A RIG-I 2CARD-MAVS200 chimeric protein reconstitutes IFN-ß induction and antiviral response in models deficient in type I IFN response

Autores: Nistal Villan, Estanislao; Rodríguez García, Estefanía; Di Scala, Marianna; Ferrero Laborda, Roberto; Olague Micheltorena, María Cristina; Vales Aranguren, África; Carte Abad, Beatriz; Crespo, I.; García-Sastre, A.; Prieto Valtueña, Jesús María; Larrea Leoz, María Esther; González Aseguinolaza, Gloria
Título de la revista: JOURNAL OF INNATE IMMUNITY
ISSN: 1662-811X
Volumen: 7
Número: 5
Páginas: 466 - 481
Fecha de publicación: 2015
RIG-I-like receptors (RLRs) are cellular sensor proteins that detect certain RNA species produced during viral infections. RLRs activate a signaling cascade that results in the production of IFN-ß as well as several other cytokines with antiviral and proinflammatory activities. We explored the potential of different constructs based on RLRs to induce the IFN-ß pathway and create an antiviral state in type I IFN-unresponsive models. A chimeric construct composed of RIG-I 2CARD and the first 200 amino acids of MAVS (2CARD-MAVS200) showed an enhanced ability to induce IFN-ß when compared to other stimulatory constructs. Furthermore, this human chimeric construct showed a superior ability to activate IFN-ß expression in cells from various species. This construct was found to overcome the restrictions of blocking IFN-ß induction or signaling by a number of viral IFN-antagonist proteins. Additionally, the antiviral activity of this chimera was demonstrated in influenza virus and HBV infection mouse models using adeno-associated virus (AAV) vectors as a delivery vehicle. We propose that AAV vectors expressing 2CARD-MAVS200 chimeric protein can reconstitute IFN-ß induction and recover a partial antiviral state in different models that do not respond to recombinant IFN-ß treatment.