Antiviral properties of a dominant negative mutant of the herpes simplex virus type 1 regulatory protein ICP0.
Dominant negative or trans-dominant mutants of viral proteins represent a new and exciting potential approach to antiviral therapy. Unfortunately, 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. However, it seems likely that dominant negative mutants of promiscuous viral trans-activator proteins, which by definition would repress rather than activate gene expression, should be able to inhibit infectious virus production for a number of different viruses. One such dominant negative mutant, derived from the herpes simplex virus type 1 (HSV-1) regulatory protein ICP0, was found previously to behave as a powerful repressor of gene expression from an assortment of HSV-1 and non-HSV-1 promoters in transient expression assays. In the present study, this ICP0 mutant was found to be capable of inhibiting the replication of both HSV-1 and a completely unrelated virus, human immunodeficiency virus, in cell culture. The properties of this dominant negative mutant indicate that it may have potential as a means of treating diseases caused by a number of DNA and RNA viruses. Moreover, a truncated form of ICP0 which can hypothetically be created by alternative splicing was found to possess similar inhibitory capabilities, suggesting that a virus-encoded version of this dominant negative mutant may play a role in down-regulating HSV-1 gene expression during infection in vivo.
Weber
P C
PC
Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Department of Microbiology and Immunology, Hershey 17033.
Kenny
J J
JJ
Wigdahl
B
B
D000998:Antiviral Agents / Q000494:pharmacology*; D005799:Genes, Dominant / Q000235:genetics*; D017874:Immediate-Early Proteins; D009154:Mutation / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics; D018139:Simplexvirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000235:genetics / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases; D014764:Viral Proteins / Q000235:genetics / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D017874:Immediate-Early Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1