection also revealed that hepatocytes with normal-appearing histology make up a major fraction of the cells undergoing clonal expansion. Thus, preneoplasia does not appear to be a factor in the clonal expansion detected in our assays. Computer simulations suggest that the large hepatocyte clones are not produced by random hepatocyte turnover but have an as-yet-unknown selective advantage that drives increased clonal expansion in the HBV-infected liver.

Original languageEnglish (US)
Pages (from-to)737-753
Number of pages17
JournalJournal of Viral Hepatitis
Volume22
Issue number9
DOIs
StatePublished - Sep 1 2015

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Chronic Hepatitis B
Virus Diseases
Hepatitis B virus
Hepatocytes
Clone Cells
Microdissection
Hepatitis B e Antigens
Surface Antigens
Lasers
Polymerase Chain Reaction
DNA Viruses
Intercellular Junctions
Liver
DNA
Hepatitis B Surface Antigens
Computer Simulation
Hepatocellular Carcinoma
Histology
Fibrosis
Age Groups

Keywords

  • clonal expansion of hepatocytes
  • hepatitis B virus
  • hepatocellular carcinoma
  • inverse nested PCR
  • laser microdissection
  • virus-cell DNA junction

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases
  • Virology

Cite this

Tu, T., Mason, W. S., Clouston, A. D., Shackel, N. A., McCaughan, G. W., Yeh, M. M., ... Jilbert, A. R. (2015). Clonal expansion of hepatocytes with a selective advantage occurs during all stages of chronic hepatitis B virus infection. Journal of Viral Hepatitis, 22(9), 737-753. https://doi.org/10.1111/jvh.12380

Clonal expansion of hepatocytes with a selective advantage occurs during all stages of chronic hepatitis B virus infection. / Tu, T.; Mason, W. S.; Clouston, A. D.; Shackel, N. A.; McCaughan, G. W.; Yeh, M. M.; Schiff, Eugene R; Ruszkiewicz, A. R.; Chen, J. W.; Harley, H. A J; Stroeher, U. H.; Jilbert, A. R.

In: Journal of Viral Hepatitis, Vol. 22, No. 9, 01.09.2015, p. 737-753.

Research output: Contribution to journalArticle

Tu, T, Mason, WS, Clouston, AD, Shackel, NA, McCaughan, GW, Yeh, MM, Schiff, ER, Ruszkiewicz, AR, Chen, JW, Harley, HAJ, Stroeher, UH & Jilbert, AR 2015, 'Clonal expansion of hepatocytes with a selective advantage occurs during all stages of chronic hepatitis B virus infection', Journal of Viral Hepatitis, vol. 22, no. 9, pp. 737-753. https://doi.org/10.1111/jvh.12380
Tu, T. ; Mason, W. S. ; Clouston, A. D. ; Shackel, N. A. ; McCaughan, G. W. ; Yeh, M. M. ; Schiff, Eugene R ; Ruszkiewicz, A. R. ; Chen, J. W. ; Harley, H. A J ; Stroeher, U. H. ; Jilbert, A. R. / Clonal expansion of hepatocytes with a selective advantage occurs during all stages of chronic hepatitis B virus infection. In: Journal of Viral Hepatitis. 2015 ; Vol. 22, No. 9. pp. 737-753.
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