5′-Triphosphate-siRNA activates RIG-I-dependent type i interferon production and enhances inhibition of hepatitis B virus replication in HepG2.2.15 cells

Xiaojuan Chen, Yuanyu Qian, Fei Yan, Jian Tu, Xingxing Yang, Yaling Xing*, Zhongbin Chen

*Corresponding author for this work

    Research output: Contribution to journalArticle

    24 Citations (Scopus)

    Abstract

    Hepatitis B virus (HBV) infection often results in acute or chronic viral hepatitis and other liver diseases including cirrhosis and hepatocellular carcinoma. Current therapies for HBV usually have severe side effects and can cause development of drug-resistant mutants. An alternative and safe immunotherapeutic approach for HBV infection is urgently needed for effective anti-HBV therapy. In this study, we propose a new strategy for anti-HBV therapy that activates type-I interferon (IFN) antiviral innate immunity through stimulating pattern-recognition receptors with RNA interference (RNAi) using a 5′-end triphosphate-modified small interfering RNA (3p-siRNA). We designed and generated a 3p-siRNA targeting overlapping region of S gene and P gene of the HBV genome at the 5′-end of pregenomic HBV RNA. Our results demonstrated that 3p-siRNA induced a RIG-I-dependent antiviral type-I IFN response when transfected into HepG2.2.15 cells that support HBV replication. The 3p-siRNA significantly inhibited HBsAg and HBeAg secretion from HepG2.2.15 cells in a RIG-I-dependent manner, and the antiviral effect of 3p-siRNA was superior to that of siRNA. Furthermore, 3p-siRNA had more pronounced inhibition effects on the replication of HBV DNA and the transcription of mRNA than that of siRNA. Finally, 3p-siRNA displayed antiviral activity with long-term suppression of HBV replication. In conclusion, our findings suggest that 3p-siRNA could act as a powerful bifunctional antiviral molecule with potential for developing a promising therapeutic against chronic HBV infection.

    Original languageEnglish
    Pages (from-to)86-95
    Number of pages10
    JournalEuropean Journal of Pharmacology
    Volume721
    Issue number1-3
    DOIs
    Publication statusPublished - 5 Dec 2013

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    Keywords

    • 5′-Triphosphated siRNA
    • Hepatitis B virus
    • HepG2.2.15 cells
    • IFNα/β
    • RNAi

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