Replication of VSV is highly sensitive to the antiviral activity of IFNs, and VSV is widely used to determine the specific activities of IFN preparations quantitatively [21] . In spite of this strong connection, it is unclear how IFN inhibits VSV replication. An early report indicated that viral primary transcription is inhibited by IFN, but it is not known which IFN-induced protein mediates this inhibition [31] . The observed sensitivity of VSV replication in vitro is reflected in vivo. IFNAR 2/2 mice are extremely susceptible to VSV infection; they rapidly die within 2 days after infection and the virus replicates to very high titers in many organs of the infected mice. The extreme sensitivity of IFNAR 2/2 mice to VSV infection suggests that type I IFN provides the majority, if not all, of the protective innate immune defense. Eventually, protection may be facilitated by immune cell-mediated antiviral actions, but this is a slow process that does not appear to function before 6-10 days post-infection [32, 33] . Thus, it is likely that one or more ISGs directly inhibit VSV replication in vivo. In this context, it has been reported that mice lacking PKR, a well-studied ISG, display higher susceptibility to VSV pathogenesis [34] . However, detailed investigation of the underlying mechanism revealed that PKR did not execute IFN's antiviral action; rather, it was required for efficient induction of IFN-a/b in the infected mice [35] . In vivo VSV-infection induces IFN synthesis in many cell types, using either the cytoplasmic RIG-I pathway or the endosomal TLR7 pathway [4, 36] ; however, it is unclear how PKR aids this process.