Therapeutic recovery of hepatitis B virus (HBV)-induced hepatocyte-intrinsic immune defect reverses systemic adaptive immune tolerance

Authors

  • Peixiang Lan,

    1. Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Shandong, China
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  • Cai Zhang,

    Corresponding author
    1. Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Shandong, China
    • Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China; fax: 86-531-8838-3782===

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    • fax: 86-531-8838-3782

  • Qiuju Han,

    1. Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Shandong, China
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  • Jian Zhang,

    1. Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Shandong, China
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  • Zhigang Tian

    Corresponding author
    1. Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Shandong, China
    2. Department of Microbiology and Immunology, School of Life Sciences, University of Science and Technology of China, Anhui, China
    • Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China; fax: 86-531-8838-3782===

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    • fax: 86-531-8838-3782


  • Potential conflict of interest: Nothing to report.

  • Supported by grants from the National 973 Basic Research Program of China (#2013CB944901), the Natural Science Foundation of China (#81273220, #31200651), and the National 115 Key Project for HBV Research (#2008ZX10002-008).

Abstract

Hepatitis B virus (HBV) persistence aggravates hepatic immunotolerance, leading to the failure of cell-intrinsic type I interferon and antiviral response, but whether and how HBV-induced hepatocyte-intrinsic tolerance influences systemic adaptive immunity has never been reported, which is becoming the major obstacle for chronic HBV therapy. In this study, an HBV-persistent mouse, established by hydrodynamic injection of an HBV-genome-containing plasmid, exhibited not only hepatocyte-intrinsic but also systemic immunotolerance to HBV rechallenge. HBV-specific CD8+ T-cell and anti-HBs antibody generation were systemically impaired by HBV persistence in hepatocytes. Interestingly, HBV-induced hepatocyte-intrinsic immune tolerance was reversed when a dually functional vector containing both an immunostimulating single-stranded RNA (ssRNA) and an HBx-silencing short hairpin RNA (shRNA) was administered, and the systemic anti-HBV adaptive immune responses, including CD8+ T-cell and anti-HBs antibody responses, were efficiently recovered. During this process, CD8+ T cells and interferon-gamma (IFN-γ) secreted play a critical role in clearance of HBV. However, when IFN-α/β receptor was blocked or the Toll-like receptor (TLR)7 signaling pathway was inhibited, the activation of CD8+ T cells and clearance of HBV was significantly impaired. Conclusion: These results suggest that recovery of HBV-impaired hepatocyte-intrinsic innate immunity by the dually functional vector might overcome systemic adaptive immunotolerance in an IFN-α- and TLR7-dependent manner. The strategy holds promise for therapeutic intervention of chronic persistent virus infection and associated cancers. (Hepatology 2013;)

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