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Mol Ther. 2014 Feb;22(2):303-311. doi: 10.1038/mt.2013.212. Epub 2013 Sep 12.

An efficient antiviral strategy for targeting hepatitis B virus genome using transcription activator-like effector nucleases.

Author information

1
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China; Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
2
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
3
Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
4
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China; Institutes of Medical Microbiology and Biomedical Sciences, Fudan University, Shanghai, China.
5
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China; Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Institutes of Medical Microbiology and Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: zhyuan@shaphc.org.

Abstract

The hepatitis B virus (HBV) is a DNA virus that can cause chronic hepatitis B (CHB) in humans. Current therapies for CHB infection are limited in efficacy and do not target the pre-existing viral genomic DNA, which are present in the nucleus as a covalently closed circular DNA (cccDNA) form. The transcription activator-like (TAL) effector nucleases (TALENs) are newly developed enzymes that can cleave sequence-specific DNA targets. Here, TALENs targeting the conserved regions of the viral genomic DNA among different HBV genotypes were constructed. The expression of TALENs in Huh7 cells transfected with monomeric linear full-length HBV DNA significantly reduced the viral production of HBeAg, HBsAg, HBcAg, and pgRNA, resulted in a decreased cccDNA level and misrepaired cccDNAs without apparent cytotoxic effects. The anti-HBV effect of TALENs was further demonstrated in a hydrodynamic injection-based mouse model. In addition, an enhanced antiviral effect with combinations of TALENs and interferon-α (IFN-α) treatment was observed and expression of TALENs restored HBV suppressed IFN-stimulated response element-directed transcription. Taken together, these data indicate that TALENs can specifically target and successfully inactivate the HBV genome and are potently synergistic with IFN-α, thus providing a potential therapeutic strategy for treating CHB infection.

PMID:
24025750
PMCID:
PMC3916035
DOI:
10.1038/mt.2013.212
[Indexed for MEDLINE]
Free PMC Article
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