CYTOKINES AND IMMUNITY TO VIRAL-INFECTIONS

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 m ediated by many of these encoded factors, including IL-2, IL-12, IFN-g amma, TNE-alpha, CD40L, Mig and Crg-2. In some cases, host defense mec hanisms were induced (IL-2, IL-12, Mig and Crg-2), whilst for others, a direct antiviral effect was demonstrated (IFN-gamma, TNF-alpha and C D40L). 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 involv ed the use of strains of mice deficient for the production of particul ar cytokines or their receptors, often in combination with our enginee red viruses. Mice deficient in either IFN-gamma, IFN-gamma R, IFN-alph a/beta R, TNFRs, CD40 or IL-6 were, in general, highly susceptible to poxvirus infection. Surprisingly, not only the TNFR1, but also the TNF R2, was able to mediate the antiviral effects of TNF-alpha in vivo, wh ilst the antiviral activity observed following CD40-CD40L interaction is a newly defined function which may involve apoptosis of infected ce lls. Through the use of perforin-deficient mice, we were able to demon strate a requirement for this molecule in the clearance of some viruse s, such as ectromelia virus, whilst for others, such as vaccinia virus , perforin was less important but. IFN-gamma was essential.