Article first published online: 23 MAY 2013
Copyright © 2013 American Association for the Study of Liver Diseases
Volume 58, Issue 1, pages 73–85, July 2013
How to Cite
Lan, P., Zhang, C., Han, Q., Zhang, J. and Tian, Z. (2013), Therapeutic recovery of hepatitis B virus (HBV)-induced hepatocyte-intrinsic immune defect reverses systemic adaptive immune tolerance. Hepatology, 58: 73–85. doi: 10.1002/hep.26339
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).
- Issue published online: 24 JUN 2013
- Article first published online: 23 MAY 2013
- Accepted manuscript online: 27 FEB 2013 09:13AM EST
- Manuscript Accepted: 11 FEB 2013
- Manuscript Received: 23 AUG 2012
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;)