MECHANISMS OF ACTION OF INTERFERON

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The antiviral and antiproliferative actions of interferons have been correlated with a number of enzyme activities (2-5A synthetase, endoribonuclease, protein kinase), which, when activiated, inhibit protein synthesis but the relevance of these enzymes to the inhibition of replication of RNA and DNA-containing viruses has not been elucidated. We have found in a vaccinia virus infected mouse L cell system that the interferon-mediated inhibition of viral protein synthesis in vivo correlates with activation of the 2-5A synthetase/endonuclease and degradation of viral RNAs. In contrast, in a number of mouse and human cells of different origins, vaccinia protein synthesis is not inhibited by interferon and a novel phenomenon has been discovered where vaccinia products block the 2-5A synthetase and protein kinase activities. In this proposal, experiments are described using vaccinia virus as a model system to elucidate: a) the in vivo role of the 2-5A synthetase/endonuclease system in the interferon-mediated inhibition of vaccinia virus protein synthesis; b) the mechanism by which a DNA virus such as vaccinia escapes blockade by the interferon system. To determine the in vivo role of the 2-5A synthetase/endonuclease on protein synthesis we will establish to what extent the integrity of viral and cellular RNAs is related to a block of translation, if specific degradation of certain RNAs occurs and if these events are the result of the formation of viral RNA during the course of infection. To define how vaccinia virus escapes inhibition by the interferon-mediated enzyme activities, we will characterize the nature and mode of action of vaccinia products with interfering properties present in cell-extracts and virions. To further define the vaccinia products with blocking effects on interferon action we will examine whether viral genes introduced into cells by DNA-mediated gene transfer can overcome specific interferon-mediated enzyme activities. By examining these cell-systems where the interferon response of the cells may be controlled by vaccinia gene(s) we may provide the means to define the mechanisms responsible for inhibition of replication of various viruses as well as the antiproliferative actions of interferons.