Abstract: Dominant negative or trans-dominant mutants of viral proteins represent a new and exciting means of antiviral therapy. However, the extreme specificity of a given dominant negative mutant limits its general utility in treating a broad spectrum of viral diseases, since it can typically interfere with the activity of only a single viral polypeptide encoded by a single virus. A dominant negative mutant of a gene encoding promiscuous viral transactivator protein was isolated in an attempt to generate a polypeptide which could inhibit gene expression and, therefore, virus replication nonspecifically. This mutant, a truncated derivative of the gene encoding herpes simplex virus type 1 (HSV-1) regulatory protein ICP0, was found to behave as a powerful repressor of gene expression from an assortment of HSV-1 and non-HSV-1 promoters in transient expression assays.