No abstract

The cellular antiviral state mediated by type I interferon (IFN) is the most important host defense mechanism occurring at the early stage of virus infection (15,42,45). IFN binds to the IFN-␣ receptor (IFNAR), which consists of two subunits, IFNAR1 and IFNAR2 (34). The binding of IFN leads to the heterodimerization of the two subunits and the subsequent phosphorylation of two tyrosine kinases, Janus kinase 1 (Jak1) and tyrosine kinase 2 (Tyk2), which are associated with the intracellular domains of the IFNAR (42, 43). Phosphorylated Jak1 and Tyk2, in turn, phosphorylate signal transducer and activator of transcription 1 (STAT1) and STAT2, which are downstream transcriptional factors located in the cytoplasm (9). Once phosphorylated, STAT1 and STAT2 form a trimeric complex with the DNA binding protein, IFN regulatory factor 9, termed IFN-stimulated gene factor 3 (ISGF3) (20,27). ISGF3 then translocates to the nucleus, where it binds to specific promoter elements of IFN-inducible genes (the IFNstimulated response element) and induces the expression of hundreds of IFN-inducible genes that have antiviral and immunoregulatory functions (10,14). However, IFN does not always induce the antiviral response effectively. The efficacy of IFN can be limited by anti-IFN proteins encoded in viral genomes or by host cellular suppressors regulating IFN signaling (24,28,50). Even IFN-sensitive viruses (not armed with anti-