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Establishment and application of hepatitis B virus persistent replication model in IFNAR−/− mouse

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Summary

The type I interferon and IFNAR play an important role in hepatitis B virus (HBV) infection and anti-HBV therapy. However, its mechanism of action is still poorly understood. To gain more insights into the role of type I interferon and type I interferon receptor (IFNAR) in HBV infection, we established an HBV persistent replication IFNAR knockout (IFNAR−/−) mouse model and preliminarily applied this model. At first, the progeny of IFNAR−/− mouse was reproduced. Then hydrodynamic injection with pAAV/HBV1.2 plasmid was conducted to establish the persistent HBV replication IFNAR−/− mouse model. At last, we applied this model to evaluate the effect of nucleoside analogues entecavir (ETV) on HBV replication. It was found that there was no difference in the serum HBsAg and HBeAg levels and HBcAg expression in the liver tissue between the ETV treated groups and normal saline (NS) treated group, but the serum HBV DNA levels were significantly suppressed 10, 25, 40 and 55 days after the ETV treatment [P=0.035, P=0.00, P=0.149 and P=0.084, IFNAR knockout (KO) control group vs. C57BL/6 ETV groups, respectively; P=0.081, P=0.001, P=0.243 and P=0.147, IFNAR KO control group vs. IFNAR KO ETV groups, respectively]. Interestingly, there was no difference in serum HBV DNA levels between the ETV treated IFNAR−/− and C57BL/6 mice. This result suggests that HBV suppression during ETV treatments doesn’t depend on type I interferon and IFNAR. Collectively, persistent HBV replication IFNAR−/− mouse model that we established is a useful and convenient tool to detect the function of the type I interferon and IFNAR in HBV infection and anti-HBV treatments.

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References

  1. Lavanchy D. Worldwide epidemiology of HBV infection, disease burden, and vaccine prevention. J Clin Virol, 2005,34(Suppl 1):S1–3

    Article  PubMed  Google Scholar 

  2. Lai CL, Ratziu V, Yuen MF, et al. Viral hepatitis B. Lancet, 2003,362(9401):2089–2094

    Article  PubMed  CAS  Google Scholar 

  3. Bhattacharya D, Thio CL. Review of hepatitis B therapeutics. Clin Infect Dis, 51(10):1201–1208

  4. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994,264(5164):1415–1421

    Article  PubMed  CAS  Google Scholar 

  5. Huang LR, Wu HL, Chen PJ, et al. An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection. Proc Natl Acad Sci U S A, 2006,103(47):17862–17867

    Article  PubMed  CAS  Google Scholar 

  6. Gao Z, Liu FJ, Liu L, et al. Application of hepatitis B virus replication mouse model. World J Gastroenterol, 2010,16(16):1979–1985

    Article  PubMed  CAS  Google Scholar 

  7. Chen Y, Wu W, Li LJ, et al. Comparison of the results for three automated immunoassay systems in determining serum HBV markers. Clin Chim Acta, 2006,372(1–2): 129–133

    Article  PubMed  CAS  Google Scholar 

  8. Yeh SH, Tsai CY, Kao JH, et al. Quantification and genotyping of hepatitis B virus in a single reaction by real-time PCR and melting curve analysis. J Hepatol, 2004,41(4):659–666

    Article  PubMed  CAS  Google Scholar 

  9. Detre S, Saclani Jotti G, Dowsett M. A “quickscore” method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. J Clin Pathol, 1995,48(9):876–878

    Article  PubMed  CAS  Google Scholar 

  10. Wang BJ, Bao JJ, Wang JZ, et al. Immunostaining of PD-1/PD-Ls in liver tissues of patients with hepatitis and hepatocellular carcinoma. World J Gastroenterol, 17(28): 3322–3329

  11. Liu F, Song Y, Liu D. Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene therapy, 1999,6(7):1258–1266

    Article  PubMed  CAS  Google Scholar 

  12. Yang PL, Althage A, Chung J, et al. Hydrodynamic injection of viral DNA: a mouse model of acute hepatitis B virus infection. Proc Natl Acad Sci U S A, 2002,99(21): 13825–13830

    Article  PubMed  CAS  Google Scholar 

  13. Suzuki T, Takehara T, Ohkawa K, et al. Intravenous injection of naked plasmid DNA encoding hepatitis B virus (HBV) produces HBV and induces humoral immune response in mice. Biochem Biophys Res Commun, 2003,300(3):784–788

    Article  PubMed  CAS  Google Scholar 

  14. Pestka S, Krause CD, Walter MR. Interferons, interferon-like cytokines, and their receptors. Immunol Rev, 2004,202:8–32

    Article  PubMed  CAS  Google Scholar 

  15. Aaronson DS, Horvath CM. A road map for those who don’t know JAK-STAT. Science, 2002,296(5573): 1653–1655

    Article  PubMed  CAS  Google Scholar 

  16. Der SD, Zhou A, Williams BR, et al. Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci U S A, 1998,95(26):15623–15628

    Article  PubMed  CAS  Google Scholar 

  17. Hansen BE, Buster EH, Steyerberg EW, et al. Prediction of the response to peg-interferon-alfa in patients with HBeAg positive chronic hepatitis B using decline of HBV DNA during treatment. J Med Virol, 2010,82(7): 1135–1142

    Article  PubMed  CAS  Google Scholar 

  18. Tian Y, Chen WL, Ou JH. Effects of interferon-alpha/beta on HBV replication determined by viral load. PLoS Pathog, 7(7):e1002159

  19. Zhou J, Huang JD, Poon VK, et al. Functional dissection of an IFN-alpha/beta receptor 1 promoter variant that confers higher risk to chronic hepatitis B virus infection. J Hepatol, 2009,51(2):322–332

    Article  PubMed  CAS  Google Scholar 

  20. Zhou J, Lu L, Yuen MF, et al. Polymorphisms of type I interferon receptor 1 promoter and their effects on chronic hepatitis B virus infection. J Hepatol, 2007,46(2): 198–205

    Article  PubMed  CAS  Google Scholar 

  21. He XX, Chang Y, Jiang HJ, et al. Persistent effect of IFNAR-1 genetic polymorphism on the long-term pathogenesis of chronic HBV infection. Viral Immunol, 23(3): 251–257

  22. Meng F, Wang J, Ge J, et al. Alteration of interferon-alpha/beta receptors in chronic hepatitis B patients. J Clin Immunol, 31(3):521–532

  23. Song CH, Yang B, Chen LM, et al. IL-10 and IFN-γ serum changes during treatment of chronic HBV infection patients with ETV. Weichangbing Xue He Ganbing Xue Zazhi (Chinese), 2010,19(12):1114–1116

    CAS  Google Scholar 

  24. Yin L, Qiao WB, Qu XJ, et al. The study of interferon induced by nucleoside analogues. Shandong Yiyao (Chinese), 1996,36(6): 5–6

    Google Scholar 

  25. Bhattacharya D, Thio CL. Review of hepatitis B therapeutics. Clin Infect Dis, 2010,51(10):1201–1208

    Article  PubMed  CAS  Google Scholar 

  26. Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med, 2006,354(10):1011–1020

    Article  PubMed  CAS  Google Scholar 

  27. Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med, 2006,354(10):1001–1010

    Article  PubMed  CAS  Google Scholar 

  28. Wu J, Lu M, Meng Z, et al. Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice. Hepatology, 2007,46(6):1769–1778

    Article  PubMed  CAS  Google Scholar 

  29. Wu J, Meng Z, Jiang M, et al. Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatology, 2009,49(4):1132–1140

    Article  PubMed  CAS  Google Scholar 

  30. Broering R, Wu J, Meng Z, et al. Toll-like receptor-stimulated non-parenchymal liver cells can regulate hepatitis C virus replication. J Hepatol, 2008,48(6): 914–922

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Ming-fa Chen  (陈明发), Yong Lin  (林 永), You-chen Xia  (夏幼辰), Chan Sun  (孙 潺), Xue-mei Feng  (冯雪梅), Dong-liang Yang  (杨东亮) & Jun Wu  (吴 珺)

  2. Department of Infectious Diseases, the Second Affiliated Hospital, Nanchang University, Nanchang, 330006, China

    Ming-fa Chen  (陈明发)

  3. Institute of Virology, Medical School of Duisburg-Essen University, Essen, 45122, Germany

    Meng-ji Lu  (陆蒙吉)

Authors
  1. Ming-fa Chen  (陈明发)
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  2. Yong Lin  (林 永)
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  3. You-chen Xia  (夏幼辰)
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  4. Chan Sun  (孙 潺)
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  5. Xue-mei Feng  (冯雪梅)
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  6. Meng-ji Lu  (陆蒙吉)
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  7. Dong-liang Yang  (杨东亮)
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  8. Jun Wu  (吴 珺)
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Corresponding authors

Correspondence to Dong-liang Yang  (杨东亮) or Jun Wu  (吴 珺).

Additional information

This project was supported by grants from the National Natural Science Foundation of China (No. 81001313), China Postdoctoral Science Foundation (No. 2009046094), National Science and Technology Major Projects (No. 2008ZX10002-011), National Key Basic Research Program of China (Nos. 2007CB512804 and 2009CB522506) and International Science and Technology Cooperation Program (No. 2011DFA31030)

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Chen, Mf., Lin, Y., Xia, Yc. et al. Establishment and application of hepatitis B virus persistent replication model in IFNAR−/− mouse. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 33, 392–397 (2013). https://doi.org/10.1007/s11596-013-1130-y

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  • DOI: https://doi.org/10.1007/s11596-013-1130-y

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