An efficient antiviral strategy for targeting hepatitis B virus genome using transcription activator-like effector nucleases
Open accessAbstract
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.
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Previous studies reported that HBV-specific TALENs have a mutagenesis rate ranging between 30 and 70%.
“Previous studies reported that HBV-specific TALENs have a mutagenesis rate ranging between 30 and 70%.9,10”
From The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo (2014) · cites this paper as [10]
The CRISPR/Cas9 system was as effective as TALENs in mediating gene disruption in vitro, although its mutagenesis rate is lower (~5% by T7E1 and ~27% by clonal sequencing) in vivo.
“Our study demonstrated that the CRISPR/Cas9 system was as effective as TALENs in mediating gene disruption in vitro, although its mutagenesis rate is lower (~5% by T7E1 and ~27% by clonal sequencing) in vivo.”
From The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo (2014) · cites this paper as [10]
ZFNs and TALENs can cleave host genomes in a site-specific fashion and have been under investigation for specific degradation of HBV genomes in vitro and in vivo.
“Two genome editing technologies, zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), can cleave the host genomes in a site-specific fashion and have been under investigation for specific degradation of the HBV genomes in vitro and in vivo.8,9,10”
From The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo (2014) · cites this paper as [10]
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References 51 · Cited by 159
- Authors
- Chen, J., Zhang, W., Lin, J., Wang, F., Wu, M., Chen, C., Zheng, Y., Peng, X., Li, J., & Yuan, Z.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- Corresponding author
- Yuan, Zhenghong
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 22
- Issue
- 2
- Pages
- 303-311
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC3916035
- OpenAlex
- W2124520571
- Cited by
- 159
- References
- 51
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 5 · 2023: 12 · 2022: 6 · 2021: 7 · 2020: 21 · 2019: 9 · 2018: 9 · 2017: 19 · 2016: 27 · 2015: 24 · 2014: 12
- FWCI
- 15.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- hepatitis B virus, TALEN, chronic hepatitis B, covalently closed circular DNA, HBeAg, hepatitis B surface antigen, HBcAg, IFN-stimulated response element, hydrodynamic injection, antiviral gene therapy
- MeSH terms
- Animals, Antiviral Agents, Cell Line, Deoxyribonucleases, Disease Models, Animal, DNA, Circular, Genetic Vectors, Hepatitis B virus, Humans, Plasmids, Protein Binding, Viral Proteins, Genome, Viral, Interferon-alpha, Hepatitis B, Chronic, Mice
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