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

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 100890581 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-0024 (Electronic) Linking ISSN: 15250016 NLM ISO Abbreviation: Mol Ther Subsets: MEDLINE
    • Publication Information:
      Publication: 2017- : Cambridge, MA : Cell Press
      Original Publication: San Diego, CA : Academic Press, 2000-
    • Subject Terms:
      Genome, Viral*; Deoxyribonucleases/*metabolism ; Hepatitis B virus/*genetics ; Hepatitis B, Chronic/*metabolism ; Hepatitis B, Chronic/*virology; Animals ; Antiviral Agents/administration & dosage ; Cell Line ; DNA, Circular/metabolism ; Deoxyribonucleases/genetics ; Disease Models, Animal ; Genetic Vectors/administration & dosage ; Genetic Vectors/genetics ; Hepatitis B, Chronic/therapy ; Humans ; Interferon-alpha/administration & dosage ; Mice ; Plasmids/administration & dosage ; Plasmids/genetics ; Protein Binding ; Viral Proteins/metabolism
    • 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.
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    • Accession Number:
      0 (Antiviral Agents)
      0 (DNA, Circular)
      0 (Interferon-alpha)
      0 (Viral Proteins)
      EC 3.1.- (Deoxyribonucleases)
    • Publication Date:
      Date Created: 20130913 Date Completed: 20141126 Latest Revision: 20211021
    • Publication Date:
      20231215
    • Accession Number:
      PMC3916035
    • Accession Number:
      10.1038/mt.2013.212
    • Accession Number:
      24025750