Targeted DNA Mutagenesis for the Cure of Chronic Viral Infections

Schiffer, Joshua T.; Aubert, Martine; Weber, Nicholas; Mintzer, Esther; Stone, Daniel; Jerome, Keith R.

doi:10.1128/jvi.00052-12

Cited by 104 publications

(89 citation statements)

References 214 publications

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“…This may be one of the reasons that the therapeutics are not very effective in elimination of HBV infections in chronic hepatitis B (CHB) patients. Control of the cccDNA level or its transcriptional activity is thought to be critical for successful treatment of HBV infection (3,4). However, the cccDNA accumulates and persists in the cell nucleus as a very stable episome with an approximately 30-50 days half-life (5,6) and there is still no therapeutic available to specifically target this nuclear viral genomes.…”

Section: Chronic Hepatitis B Virus (Hbv) Infection Is a Serious Healtmentioning

confidence: 99%

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An Efficient Antiviral Strategy for Targeting Hepatitis B Virus Genome Using Transcription Activator-Like Effector Nucleases

et al. 2014

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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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Section: Chronic Hepatitis B Virus (Hbv) Infection Is a Serious Healtmentioning

confidence: 99%

“…RNA interference (RNAi)-and RNaseP-associated external guide sequence (EGS)-based approaches have been investigated(35)(36)(37) but are limited because they do not directly eliminate the pre-existing HBV genomic DNAs. Recently, many techniques have been developed for selectively targeting genes(4,38,39).…”

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confidence: 99%

An Efficient Antiviral Strategy for Targeting Hepatitis B Virus Genome Using Transcription Activator-Like Effector Nucleases

et al. 2014

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“…Although a given target sequence is unlikely to be perfectly conserved in all the HIV strains circulating worldwide, this approach should benefit from targeting highly conserved regions of the virus, tailoring the choice of endonuclease based on viral genotype at the target site, and perhaps by targeting multiple regions of HIV simultaneously. [22][23][24] Such approaches should also address the issue of viral quasispecies present within an infected individual.…”

Section: Resistancementioning

confidence: 99%

Disruption or Excision of Provirus as an Approach to HIV Cure

Jerome

2016

AIDS Patient Care and STDs

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An effective approach to HIV cure will almost certainly require a combination of strategies, including some means of reducing the latent HIV reservoir. Because the integrated HIV provirus represents the major source of viral persistence and reactivation, one attractive approach is the direct targeting of provirus for disruption or excision using targeted endonucleases, such as CRISPR/Cas9, zinc finger nucleases, TAL effector nucleases, or meganucleases (homing endonucleases). This article highlights some of the challenges for successful endonuclease therapy for HIV, including optimization of enzyme activity and specificity, the possible emergence of viral resistance, and most importantly, efficient in vivo delivery of the enzymes to a sufficient portion of the latent reservoir.

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“…To keep off-target interaction to a minimum, it is estimated that at least 17 bases within a viral DNA sequence need to be targeted [1]. The probability of a random 17 bp target site within a viral sequence occurring within the human genome is approximately 0.15.…”

Section: Introductionmentioning

confidence: 99%

Transcription Activator-Like Effector (TALE) Nucleases and Repressor TALEs for Antiviral Gene Therapy

Bloom¹,

Mussolino²,

Arbuthnot

2015

Curr Stem Cell Rep

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Genome modification platforms are fast becoming valuable tools for the development of novel therapies. The use of sequence-specific DNA binding proteins in conjunction with various effector domains enables targeted gene editing to be employed as a mode of therapy. Although this field of research has largely focused on the engineering and repair of mammalian genes, the technology may also be used to disrupt viral DNA or host factors associated with pathogenesis of viral disease. For persistent or latent infections, targeted mutagenesis of the episomal or proviral DNA could render the virus inactive. Alternatively, virus-resistant cells may be generated by disrupting the expression of host factors that are required for viral infection. This review highlights some of the approaches currently used to disable viruses, with a particular focus on TALENs and repressor TALEs for antiviral therapy.

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Targeted DNA Mutagenesis for the Cure of Chronic Viral Infections

Cited by 104 publications

References 214 publications

An Efficient Antiviral Strategy for Targeting Hepatitis B Virus Genome Using Transcription Activator-Like Effector Nucleases

An Efficient Antiviral Strategy for Targeting Hepatitis B Virus Genome Using Transcription Activator-Like Effector Nucleases

Disruption or Excision of Provirus as an Approach to HIV Cure

Transcription Activator-Like Effector (TALE) Nucleases and Repressor TALEs for Antiviral Gene Therapy

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