Upregulation of a Small Subset of Genes Drives Type I Interferon-induced Antiviral Memory

Interferons (IFNs) stand in the frontline of defense against viral infections. In this study, we aimed at characterizing the gene expression profile specific to the antiviral effect out of the hundreds of genes involved also in other IFN activities. We found that the IFN-induced antiviral state is maintained for a prolonged time even after IFN occlusion. This was achieved through the active expression of a small set of <40 genes long after IFN was occluded, from which two groups are distinguished: one includes genes participating in direct inhibition of viral replication, such as Mx and OAS; the second group is related to antigen presentation, including all genes involved in the proteasome-to-immunoproteasome switch and class I MHC genes. Transcription of these genes continued after IFN removal and was Stat1 independent, suggesting the involvement of other signaling elements in addition to the canonical signal transduction pathway. Not less important were genes whose upregulation, in cases by many fold, is terminated once IFN is removed. Among these are viral sensing genes, such as retinoic acid-inducible gene-I protein (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and toll-like receptor (TLR), cytokines, and apoptotic-related genes. Our findings provide a systemwide depiction of prolonged intracellular antiviral protection without the need for ongoing IFN stimulation.