The present study was undertaken to discover antiviral therapeutics that broadly increase host defense. We focused on the IFN system that is central to the antiviral response, although we recognized that other labs have pursued this target with limited success in the past. Some of these previous investigators have used administration of IFN itself to increase the antiviral response, but for this therapeutic goal and others, the side effects of IFN administration have proven to be rate-limiting [29] . Similarly, other investigators have attempted to boost IFN production, e.g., through administration Toll-like receptor (TLR) agonists CpG or Imiquimod, but these agents have also caused similar side effects [30] [31] [32] [33] . The small molecule DMXAA activates multiple immune pathways (NF-kB, TBK1/IRF3, NOD, and MAP kinase) but was ineffective as an antiviral unless it was administered before infection [34] [35] [36] [37] . To circumvent at least some of these issues with IFN production, toxicity, and specificity, we therefore pursued the goal of antiviral drug discovery with a novel screening approach for identifying small molecule enhancers that might selectively boost the activity or efficiency of the IFN signaling pathway.