Meganuclease-mediated Inhibition of HSV1 Infection in Cultured Cells

Grosse, Stéphanie; Huot, Nicolas; Mahiet, Charlotte; Arnould, Sylvain; Barradeau, Sébastien; Clerre, Diane Le; Chion-Sotinel, Isabelle; Jacqmarcq, Cécile; Chapellier, Benoît; Ergani, Ayla; Desseaux, Carole; Cédrone, Frédéric; Conseiller, Emmanuel; Pâques, Frédéric; Labétoulle, Marc; Smith, Julianne

doi:10.1038/mt.2010.302

Cited by 71 publications

(75 citation statements)

References 47 publications

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“…In addition, viral replication and infection of cultured cells was substantially diminished when HEs were introduced prior to HSV infection at various multiplicities of infection. This study demonstrated that HSV genomes can be mutated following HE exposure, although cellular toxicity was evident with certain engineered HEs (63).…”

Section: Herpes Simplex Virusmentioning

confidence: 99%

“…Furthermore, the association of DNA binding and cleavage activity within the same protein domain means that alterations in protein structure to facilitate DNA binding can have deleterious effects on the cleavage activity of the HE. Despite these obstacles, there have recently been several impressive achievements in redirecting HEs toward useful targets (7,63,185), and technical advances in HE redesign and targeting are occurring continually (173). Thus, the 3 classes of proteins (ZFNs, HEs, and TALENs) each have unique advantages and disadvantages, and the ideal protein may vary depending on the particular application envisioned.…”

Section: Specific Types Of Cleavage Enzymesmentioning

confidence: 99%

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Targeted DNA Mutagenesis for the Cure of Chronic Viral Infections

Schiffer

Aubert

Weber

et al. 2012

J Virol

104

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Human immunodeficiency virus type 1 (HIV-1), hepatitis B virus (HBV), and herpes simplex virus (HSV) have been incurable to date because effective antiviral therapies target only replicating viruses and do not eradicate latently integrated or nonreplicating episomal viral genomes. Endonucleases that can target and cleave critical regions within latent viral genomes are currently in development. These enzymes are being engineered with high specificity such that off-target binding of cellular DNA will be absent or minimal. Imprecise nonhomologous-end-joining (NHEJ) DNA repair following repeated cleavage at the same critical site may permanently disrupt translation of essential viral proteins. We discuss the benefits and drawbacks of three types of DNA cleavage enzymes (zinc finger endonucleases, transcription activator-like [TAL] effector nucleases [TALENs], and homing endonucleases [also called meganucleases]), the development of delivery vectors for these enzymes, and potential obstacles for successful treatment of chronic viral infections. We then review issues regarding persistence of HIV-1, HBV, and HSV that are relevant to eradication with genome-altering approaches.

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Section: Herpes Simplex Virusmentioning

confidence: 99%

Section: Specific Types Of Cleavage Enzymesmentioning

confidence: 99%

Targeted DNA Mutagenesis for the Cure of Chronic Viral Infections

Schiffer

Aubert

Weber

et al. 2012

J Virol

104

View full text Add to dashboard Cite

show abstract

“…Resulting reduced viral gene expression and elimination of the integrated proviral DNA have been demonstrated [26][27][28]34]. HSV antiviral activity has been observed following site-directed cleavage of the episomal DNA using HEs [31,32] and CRISPR/Cas9 endonucleases [33] in cell culture models of infection. In addition, Aubert and colleagues used an adeno-associated viral vector (AAV) to deliver these anti-HSV HEs [32].…”

Section: General Principles Of Using Gene Editing To Disable Viral Rementioning

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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“…Prior studies of the efficacy of endonuclease treatment of herpesviridae infections, however, had significant limitations. It was shown that meganuclease treatment of cell lines could prevent infection by HSV (28), but the effects of previously existing latent infections were not explored. Another study explored latency treatment using a meganuclease combined with an exonuclease in an HSV model system (5).…”

Section: Discussionmentioning

confidence: 99%

RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection

Wang

Quake

2014

Proc. Natl. Acad. Sci. U.S.A.

196

153

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Latent viral infection is a persistent cause of human disease. Although standard antiviral therapies can suppress active viral replication, no existing treatment can effectively eradicate latent infection and therefore a cure is lacking for many prevalent viral diseases. The prokaryotic immune system clustered regularly interspaced short palindromic repeat (CRISPR)/Cas evolved as a natural response to phage infections, and we demonstrate here that the CRISPR/Cas9 system can be adapted for antiviral treatment in human cells by specifically targeting the genomes of latent viral infections. Patient-derived cells from a Burkitt's lymphoma with latent Epstein-Barr virus infection showed dramatic proliferation arrest and a concomitant decrease in viral load after exposure to a CRISPR/Cas9 vector targeted to the viral genome.genome editing | latency | herpes virus T he herpesviridae virus family consists of some of the most widespread human pathogens in the world. More than 90% of adults have been infected with at least one of the eight subtypes of herpes viruses, and latent infection persists in most people (1). These herpes virus subtypes infect a wide range of cells, including epithelium, neuron, monocyte, and lymphocyte, and the consequences can be either mild (herpes simplex by HSV-1) or severe [cancer by Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpes virus]. HSV infection is also a known risk factor for HIV (2). In its latent state, the viral genome persists within the host cells and it has not been possible to find therapeutic approaches that completely eradicate such infections.Since its discovery 50 y ago, EBV has been a closely studied member of the herpesviridae. As one of the most common human viruses, EBV causes infectious mononucleosis and is associated with certain forms of lymphoma. To date, however, no EBV vaccine or treatment exists. EBV is highly efficient at transforming quiescent human B lymphocytes; the resulting lymphoblastoid cell lines are now commonly used for human genetic studies, and it is possible to use patient-derived cells that propagate directly in culture because of the viral infection and require no other manipulation. The EBV genome encodes about 85 genes, several of which are essential for lytic or latent infection. During latency, the EBV genome circularizes and resides in the cell nucleus as an episome. EBV latency usually progresses through three programs, with protein production decreasing from full sets of EBV nuclear antigens (EBNAs) and latent membrane proteins to just EBNA1. EBNA1 binds to the EBV origin of replication (oriP) to maintain viral episomes; it also regulates expression of other viral genes.Most current antiviral drug development programs are focused on protein targets and are only effective in preventing active viral replication. It has been recognized that it would be useful to target latent infections with viral genome-specific nucleases (3-5), but the challenges of engineering sequence-specific nucleases have hampered progress. Clustered reg...

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Meganuclease-mediated Inhibition of HSV1 Infection in Cultured Cells

Cited by 71 publications

References 47 publications

Targeted DNA Mutagenesis for the Cure of Chronic Viral Infections

Targeted DNA Mutagenesis for the Cure of Chronic Viral Infections

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

RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection

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