Remarkably, accumulation of DVGs was directly associated with phosphorylation of IRF3 (Fig. 3C) and with the expression of Ifnb mRNA (Fig. 3D), demonstrating that standard viral genomes alone are not sufficient to initiate this response during infection in vitro and strongly supporting a unique ability of naturally arising DVGs to initiate the cellular antiviral response. Here, IRF3 is linked to infection.