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Reversal of hepatitis B virus‐induced immune tolerance by an immunostimulatory 3p‐HBx‐siRNAs in a retinoic acid inducible gene I–dependent manner
Author(s) -
Han Qiuju,
Zhang Cai,
Zhang Jian,
Tian Zhigang
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24505
Subject(s) - hbx , small interfering rna , hepatitis b virus , biology , immune system , interferon , virology , rna interference , microbiology and biotechnology , cancer research , virus , transfection , cell culture , immunology , rna , gene , biochemistry , genetics
Abstract 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. (H EPATOLOGY 2011;)