A RIG-I 2CARD-MAVS200 Chimeric Protein Reconstitutes IFN-beta Induction and Antiviral Response in Models Deficient in Type I IFN Response

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-beta 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-beta 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-beta when compared to other stimulatory constructs. Furthermore, this human chimeric construct showed a superior ability to activate IFN-beta expression in cells from various species. This construct was found to overcome the restrictions of blocking IFN-beta 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-beta induction and recover a partial antiviral state in different models that do not respond to recombinant IFN-beta treatment. (C) 2015 S. Karger AG, Basel