The interferon (IFN) response represents an early host defense mechanism against viral infections, and it is known to be an important component of innate immunity (Vilcek and Sen, 1996). IFNs were discovered as acidpH-resistant factors which were induced by treatment of cells with heat-inactivated influenza virus and which were able to inhibit (interfere with) virus replication (Isaacs and Lindenmann, 1957). Type I IFNs are typically secreted by eukaryotic cells in response to viral infection, leading to the stimulation of signal transduction pathways involved in the establishment of an antiviral state (for recent reviews, see Imada and Leonard, 2000; Stark et al., 1998). Type II IFN or IFN is an important regulator of the cellular immune response and it is secreted by cells of lymphoid origin in response to various cytokine stimuli. The type I IFN genes consist of IFN and several IFN subtypes. All type I IFN proteins recognize the same receptor, IFNAR, on the surface of eukaryotic cells within the same organism. Binding of type I IFN to its receptor results in the activation of two members of the Janus tyrosine kinase family, JAK1 and Tyk2, which in turn activate (phosphorylate) STAT1 and STAT2 transcription factors. As a consequence of phosphorylation, STAT1 and STAT2 heterodimerize, translocate to the nucleus, and associate with p48/IRF-9 to form the IFN-stimulated gene factor-3 (ISGF3). The ISGF3 complex binds specific DNA sequences containing IFN-stimulated regulatory elements (ISREs), promoting the transcription of downstream genes. Approximately 100 and 300 genes are known to be transcriptionally stimulated by IFN and IFN, respectively (Der et al., 1998). Among these genes, those encoding the dsRNA-activated protein kinase (PKR), the 2!, 5!-oligoadenylate synthetases (2-5A synthetases), and the Mx proteins are known to interfere with viral replication by different mechanisms (Khabar et al., 2000). Thus, secretion of type I IFN by virus-infected cells contributes to the induction of an antiviral state in neighboring uninfected cells. Although the levels of PKR increase in cells in response to IFN, this antiviral enzyme is usually inactive unless it binds dsRNA. The same principle applies to the 2-5A synthetases. Binding of dsRNA to PKR causes a conformational change in this protein. As a result, PKR dimerizes, autophosphorylates, and becomes enzymatically active. A major target of the kinase activity of PKR is the translation initiation factor eIF-2. PKR-mediated phosphorylation of eIF-2 leads to inactivation of this factor and to inhibition of protein synthesis (for recent reviews, see Gale et al., 2000; Williams, 1999). On the other hand, dsRNA activation of 2-5A synthetases results in the synthesis of 2-5As, which in turn bind to and activate a latent RNase (RNase L). Activated RNase L induces the degradation of RNAs, including mRNAs and rRNAs, also contributing to inhibition of protein synthesis (Stark et al., 1998). Finally, the IFN-induced Mx proteins are GTPases which inhibit replication of specific groups of viruses by mechanisms which are not well understood (Arnheiter et al., 1996). In addition, it has become evident from studies using triple-knockout (PKRJ/J, RNase LJ/J, and MxJ/J) mice that additional IFN-regulated genes participate in the induction of the antiviral state by uncharacterized mechanisms (Zhou et al., 1999). Some of these genes are known to interact with cellular components involved in translation, RNA synthesis, cell growth, and differentiation (Sen, 2000). dsRNA appears to play a major role in the induction of the IFN response upon viral infection (Jacobs and Langland, 1996). dsRNAs are generated during virus infections as a result of …