Relief of cytotoxicity and enhancement of interferon inducer activity of double-stranded RNA by eukaryotic initiation factor 2

Double-stranded RNA (dsRNA) is a powerful interferon inducer but also possesses toxic properties. dsRNA was shown previously to inhibit translation by causing the inactivation of eukaryotic initiation factor 2 (eIF-2) and to bind tightly to this protein. The cytoxicity of dsRNA was analyzed simultaneously with the induction of interferon in murine fibroblast cultures. Incubation of dsRNA with eIF-2 leads to a significant reduction in toxicity, concomitant with a marked stimulation of interferon induction. The enhancement of dsRNA-dependent interferon induction by eIF-2 is sensitive to a monoclonal antibody directed against the β of eIF-2. When injected in combination with dsRNA, elF-2 potentiates the dsRNA-dependent survival of mice infected with a lethal dose of Mango virus.