In this review, we discuss two broad approaches we have taken to study the role of cytokines and chemokines in antiviral immunity. Firstly, recombinant vaccinia viruses were engineered to express genes encoding cytokines and chemokines of interest. Potent antiviral activity was mediated by many of these encoded factors, including IL-2, IL-12, IFN-gamma, TNF-alpha, CD40L, Mig and Crg-2. In some cases, host defense mechanisms were induced (IL-2, IL-12, Mig and Crg-2), whilst for others, a direct antiviral effect was demonstrated (IFN-gamma, TNF-alpha and CD40L). In sharp contrast, vector-directed expression of IL-4, a type 2 factor, greatly increased virus virulence, due to a downregulation of host type 1 immune responses. Our second experimental approach involved the use of strains of mice deficient for the production of particular cytokines or their receptors, often in combination with our engineered viruses. Mice deficient in either IFN-gamma, IFN-gamma R, IFN-alpha/beta R, TNFRs, CD40 or IL-6 were, in general, highly susceptible to poxvirus infection. Surprisingly, not only the TNFR1, but also the TNFR2, was able to mediate the antiviral effects of TNF-alpha in vivo, whilst the antiviral activity observed following CD40-CD40L interaction is a newly defined function which may involve apoptosis of infected cells. Through the use of perforin-deficient mice, we were able to demonstrate a requirement for this molecule in the clearance of some viruses, such as ectromelia virus, whilst for others, such as vaccinia virus, perforin was less important but IFN-gamma was essential.
