Article first published online: 23 MAY 2013
Copyright © 2013 American Association for the Study of Liver Diseases
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. 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).
- 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;)