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Virology Journal
Published in: Virology Journal 1/2012

Open Access 01-12-2012 | Research

Anti-HBV efficacy of combined siRNAs targeting viral gene and heat shock cognate 70

Authors: Zhongqi Bian, An Xiao, Mingmei Cao, Mingqiu Liu, Shuang Liu, Ye Jiao, Weiyao Yan, Zhongtian Qi, Zhaoxin Zheng

Published in: Virology Journal | Issue 1/2012

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Abstract

Background

Hepatitis B virus (HBV) infection is a major health concern with more than two billion individuals currently infected worldwide. Because of the limited effectiveness of existing vaccines and drugs, development of novel antiviral strategies is urgently needed. Heat stress cognate 70 (Hsc70) is an ATP-binding protein of the heat stress protein 70 family. Hsc70 has been found to be required for HBV DNA replication. Here we report, for the first time, that combined siRNAs targeting viral gene and siHsc70 are highly effective in suppressing ongoing HBV expression and replication.

Methods

We constructed two plasmids (S1 and S2) expressing short hairpin RNAs (shRNAs) targeting surface open reading frame of HBV(HBVS) and one plasmid expressing shRNA targeting Hsc70 (siHsc70), and we used the EGFP-specific siRNA plasmid (siEGFP) as we had previously described. First, we evaluated the gene-silencing efficacy of both shRNAs using an enhanced green fluorescent protein (EGFP) reporter system and flow cytometry in HEK293 and T98G cells. Then, the antiviral potencies of HBV-specific siRNA (siHBV) in combination with siHsc70 in HepG2.2.15 cells were investigated. Moreover, type I IFN and TNF-α induction were measured by quantitative real-time PCR and ELISA.

Results

Cotransfection of either S1 or S2 with an EGFP plasmid produced an 80%–90% reduction in EGFP signal relative to the control. This combinational RNAi effectively and specifically inhibited HBV protein, mRNA and HBV DNA, resulting in up to a 3.36 log10 reduction in HBV load in the HepG2.2.15 cell culture supernatants. The combined siRNAs were more potent than siHBV or siHsc70 used separately, and this approach can enhance potency in suppressing ongoing viral gene expression and replication in HepG2.2.15 cells while forestalling escape by mutant HBV. The antiviral synergy of siHBV used in combination with siHsc70 produced no cytotoxicity and induced no production of IFN-α, IFN-β and TNF-α in transfected cells.

Conclusions

Our combinational RNAi was sequence-specific, effective against wild-type and mutant drug-resistant HBV strains, without triggering interferon response or producing any side effects. These findings indicate that combinational RNAi has tremendous promise for developing innovative therapy against viral infection.
Appendix
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Metadata
Title
Anti-HBV efficacy of combined siRNAs targeting viral gene and heat shock cognate 70
Authors
Zhongqi Bian
An Xiao
Mingmei Cao
Mingqiu Liu
Shuang Liu
Ye Jiao
Weiyao Yan
Zhongtian Qi
Zhaoxin Zheng
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Virology Journal / Issue 1/2012
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/1743-422X-9-275

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Keynote webinar | Spotlight on medication adherence

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WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

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