Detection of clonally expanded hepatocytes in chimpanzees with chronic hepatitis B virus infection

William S. Mason, Huey Chi Low, Chunxiao Xu, Carol E. Aldrich, Catherine A. Scougall, Arend Grosse, Andrew Clouston, Deborah Chavez, Samuel Litwin, Suraj Peri, Allison R. Jilbert, Robert E. Lanford

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    44 Scopus citations

    Abstract

    During a hepadnavirus infection, viral DNA integrates at a low rate into random sites in the host DNA, producing unique virus-cell junctions detectable by inverse nested PCR (invPCR). These junctions serve as genetic markers of individual hepatocytes, providing a means to detect their subsequent proliferation into clones of two or more hepatocytes. A previous study suggested that the livers of 2.4-year-old woodchucks (Marmota monax) chronically infected with woodchuck hepatitis virus contained at least 100,000 clones of >1,000 hepatocytes (W. S. Mason, A. R. Jilbert, and J. Summers, Proc. Natl. Acad. Sci. USA 102:1139-1144, 2005). However, possible correlations between sites of viral-DNA integration and clonal expansion could not be explored because the woodchuck genome has not yet been sequenced. In order to further investigate this issue, we looked for similar clonal expansion of hepatocytes in the livers of chimpanzees chronically infected with hepatitis B virus (HBV). Liver samples for invPCR were collected from eight chimpanzees chronically infected with HBV for at least 20 years. Fifty clones ranging in size from ∼35 to 10,000 hepatocytes were detected using invPCR in 32 liver biopsy fragments (∼1 mg) containing, in total, ∼3 x 107 liver cells. Based on searching the analogous human genome, integration sites were found on all chromosomes except Y, ∼30% in known or predicted genes. However, no obvious association between the extent of clonal expansion and the integration site was apparent. This suggests that the integration site per se is not responsible for the outgrowth of large clones of hepatocytes.

    Original languageEnglish (US)
    Pages (from-to)8396-8408
    Number of pages13
    JournalJournal of virology
    Volume83
    Issue number17
    DOIs
    StatePublished - 2009

    ASJC Scopus subject areas

    • Microbiology
    • Immunology
    • Insect Science
    • Virology

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    Mason, W. S., Low, H. C., Xu, C., Aldrich, C. E., Scougall, C. A., Grosse, A., Clouston, A., Chavez, D., Litwin, S., Peri, S., Jilbert, A. R., & Lanford, R. E. (2009). Detection of clonally expanded hepatocytes in chimpanzees with chronic hepatitis B virus infection. Journal of virology, 83(17), 8396-8408. https://doi.org/10.1128/JVI.00700-09