Mammalian innate antiviral defenses: beyond interferon

Mammalian cells employ a wide array of antiviral defense mechanisms to restrict viral replication at virtually all steps of the viral life cycle. Notably, the interferon (IFN) response has been shown to play a central role in restricting the replication of disparate viral pathogens in mammals. Consequently, since its discovery in 1957, the IFN response has dominated antiviral immunity research, leaving IFN-independent pathways relatively understudied. Exploring these alternative host defenses is crucial for understanding the complete arsenal that mammalian hosts deploy to combat viral disease, as IFN responses undoubtedly work in concert with other antiviral defenses to achieve virus restriction. Here, we discuss selected examples of antiviral factors and pathways in mammals that are not classically associated with the IFN response. These defenses range from constitutively expressed host restriction factors that directly inhibit specific steps of the viral life cycle to signaling pathways that invoke IFN-independent antiviral gene expression programs to cell death mechanisms that sacrifice the infected cell to prevent viral spread. Ultimately, our goal is to highlight the diversity of IFN-independent antiviral defenses that mammalian hosts utilize to block viral infection.