The long-term objective of this study is to determine the biological role of the interferon (IFN) system in viral infection and virus-induced neoplasia by using mice as a model system; the use of mice provides many advantages to this study, such as availability of a single genetic background, mice strains that are genetically restricted in IFN production, and the possibility of analyzing the expression of IFN and viral genes during the progression of infection. In the past and current funding periods, we cloned and characterized a cluster of IFN genes and studied the regulation of their expression both in infected cells and in mice. The present proposal focuses on: 1) Identification of a virus-mediated signal transduction pathway that leads to the activation of IFN genes by use of primary macrophage cultures isolated from mice expressing different genotypes. We will examine the relationship between virus-induced 1,2-DG and PKC-dependent accumulation of IFN mRNA; 2) Detection of factors that determine the cell- specific expression of IFN-alpha genes in macrophages and spleen cells. We will characterize the binding of induction-specific nuclear proteins to IFN-alpha promoter regions and identify the factors that are critical for induction of these genes; 3) Determination of factors that modulate the IFN synthesis in vivo. We will examine the mechanism by which the IF-1 locus modulate IFN synthesis and examine the effect of retroviral infection on the expression of IFN genes; and 4) Purification and cloning of the F1 protein; we will purify the F1 protein (nuclear factor we identified to be essential for expression of IFN-alpha4 gene in L-cells), clone and sequence its cDNA. We believe that the knowledge of the regulation of IFN gene expression and its dependence on genetic factors is essential for our understanding of the IFN system in man, where the deletion (or defect) in IFN genes can be often found in tumor cells and aberrant expression can be associated both with predisposition to infection and with an increase in pathogenicity of viral infections. In addition, this study will provide a more rational basis for the possible therapeutic manipulation of the IFN system in man.