Interferon-stimulated genes and their antiviral effector functions

Abstract

Many viruses trigger the type I interferon (IFN) system, leading to the transcription of hundreds of interferon-stimulated genes (ISGs). The products of these ISGs exert numerous antiviral effector functions, many of which are still not fully described. Recent efforts have been aimed at identifying which ISGs are antiviral and further characterizing their mechanisms of action. IFN effectors vary widely in their magnitude of inhibitory activity and display combinatorial antiviral properties. Collectively, ISGs can target almost any step in a virus life cycle. Some of the most potent antiviral effectors reinforce the system by further inducing IFN or ISGs. Other genes enhance or facilitate viral replication, suggesting that some viruses may have evolved to co-opt IFN effectors for a survival advantage.

Figure 1

Diverse roles for ISGs in the IFN antiviral pathway. Incoming viruses are sensed by pattern recognition receptors (PRR), leading to activation of interferon regulatory factors (IRFs) and transcriptional induction of IFNs. Antiviral IFNs signal through the JAK/STAT pathway to induce ISG production. ISGs can also be directly induced by some IRFs in an IFN-independent pathway (thin blue arrow). Some ISGs function to block virus replication (thick red bars), while others have the ability to promote or enhance replication of certain viruses (green arrow). A subset of ISGs are themselves components of the IFN pathway or promote its signaling (red dotted arrows). IFN also induces several negative regulators that can target PRR, IRFs, or JAK/STAT to dampen the response (thin red bars).

Figure 2

Frequency of antiviral ISG activity against six viruses. Data from large-scale ISG screens presented in ref [22^••] were analyzed for the frequency with which a given ISG was shown to have antiviral activity against six viruses (HCV, HIV-1, YFV, WNV, VEEV, CHIKV). A list of genes and the number of viruses each gene targeted was submitted to wordle.net to generate a word cloud of ISGs. The font size is directly proportional to the prevalence of antiviral activity, with IRF1 demonstrating antiviral activity against all six viruses.