DNA sequences encoding mutant antiviral regulatory proteins

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. Unexpectedly, it was also capable of inhibiting the replication of both HSV- 1 and a completely unrelated virus, human immunodeficiency virus, in cell culture. Moreover, a derivative of ICP0 with dominant mutant properties similar to that of pD19T can potentially be created by a failure to splice out the intron 2 sequences; translation of this message results in a derivative of ICP0, called ICPOR, which contains all 241 amino acids encoded by exons 1 and 2 plus an additional 21 amino acids derived from translation into the unspliced second intron. The properties of this dominant negative mutant indicate that it may be successfully utilized in treating a wide variety of different viral infections in vivo.

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