A multitude of type I IFNs signal through a shared heterodimeric receptor complex. The binding of any one leads to the expression of hundreds of IFN-stimulated genes that render cells highly resistant to virus infection. Type I IFNs display a marked difference in their receptor binding affinities, and at varying concentrations, give rise to quantifiable differences in gene induction; however, whether or not type I IFNs can give rise to gene induction profiles that are qualitatively distinct from one another and whether diverse classes of viruses are differentially susceptible to their antiviral properties remain unanswered questions. Here, we present data on the characterization of several type I IFNs and synthetic IFN variants with respect to their effect on gene expression and their ability to restrict diverse viruses.

In physiological settings, biologically important differences in signaling by type I IFNs may arise from variation in the intrinsic abundance and availability of signaling components. We find that in the presence of high IFN concentrations, STAT1^-/- cells are capable of launching an effective antiviral response; however, the IFNs tested are indistinguishable with respect to antiviral potency. In stark contrast, in TYK2^-/- cells, differences in the antiviral potencies are substantially exaggerated. Despite the large variation in potencies among the IFNs in different cellular environments, the relative differences are consistent across viruses. These results provide additional support for a model where a low level of type I IFN signaling is sufficient to elicit a potent pan-antiviral state and suggest that variations in the level available signaling components may be important for distinguishing type I IFN signaling and fine tuning the IFN response in biologically relevant cellular environments. In ongoing work, we aim to determine whether distinct gene expression profiles are induced by type I IFNs in cells with deficiencies in JAK-STAT signaling components.