5′-Triphosphate-siRNA activates RIG-I-dependent type I interferon production and enhances inhibition of hepatitis B virus replication in HepG2.215 cells

被引:39
作者
Chen, Xiaojuan [1 ]
Qian, Yuanyu [2 ]
Yan, Fei [1 ]
Tu, Jian [3 ]
Yang, Xingxing [1 ]
Xing, Yaling [1 ]
Chen, Zhongbin [1 ]
机构
[1] Beijing Inst Radiat Med, Div Infect & Immun, Dept Electromagnet & Laser Biol, Beijing 100850, Peoples R China
[2] Chinese Peoples Liberat Army Gen Hosp, Dept Emergency, Beijing, Peoples R China
[3] Macquarie Univ, Australian Sch Adv Med, N Ryde, NSW 2109, Australia
基金
中国国家自然科学基金;
关键词
Hepatitis B virus; 5 '-Triphosphated siRNA; IFN alpha/beta; RNAi; HepG2.2.15; cells; IMMUNE-RESPONSES; RNA; INNATE; THERAPY; RECOGNITION; COMBINATION; LAMIVUDINE; ALPHA;
D O I
10.1016/j.ejphar.2013.09.050
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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. (C) 2013 Elsevier B.V. All rights reserved.
引用
收藏
页码:86 / 95
页数:10
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