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Journal of General Virology header logo Journal of General Virology

Volume 92, Issue 3

Establishing a new animal model for hepadnaviral infection: susceptibility of Chinese -species to woodchuck hepatitis virus infection No Access

Abstract

Hepatitis B virus infection (HBV) is a major medical problem in China. The lack of a suitable infection model in China is recognized as an obstacle for research on HBV in China. Chinese -species is phylogenetically closely related to , thus, it might be suitable to serve as an animal model for HBV infection. Therefore, we attempted to prove the claim about the existence of woodchuck hepatitis virus (WHV)-like viruses in Chinese -species and to determine the susceptibility of these species to experimental WHV infection. In the present study, 653 sera from three Chinese -species, , and , were screened for WHV-like viruses by serological and molecular assays. The susceptibility to WHV of three species was investigated by experimental infection and monitored by testing of anti-WHc and WHsAg by ELISA, detection of WHV DNA by PCR, and detection of WHV replication intermediates and antigens in liver samples. No evidence for the existence of a genetically closely related virus to WHV in three Chinese -species was found by serological assays and PCR. was susceptible to WHV infection as inoculated animals became positive for anti-WHc, WHsAg and WHV DNA. Further, WHV replication intermediates and proteins were detected in liver samples. In contrast, remained negative for tested virological parameters. species showed a limited susceptibility to WHV. Our data do not support early reports about WHV-like viruses in China. is suitable for the establishment of a model for hepadnaviral infection.

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2011-03-01
2025-03-19
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References

  1. Beasley, R. P., Hwang, L. Y., Lin, C. C. & Chien, C. S.(1981). Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 318, 1129–1133.[CrossRef] [Google Scholar]
  2. Cardini, A.(2003). The geometry of the marmot (Rodentia: Sciuridae) mandible: phylogeny and patterns of morphological evolution. Syst Biol 52, 186–205.[CrossRef] [Google Scholar]
  3. Colonno, R. J., Genovesi, E. V., Medina, I., Lamb, L., Durham, S. K., Huang, M. L., Corey, L., Littlejohn, M., Locarnini, S. & other authors(2001). Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection. J Infect Dis 184, 1236–1245.[CrossRef] [Google Scholar]
  4. Cote, P. J. & Gerin, J. L.(1995). In vitro activation of woodchuck lymphocytes measured by radiopurine incorporation and interleukin-2 production: implications for modeling immunity and therapy in hepatitis B virus infection. Hepatology 22, 687–699. [Google Scholar]
  5. Cote, P. J., Korba, B. E., Steinberg, H., Ramirez-Mejia, C., Baldwin, B., Hornbuckle, W. E., Tennant, B. C. & Gerin, J. L.(1991). Cyclosporin A modulates the course of woodchuck hepatitis virus infection and induces chronicity. J Immunol 146, 3138–3144. [Google Scholar]
  6. Cote, P. J., Korba, B. E., Baldwin, B., Hornbuckle, W. E., Tennant, B. C. & Gerin, J. L.(1992). Immunosuppression with cyclosporine during the incubation period of experimental woodchuck hepatitis virus infection increases the frequency of chronic infection in adult woodchucks. J Infect Dis 166, 628–631.[CrossRef] [Google Scholar]
  7. Cote, P. J., Korba, B. E., Miller, R. H., Jacob, J. R., Baldwin, B. H., Hornbuckle, W. E., Purcell, R. H., Tennant, B. C. & Gerin, J. L.(2000). Effects of age and viral determinants on chronicity as an outcome of experimental woodchuck hepatitis virus infection. Hepatology 31, 190–200.[CrossRef] [Google Scholar]
  8. Dahmen, U., Li, J., Dirsch, O., Fiedler, M., Lu, M., Roggendorf, M. & Broelsch, C. E.(2002). A new model of hepatitis B virus reinfection: liver transplantation in the woodchuck1. Transplantation 74, 373–380.[CrossRef] [Google Scholar]
  9. Fiedler, M., Lu, M., Siegel, F., Whipple, J. & Roggendorf, M.(2001). Immunization of woodchucks (Marmota monax) with hepatitis delta virus DNA vaccine. Vaccine 19, 4618–4626.[CrossRef] [Google Scholar]
  10. Freiman, J. S., Jilbert, A. R., Dixon, R. J., Holmes, M., Gowans, E. J., Burrell, C. J., Wills, E. J. & Cossart, Y. E.(1988). Experimental duck hepatitis B virus infection: pathology and evolution of hepatic and extrahepatic infection. Hepatology 8, 507–513.[CrossRef] [Google Scholar]
  11. Galibert, F., Chen, T. N. & Mandart, E.(1981). Localization and nucleotide sequence of the gene coding for the woodchuck hepatitis virus surface antigen: comparison with the gene coding for the human hepatitis B virus surface antigen. Proc Natl Acad Sci U S A 78, 5315–5319.[CrossRef] [Google Scholar]
  12. Guidotti, L. G., Rochford, R., Chung, J., Shapiro, M., Purcell, R. & Chisari, F. V.(1999). Viral clearance without destruction of infected cells during acute HBV infection. Science 284, 825–829.[CrossRef] [Google Scholar]
  13. Guo, J. T., Zhou, H., Liu, C., Aldrich, C., Saputelli, J., Whitaker, T., Barrasa, M. I., Mason, W. S. & Seeger, C.(2000). Apoptosis and regeneration of hepatocytes during recovery from transient hepadnavirus infections. J Virol 74, 1495–1505.[CrossRef] [Google Scholar]
  14. Hsu, T., Möröy, T., Etiemble, J., Louise, A., Trépo, C., Tiollais, P. & Buendia, M. A.(1988). Activation of c-myc by woodchuck hepatitis virus insertion in hepatocellular carcinoma. Cell 55, 627–635.[CrossRef] [Google Scholar]
  15. Jin, Z. H., Zhao, G. L., Ziong, S. S., Kou, P. Y., Ma, L. L., Chen, H. T., Qi, J. Y., Ba, Q. J. & Mai, K.(1988). An experimental transmission of woodchuck hepatitis virus to young Chinese marmots. Hepatology 8, 371–373.[CrossRef] [Google Scholar]
  16. Jung, M. C. & Pape, G. R.(2002). Immunology of hepatitis B infection. Lancet Infect Dis 2, 43–50.[CrossRef] [Google Scholar]
  17. Kajino, K., Jilbert, A. R., Saputelli, J., Aldrich, C. E., Cullen, J. & Mason, W. S.(1994). Woodchuck hepatitis virus infections: very rapid recovery after a prolonged viremia and infection of virtually every hepatocyte. J Virol 68, 5792–5803. [Google Scholar]
  18. Korba, B. E., Cote, P., Hornbuckle, W., Tennant, B. C. & Gerin, J. L.(2000). Treatment of chronic woodchuck hepatitis virus infection in the Eastern woodchuck (Marmota monax) with nucleoside analogues is predictive of therapy for chronic hepatitis B virus infection in humans. Hepatology 31, 1165–1175.[CrossRef] [Google Scholar]
  19. Kremsdorf, D., Soussan, P., Paterlini-Brechot, P. & Brechot, C.(2006). Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis. Oncogene 25, 3823–3833.[CrossRef] [Google Scholar]
  20. Lohrengel, B., Lu, M. & Roggendorf, M.(1998). Molecular cloning of the woodchuck cytokines: TNFα, IFN-γ, and IL-6. Immunogenetics 47, 332–335.[CrossRef] [Google Scholar]
  21. Lu, M. & Roggendorf, M.(2001). Evaluation of new approaches to prophylactic and therapeutic vaccinations against hepatitis B viruses in the woodchuck model. Intervirology 44, 124–131.[CrossRef] [Google Scholar]
  22. Lu, M., Hilken, G., Yang, D., Kemper, T. & Roggendorf, M.(2001). Replication of naturally occurring woodchuck hepatitis virus deletion mutants in primary hepatocyte cultures and after transmission to naive woodchucks. J Virol 75, 3811–3818.[CrossRef] [Google Scholar]
  23. Lu, M., Lohrengel, B., Hilken, G., Kemper, T. & Roggendorf, M.(2002). Woodchuck gamma interferon upregulates major histocompatibility complex class I transcription but is unable to deplete woodchuck hepatitis virus replication intermediates and RNAs in persistently infected woodchuck primary hepatocytes. J Virol 76, 58–67.[CrossRef] [Google Scholar]
  24. Lu, M., Menne, S., Yang, D., Xu, Y. & Roggendorf, M.(2007). Immunomodulation as an option for the treatment of chronic hepatitis B virus infection: preclinical studies in the woodchuck model. Expert Opin Investig Drugs 16, 787–801.[CrossRef] [Google Scholar]
  25. Lu, Y., Wang, B., Huang, H., Tian, Y., Bao, J., Dong, J., Roggendorf, M., Lu, M. & Yang, D.(2008). The interferon-α gene family of Marmota himalayana, a Chinese marmot species with susceptibility to woodchuck hepatitis virus infection. Dev Comp Immunol 32, 445–457.[CrossRef] [Google Scholar]
  26. Marion, P. L., Oshiro, L. S., Regnery, D. C., Scullard, G. H. & Robinson, W. S.(1980). A virus in Beechey ground squirrels that is related to hepatitis B virus of humans. Proc Natl Acad Sci U S A 77, 2941–2945.[CrossRef] [Google Scholar]
  27. Mason, W. S., Seal, G. & Summers, J.(1980). Virus of Pekin ducks with structural and biological relatedness to human hepatitis B virus. J Virol 36, 829–836. [Google Scholar]
  28. Mason, W. S., Aldrich, C., Summers, J. & Taylor, J. M.(1982). Asymmetric replication of duck hepatitis B virus DNA in liver cells: free minus-strand DNA. Proc Natl Acad Sci U S A 79, 3997–4001.[CrossRef] [Google Scholar]
  29. Mason, W. S., Cullen, J., Moraleda, G., Saputelli, J., Aldrich, C. E., Miller, D. S., Tennant, B., Frick, L., Averett, D. & other authors(1998). Lamivudine therapy of WHV-infected woodchucks. Virology 245, 18–32.[CrossRef] [Google Scholar]
  30. Mason, W. S., Jilbert, A. R. & Summers, J.(2005). Clonal expansion of hepatocytes during chronic woodchuck hepatitis virus infection. Proc Natl Acad Sci U S A 102, 1139–1144.[CrossRef] [Google Scholar]
  31. Menne, S., Maschke, J., Tolle, T. K., Lu, M. & Roggendorf, M.(1997). Characterization of T-cell response to woodchuck hepatitis virus core protein and protection of woodchucks from infection by immunization with peptides containing a T-cell epitope. J Virol 71, 65–74. [Google Scholar]
  32. Menne, S., Maschke, J., Lu, M., Grosse-Wilde, H. & Roggendorf, M.(1998). T-Cell response to woodchuck hepatitis virus (WHV) antigens during acute self-limited WHV infection and convalescence and after viral challenge. J Virol 72, 6083–6091. [Google Scholar]
  33. Michalak, T. I., Mulrooney, P. M. & Coffin, C. S.(2004). Low doses of hepadnavirus induce infection of the lymphatic system that does not engage the liver. J Virol 78, 1730–1738.[CrossRef] [Google Scholar]
  34. Molnar-Kimber, K. L., Summers, J., Taylor, J. M. & Mason, W. S.(1983). Protein covalently bound to minus-strand DNA intermediates of duck hepatitis B virus. J Virol 45, 165–172. [Google Scholar]
  35. Muchmore, E. A.(2001). Chimpanzee models for human disease and immunobiology. Immunol Rev 183, 86–93.[CrossRef] [Google Scholar]
  36. Murray, J. M., Wieland, S. F., Purcell, R. H. & Chisari, F. V.(2005). Dynamics of hepatitis B virus clearance in chimpanzees. Proc Natl Acad Sci U S A 102, 17780–17785.[CrossRef] [Google Scholar]
  37. Nakamura, I., Nupp, J. T., Cowlen, M., Hall, W. C., Tennant, B. C., Casey, J. L., Gerin, J. L. & Cote, P. J.(2001). Pathogenesis of experimental neonatal woodchuck hepatitis virus infection: chronicity as an outcome of infection is associated with a diminished acute hepatitis that is temporally deficient for the expression of interferon gamma and tumor necrosis factor-alpha messenger RNAs. Hepatology 33, 439–447.[CrossRef] [Google Scholar]
  38. Ogata, N., Cote, P. J., Zanetti, A. R., Miller, R. H., Shapiro, M., Gerin, J. & Purcell, R. H.(1999). Licensed recombinant hepatitis B vaccines protect chimpanzees against infection with the prototype surface gene mutant of hepatitis B virus. Hepatology 30, 779–786.[CrossRef] [Google Scholar]
  39. Peek, S. F., Cote, P. J., Jacob, J. R., Toshkov, I. A., Hornbuckle, W. E., Baldwin, B. H., Wells, F. V., Chu, C. K., Gerin, J. L. & other authors(2001). Antiviral activity of clevudine [L-FMAU, (1-(2-fluoro-5-methyl-β, L-arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax). Hepatology 33, 254–266.[CrossRef] [Google Scholar]
  40. Prince, A. M. & Brotman, B.(2001). Perspectives on hepatitis B studies with chimpanzees. ILAR J 42, 85–88.[CrossRef] [Google Scholar]
  41. Roggendorf, M. & Lu, M.(2005). Woodchuck hepatitis virus. In Viral Hepatitis, 3rd edn, pp. 210–224. Edited by Thomas, T. H., Zuckermann, A. & Lemon, S.. Oxford. : Blackwell. . [Google Scholar]
  42. Roggendorf, M. & Tolle, T. K.(1995). The woodchuck: an animal model for hepatitis B virus infection in man. Intervirology 38, 100–112. [Google Scholar]
  43. Rollier, C., Sunyach, C., Barraud, L., Madani, N., Jamard, C., Trepo, C. & Cova, L.(1999). Protective and therapeutic effect of DNA-based immunization against hepadnavirus large envelope protein. Gastroenterology 116, 658–665.[CrossRef] [Google Scholar]
  44. Schultz, U., Grgacic, E. & Nassal, M.(2004). Duck hepatitis B virus: an invaluable model system for HBV infection. Adv Virus Res 63, 1–70. [Google Scholar]
  45. Shepard, C. W., Simard, E. P., Finelli, L., Fiore, A. E. & Bell, B. P.(2006). Hepatitis B virus infection: epidemiology and vaccination. Epidemiol Rev 28, 112–125.[CrossRef] [Google Scholar]
  46. Steppan, S. J., Akhverdyan, M. R., Lyapunova, E. A., Fraser, D. G., Vorontsov, N. N., Hoffmann, R. S. & Braun, M. J.(1999). Molecular phylogeny of the marmots (Rodentia: Sciuridae): tests of evolutionary and biogeographic hypotheses. Syst Biol 48, 715–734.[CrossRef] [Google Scholar]
  47. Summers, J. & Mason, W. S.(1982). Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 29, 403–415.[CrossRef] [Google Scholar]
  48. Summers, J. & Mason, W. S.(2004). Residual integrated viral DNA after hepadnavirus clearance by nucleoside analog therapy. Proc Natl Acad Sci U S A 101, 638–640.[CrossRef] [Google Scholar]
  49. Summers, J., Smolec, J. M. & Snyder, R.(1978). A virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woodchucks. Proc Natl Acad Sci U S A 75, 4533–4537.[CrossRef] [Google Scholar]
  50. Tennant, B. C.(2001). Animal models of hepadnavirus-associated hepatocellular carcinoma. Clin Liver Dis 5, 43–68.[CrossRef] [Google Scholar]
  51. Tennant, B. C. & Gerin, J. L.(2001). The woodchuck model of hepatitis B virus infection. ILAR J 42, 89–102.[CrossRef] [Google Scholar]
  52. Testut, P., Renard, C. A., Terradillos, O., Vitvitski-Trepo, L., Tekaia, F., Degott, C., Blake, J., Boyer, B. & Buendia, M. A.(1996). A new hepadnavirus endemic in arctic ground squirrels in Alaska. J Virol 70, 4210–4219. [Google Scholar]
  53. Thimme, R., Wieland, S., Steiger, C., Ghrayeb, J., Reimann, K. A., Purcell, R. H. & Chisari, F. V.(2003). CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol 77, 68–76.[CrossRef] [Google Scholar]
  54. Triyatni, M., Jilbert, A. R., Qiao, M., Miller, D. S. & Burrell, C. J.(1998). Protective efficacy of DNA vaccines against duck hepatitis B virus infection. J Virol 72, 84–94. [Google Scholar]
  55. Wang, B., Lohrengel, B., Lu, Y., Meng, Z., Xu, Y., Yang, D., Roggendorf, M. & Lu, M.(2005). Molecular characterization of woodchuck interleukin 15 (wIL-15) and detection of its expression in liver samples of woodchucks infected with woodchuck hepatitis virus (WHV). Cytokine 32, 296–303.[CrossRef] [Google Scholar]
  56. Whorley, J. R., Alvarez-Castañeda, S. T. & Kenagy, G. J.(2004). Genetic structure of desert ground squirrels over a 20-degree-latitude transect from Oregon through the Baja California peninsula. Mol Ecol 13, 2709–2720.[CrossRef] [Google Scholar]
  57. Williams, R.(2006). Global challenges in liver disease. Hepatology 44, 521–526.[CrossRef] [Google Scholar]
  58. Yim, H. J. & Lok, A. S.(2006). Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology 43 (Suppl. 1), S173–S181.[CrossRef] [Google Scholar]
  59. Zhang, Z., Tian, Y., Li, L., Fiedler, M., Schmid, E., Roggendorf, M., Xu, Y., Lu, M. & Yang, D.(2006). A conserved linear B-cell epitope at the N-terminal region of woodchuck hepatitis virus core protein (WHcAg). J Virol Methods 135, 17–25.[CrossRef] [Google Scholar]
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Establishing a new animal model for hepadnaviral infection: susceptibility of Chinese Marmota-species to woodchuck hepatitis virus infection
J. Gen. Virol. 92, 681 (2011); https://doi.org/10.1099/vir.0.025023-0
/content/journal/jgv/10.1099/vir.0.025023-0
/content/journal/jgv/10.1099/vir.0.025023-0
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vol. , part 3, pp. 681 - 691

Basic information about the animals included in the study

Primers used for PCR and RT-PCR

Detailed information about Chinese marmots included for b sequence analysis

WHV-like virus DNA screening in sera samples of Chinese marmots [Single PDF file](116 KB)

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