Vaccinia virus recombinants as a model system to analyze interferon-induced pathways

The interferons (IFNs) are a family of cytokines with broad antiviral activities that also control cell proliferation and modulate immune responses. IFNs exert their pleiotropic actions through the regulation of multiple pathways that have been subjected to extensive study using diverse approaches. The scope of this review is to show how we can take advantage of vaccinia virus (VV) to study IFN-related pathways. We summarize and present the different VV models available for studying IFN function and the possibilities that they offer to analyze IFN-induced pathways, IFN modulators, and the biologic effects at the molecular and cellular levels. Emphasis is given to studies of dsRNA-activated signaling with VV lacking E3L (VV DeltaE3L) and in RNA-activated protein kinase (PKR)-related pathways, through the use of VV recombinants (VVr) with inducible PKR (VV PKR). The latest system is versatile, as expression of PKR can be regulated and induced at different times; similarly, VVr can be generated expressing other PKR modulators. As an example of the utility of VVr, we describe how this model has been used to analyze the antiviral and proapoptotic functions of PKR, the impact of PKR on translation, and the PKR-induced activation of the nuclear factor-kappaB (NF-kappaB) pathway.