title: Meganuclease-mediated Inhibition of HSV1 Infection in Cultured Cells.
abstract: Herpes simplex virus type 1 (HSV1) is a major health problem. As for most viral diseases, current antiviral treatments are based on the inhibition of viral replication once it has already started. As a consequence, they impair neither the viral cycle at its early stages nor the latent form of the virus, and thus cannot be considered as real preventive treatments. Latent HSV1 virus could be addressed by rare cutting endonucleases, such as meganucleases. With the aim of a proof of concept study, we generated several meganucleases recognizing HSV1 sequences, and assessed their antiviral activity in cultured cells. We demonstrate that expression of these proteins in African green monkey kidney fibroblast (COS-7) and BSR cells inhibits infection by HSV1, at low and moderate multiplicities of infection (MOIs), inducing a significant reduction of the viral load. Furthermore, the remaining viral genomes display a high rate of mutation (up to 16%) at the meganuclease cleavage site, consistent with a mechanism of action based on the cleavage of the viral genome. This specific mechanism of action qualifies meganucleases as an alternative class of antiviral agent, with the potential to address replicative as well as latent DNA viral forms.
authors.affiliation: Cellectis Genome Surgery, Romainville, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Grosse
authors.forename: Nicolas
authors.initials: N
authors.lastname: Huot
authors.forename: Charlotte
authors.initials: C
authors.lastname: Mahiet
authors.forename: Sylvain
authors.initials: S
authors.lastname: Arnould
authors.forename: Sébastien
authors.initials: S
authors.lastname: Barradeau
authors.forename: Diane Le
authors.initials: DL
authors.lastname: Clerre
authors.forename: Isabelle
authors.initials: I
authors.lastname: Chion-Sotinel
authors.forename: Cécile
authors.initials: C
authors.lastname: Jacqmarcq
authors.forename: Benoît
authors.initials: B
authors.lastname: Chapellier
authors.forename: Ayla
authors.initials: A
authors.lastname: Ergani
authors.forename: Carole
authors.initials: C
authors.lastname: Desseaux
authors.forename: Frédéric
authors.initials: F
authors.lastname: Cédrone
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Conseiller
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pâques
authors.forename: Marc
authors.initials: M
authors.lastname: Labetoulle
authors.forename: Julianne
authors.initials: J
authors.lastname: Smith
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D003851:Deoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D006566:Herpesviridae Infections / Q000517:prevention & control*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000472:pathogenicity; D006801:Humans
chemical_list: D003851:Deoxyribonucleases