Article first published online: 19 AUG 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 4, pages 1179–1189, October 2011
How to Cite
Han, Q., Zhang, C., Zhang, J. and Tian, Z. (2011), Reversal of hepatitis B virus-induced immune tolerance by an immunostimulatory 3p-HBx-siRNAs in a retinoic acid inducible gene I–dependent manner. Hepatology, 54: 1179–1189. doi: 10.1002/hep.24505
Potential conflict of interest: Nothing to report.
This work was supported by grants from the Natural Science Foundation of China (#90713033), the National 973 Basic Research Program of China (#2007CB815803), and the National 115 Key Project for HBV Research (#2008ZX10002-008).
- Issue published online: 27 SEP 2011
- Article first published online: 19 AUG 2011
- Accepted manuscript online: 30 JUN 2011 07:10PM EST
- Manuscript Accepted: 5 JUN 2011
- Manuscript Received: 10 JAN 2011
It is extensively accepted that hepatitis B virus (HBV) escapes from innate immunity by inhibiting type I interferon (IFN) production, but efficient intervention to reverse the immune tolerance is still not achieved. Here, we report that 5′-end triphosphate hepatitis B virus X gene (HBx)-RNAs (3p-HBx-short interfering [si]RNAs) exerted significantly stronger inhibitory effects on HBV replication than regular HBx-siRNAs in stably HBV-expressing hepatoplastoma HepG2.2.15 cells through extremely higher expression of type I IFNs, IFN-induced genes and proinflammatory cytokines, and retinoic acid inducible gene I (RIG-I) activation. Also, 3p-HBx-siRNA were more efficient to stimulate type I IFN response than HBx sequence-unrelated 3p-scramble-siRNA in HepG2.2.15 cells, indicating that a stronger immune-stimulating effect may partly result from the reversal of immune tolerance through decreasing HBV load. In RIG-I-overexpressed HepG2.2.15 cells, 3p-HBx-siRNAs exerted stronger inhibitory effects on HBV replication with greater production of type I IFNs; on the contrary, in RIG-I-silenced HepG2.2.15 cells or after blockade of IFN receptor by monoclocnal antibody, inhibitory effect of 3p-HBx-siRNAs on HBV replication was largely attenuated, indicating that immunostimulatory function of 3p-HBx-siRNAs was RIG-I and type I IFN dependent. Moreover, in HBV-carrier mice, 3p-HBx-siRNA more strongly inhibited HBV replication and promoted IFN production than HBx-siRNA in primary HBV+ hepatocytes and, therefore, significantly decreased serum hepatitis B surface antigen and increased serum IFN-β. Conclusion: 3p-HBx-siRNAs may not only directly inhibit HBV replication, but also stimulate innate immunity against HBV, which are both beneficial for the inversion of HBV-induced immune tolerance. (HEPATOLOGY 2011;)