Display options
Cite
Chauhan R, Churchill ND, Mulrooney-Cousins PM, et al. Initial sites of hepadnavirus integration into host genome in human hepatocytes and in the woodchuck model of hepatitis B-associated hepatocellular carcinoma. Oncogenesis. 2017;6(4):e317doi: 10.1038/oncsis.2017.22.
Chauhan, R., Churchill, N. D., Mulrooney-Cousins, P. M., & Michalak, T. I. (2017). Initial sites of hepadnavirus integration into host genome in human hepatocytes and in the woodchuck model of hepatitis B-associated hepatocellular carcinoma. Oncogenesis, 6(4), e317. https://doi.org/10.1038/oncsis.2017.22
Chauhan, R, et al. "Initial sites of hepadnavirus integration into host genome in human hepatocytes and in the woodchuck model of hepatitis B-associated hepatocellular carcinoma." Oncogenesis vol. 6,4 (2017): e317. doi: https://doi.org/10.1038/oncsis.2017.22
Chauhan R, Churchill ND, Mulrooney-Cousins PM, Michalak TI. Initial sites of hepadnavirus integration into host genome in human hepatocytes and in the woodchuck model of hepatitis B-associated hepatocellular carcinoma. Oncogenesis. 2017 Apr 17;6(4):e317. doi: 10.1038/oncsis.2017.22. PMID: 28414318; PMCID: PMC5520499.
Copy Download .nbib Format: NLM
Share it on

Oncogenesis. 2017 Apr 17;6(4):e317. doi: 10.1038/oncsis.2017.22.

Initial sites of hepadnavirus integration into host genome in human hepatocytes and in the woodchuck model of hepatitis B-associated hepatocellular carcinoma.

Oncogenesis

R Chauhan, N D Churchill, P M Mulrooney-Cousins, T I Michalak

Affiliations

  1. Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Health Sciences Centre, Memorial University, St John's, Newfoundland and Labrador, St John's, NL, Canada.

PMID: 28414318 PMCID: PMC5520499 DOI: 10.1038/oncsis.2017.22

Abstract

Hepatitis B virus (HBV) and the closely related woodchuck hepatitis virus (WHV) are potent carcinogens that trigger development of primary hepatocellular carcinoma (HCC). The initial sites of hepadnavirus-host genome integration, their diversity and kinetics of formation can be central to virus persistence and the initiation and progression of HCC. To recognize the nature of the very early virus-host interactions, we explored de novo infection of human hepatocyte-like HepaRG cells with authentic HBV and naive woodchucks with WHV. HepaRG were analyzed from several minutes post exposure to HBV onwards, whereas woodchuck liver biopsies at 1 or 3 h and 6 weeks post infection with WHV. Inverse PCR and clonal sequencing of the amplicons were applied to identify virus-host genomic junctions. HBV and WHV DNA and their replication intermediates became detectable in one hour after virus exposure. Concomitantly, HBV DNA integration into various host genes was detected. Notably, junctions of HBV X gene with retrotransposon sequences, such as LINE1 and LINE2, became prominent shortly after infection. In woodchucks, insertion of WHV X and preS sequences into host genome was evident at 1 and 3 h post infection (h.p.i.), confirming that hepadnavirus under natural conditions integrates into hepatocyte DNA soon after invasion. The HBV and WHV X gene enhancer II/core promotor sequence most often formed initial junctions with host DNA. Moreover, multiple virus-virus DNA fusions appeared from 1 h.p.i. onwards in both infected hepatocytes and woodchuck livers. In summary, HBV DNA integrates almost immediately after infection with a variety of host's sequences, among which tandemly repeating non-coding DNAs are common. This study revealed that HBV can engage mobile genetic elements from the beginning of infection to induce pro-oncogenic perturbations throughout the host genome. Such swift virus insertion was also evident in natural hepadnaviral infection in woodchucks.

References

  1. J Clin Transl Hepatol. 2015 Sep 28;3(3):211-9 - PubMed
  2. Gastroenterology. 2007 May;132(5):1937-46 - PubMed
  3. Hepatology. 2011 Sep 2;54(3):829-36 - PubMed
  4. Nat Genet. 2012 May 27;44(7):765-9 - PubMed
  5. Mol Cell Biochem. 2006 Oct;290(1-2):79-85 - PubMed
  6. Nucleic Acids Res. 2013 Jan;41(Database issue):D70-82 - PubMed
  7. J Clin Invest. 1994 Jan;93(1):230-9 - PubMed
  8. Gastroenterology. 2004 Jan;126(1):102-10 - PubMed
  9. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6634-9 - PubMed
  10. Gastroenterology. 2008 May;134(5):1470-81 - PubMed
  11. J Hepatol. 2016 Feb;64(2):278-91 - PubMed
  12. J Virol. 2004 Feb;78(4):1730-8 - PubMed
  13. ALTEX. 2003;20(3):131-42 - PubMed
  14. Elife. 2012 Nov 13;1:e00049 - PubMed
  15. J Virol. 2008 Sep;82(17):8579-91 - PubMed
  16. Virology. 1986 Jul 30;152(2):477-82 - PubMed
  17. Cancer Cell. 2014 Mar 17;25(3):335-49 - PubMed
  18. Liver Transpl. 2011 Aug;17(8):955-62 - PubMed
  19. J Hepatol. 2016 Apr;64(1 Suppl):S84-101 - PubMed
  20. J Virol. 1993 Aug;67(8):4867-74 - PubMed
  21. Hepatology. 2002 Jan;35(1):217-23 - PubMed
  22. Cell. 2013 Mar 28;153(1):101-11 - PubMed
  23. J Virol. 1995 Sep;69(9):5697-704 - PubMed
  24. J Virol. 2013 Jan;87(2):1035-48 - PubMed
  25. PLoS Genet. 2012;8(12):e1003065 - PubMed
  26. J Virol. 1986 Sep;59(3):731-4 - PubMed
  27. Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11135-40 - PubMed
  28. J Virol. 1990 Feb;64(2):822-8 - PubMed
  29. Nat Rev Gastroenterol Hepatol. 2010 Aug;7(8):448-58 - PubMed
  30. Hepatology. 2012 Feb;55(2):373-83 - PubMed
  31. PLoS Pathog. 2013 Jan;9(1):e1003125 - PubMed
  32. Cold Spring Harb Perspect Med. 2015 Apr 01;5(4):null - PubMed
  33. Nucleic Acids Res. 2015 Feb 27;43(4):2188-98 - PubMed
  34. Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):15148-53 - PubMed
  35. Microbiol Spectr. 2015 Apr;3(2):MDNA3-0061-2014 - PubMed
  36. PLoS Pathog. 2014 Aug 28;10(8):e1004332 - PubMed
  37. J Virol. 1995 Jun;69(6):3647-57 - PubMed
  38. Biomark Cancer. 2016 Jul 04;8(Suppl 1):37-55 - PubMed
  39. Science. 2011 Feb 4;331(6017):593-6 - PubMed
  40. Curr Biol. 2012 Feb 21;22(4):320-5 - PubMed
  41. Hum Mutat. 2008 May;29(5):703-8 - PubMed
  42. Eur J Cancer. 2010 Aug;46(12):2178-86 - PubMed
  43. PLoS Pathog. 2013 Jan;9(1):e1003161 - PubMed
  44. Oncogene. 1988 Nov;3(5):545-52 - PubMed
  45. Nucleic Acids Res. 2011 Oct;39(19):8457-71 - PubMed
  46. Nature. 1986 Nov 20-26;324(6094):276-9 - PubMed
  47. Liver Int. 2015 Oct;35(10):2311-7 - PubMed
  48. Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15655-60 - PubMed
  49. Nucleic Acids Res. 2013 Jan;41(Database issue):D83-9 - PubMed
  50. J Cell Biochem. 2011 Nov;112(11):3440-8 - PubMed
  51. World J Gastroenterol. 2014 Jan 14;20(2):425-35 - PubMed
  52. Structure. 1995 Feb 15;3(2):131-4 - PubMed
  53. J Virol. 1990 Sep;64(9):4281-7 - PubMed
  54. J Clin Invest. 1999 Jul;104(2):203-12 - PubMed
  55. Nat Genet. 2012 May 27;44(7):760-4 - PubMed
  56. Gastroenterology. 2004 Nov;127(5 Suppl 1):S283-93 - PubMed
  57. J Gen Virol. 2009 Jan;90(Pt 1):127-35 - PubMed
  58. Hepatology. 1989 Mar;9(3):461-70 - PubMed
  59. J Virol. 2010 Aug;84(16):8308-15 - PubMed
  60. Genes Dev. 1987 Oct;1(8):773-82 - PubMed
  61. Hepatology. 1999 Mar;29(3):928-38 - PubMed
  62. Cell Host Microbe. 2014 Mar 12;15(3):249-50 - PubMed

Publication Types