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An Efficient Antiviral Strategy for Targeting Hepatitis B Virus Genome Using Transcription Activator-Like Effector Nucleases
- Publication Year :
- 2013
- Publisher :
- Nature Publishing Group, 2013.
-
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.
- Subjects :
- HBsAg
Hepatitis B virus
Genetic Vectors
Genome, Viral
Biology
medicine.disease_cause
Antiviral Agents
Virus
Cell Line
chemistry.chemical_compound
Mice
Viral Proteins
Hepatitis B, Chronic
Drug Discovery
Genetics
medicine
Animals
Humans
Molecular Biology
Pharmacology
Transcription activator-like effector nuclease
Deoxyribonucleases
virus diseases
Interferon-alpha
cccDNA
Virology
Molecular biology
digestive system diseases
HBcAg
Disease Models, Animal
HBeAg
chemistry
Molecular Medicine
Original Article
DNA, Circular
DNA
Plasmids
Protein Binding
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....9b60473638492d473db13a0c812ed396