A diverse array of gene products are effectors of the type I interferon antiviral response

The type I interferon (IFN) response protects cells from invading viral pathogens. The cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery over 25 years ago(1,2,3), only few have been characterized with respect to antiviral activity. For most, little is known about their antiviral potential, their target specificity, and their mechanisms of action. Using an overexpression screening approach, we show that different viruses are targeted by unique sets of ISGs, with each viral species susceptible to multiple antiviral genes with a range of inhibitory activities. To conduct the screen, over 380 ISGs were tested for their ability to inhibit the replication of several important viruses including hepatitis C virus (HCV), yellow fever virus (YFV), West Nile virus (WNV), chikungunya virus (CHIKV), Venezuelan equine encephalitis virus (VEEV), and human immunodeficiency virus (HIV-1). Broadly acting effectors included IRF1, C6orf150, HPSE, RIG-I, MDA5, and IFITM3, while more targeted antiviral specificity was observed with DDX60, IFI44L, IFI6, IFITM2, MAP3K14, MOV10, NAMPT, OASL, RTP4, TREX1, and UNC84B. Combined expression of two-ISG pairs showed additive antiviral effects similar to moderate IFN doses. Mechanistic studies revealed a common theme of translational inhibition for numerous effectors. Several ISGs, including ADAR, FAM46C, LY6E, and MCOLN2, enhanced replication of certain viruses, highlighting another layer of complexity in the highly pleiotropic IFN system.