J. Clin. Invest. 109: 1271–1277 (2002). doi: 10.1172/JCI200215770. step in this pathway, the transcription factor IFN regulatory factor 3 (IRF3) becomes phosphorylated on serine residues by a still-unidentified kinase. Activated IRF3 then stimulates transcription of IFN-α4 and IFN-β, and these secreted “early” IFNs activate ISGF3 and its target gene Irf7. IRF7 closes a positive feedback loop of IFN production by initiating a second, larger wave of IFN gene expression, consisting of non-α4 IFN-α subtypes. Studies in virus-infected mice confirm the importance of the IRF7-dependent positive feedback loop but show that its relative contribution to overall IFN production varies. Some viruses cause secretion of the non-α4 IFN-α subtypes already early during infection. Constitutive expression of IRF7, or the employment of another IRF family member, eg, IRF5, in the producing cell have been proposed as potential molecular causes for immediate production of all IFN-α subtypes (reviewed in ref. 6). In support of the positive feedback model, deletion of genes encoding the ISGF3 subunits blocks IFN production and thereby reduces antiviral responses (7, 8). Loss of IFN-β, likewise, reduces IFN-α production by virusinfected fibroblasts and increases sensitivity of mice to Vaccinia virus (9).