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A mouse model for HBV immunotolerance and immunotherapy

Cellular & Molecular Immunology volume 11, pages 71–78 (2014)Cite this article

Abstract

Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus (HBV) infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus (AAV) carrying a replicable HBV genome (AAV/HBV). Similar to the clinical HBV carriers, the mice infected with AAV/HBV were sero-negative for antibodies against HBV surface antigen (HBsAg). Immunization with the conventional HBV vaccine in the presence of aluminum adjuvant failed to elicit an immune response against HBV in these mice. To identify a vaccine that can potentially circumvent this tolerance, the TLR9 agonist CpG was added to HBsAg as an adjuvant. Vaccination of mice with HBsAg/CpG induced not only clearance of viremia, but also strong antibody production and T-cell responses. Furthermore, both the DNA replication and protein expression of HBV were significantly reduced in the livers of AAV/HBV-infected mice. Accordingly, AAV/HBV-infected mice may be used as a robust model for investigating the underlying mechanism(s) of HBV immunotolerance and for developing novel immunotherapies to eradicate HBV infections.

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Acknowledgements

The authors acknowledge Dr Xiaoyan Dong for providing AAV/HBV and for helpful discussions. This work was supported by grants from the National Basic Research Program 973 of China (Nos. 2009CB522502, 2012CB910203 and 2012CB519000) and the National Science and Technology Major Project of China (No. 2012ZX10002006) to YXF; grants from the Ministry of Science and Technology (2009CB522507, 2010-Biols-CAS-0201 and KSCX20YW-R-150) to LZ; grants from the Ministry of Health (2011ZX10004503-007) to LZ and LS; and funding from the National Institutes of Health (NIH) (R01AI095097) to LS. We would like to give special thanks to Mendy Miller for editing and to the NIH for partial funding (DK095962) provided to Y-XF and LS.

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Author notes

  1. Dan Yang and Longchao Liu: These two authors contribute equally to this work.

Authors and Affiliations

  1. IBP-UC Group for Immunotherapy, CAS Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Dan Yang, Longchao Liu, Danming Zhu, Hua Peng, Yang-Xin Fu & Liguo Zhang

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Dan Yang & Longchao Liu

  3. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Lishan Su

  4. Department of Pathology, the University of Chicago, 924E, 57 Street, Chicago, IL 60637,

    Yang-Xin Fu

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  1. Dan Yang
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Correspondence to Yang-Xin Fu or Liguo Zhang.

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Yang, D., Liu, L., Zhu, D. et al. A mouse model for HBV immunotolerance and immunotherapy. Cell Mol Immunol 11, 71–78 (2014). https://doi.org/10.1038/cmi.2013.43

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