biostudies-literatureShaw AEMedical Research CouncilWellcome Truste3001352https://www.ebi.ac.uk/biostudies/studies/S-EPMC8423302biostudies-literatureUnknown19(9)Antiviral defenses can sense viral RNAs and mediate their destruction. This presents a challenge for host cells since they must destroy viral RNAs while sparing the host mRNAs that encode antiviral effectors. Here, we show that highly upregulated interferon-stimulated genes (ISGs), which encode antiviral proteins, have distinctive nucleotide compositions. We propose that self-targeting by antiviral effectors has selected for ISG transcripts that occupy a less self-targeted sequence space. Following interferon (IFN) stimulation, the CpG-targeting antiviral effector zinc-finger antiviral protein (ZAP) reduces the mRNA abundance of multiple host transcripts, providing a mechanistic explanation for the repression of many (but not all) interferon-repressed genes (IRGs). Notably, IRGs tend to bePLoS biologyThe antiviral state has shaped the CpG composition of the vertebrate interferome to avoid self-targeting.PMC8423302MR/K024752/1MR/R021562/1201366/Z/16/ZMC_UU_12014/10MC_UU_12014/8MC_UU_12014/12MR/P022642/1217221/Z/19/ZDa Silva AFStewart DGWickenhagen ABusby JPalmarini MMollentze NRobertson DLOrton RJTurnbull MLRihn SJJohnson PCDCollados MRShaw AEKuchi SCastello AStreicker DGWilson SJSugrue ESmollett KGu QBamford CGGBakshi SfalseThe antiviral state has shaped the CpG composition of the vertebrate interferome to avoid self-targeting.Antiviral defenses can sense viral RNAs and mediate their destruction. This presents a challenge for host cells since they must destroy viral RNAs while sparing the host mRNAs that encode antiviral effectors. Here, we show that highly upregulated interferon-stimulated genes (ISGs), which encode antiviral proteins, have distinctive nucleotide compositions. We propose that self-targeting by antiviral effectors has selected for ISG transcripts that occupy a less self-targeted sequence space. Following interferon (IFN) stimulation, the CpG-targeting antiviral effector zinc-finger antiviral protein (ZAP) reduces the mRNA abundance of multiple host transcripts, providing a mechanistic explanation for the repression of many (but not all) interferon-repressed genes (IRGs). Notably, IRGs tend to be2021-01-01T00:00:00Z2021 Sep2026-04-08T08:25:43.57Z2022-02-11T10:50:23.166ZS-EPMC84233023449198210.1371/journal.pbio.3001352