Varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, is the etiologic agent of two distinct clinical syndromes: chickenpox (varicella) and shingles (zoster). VZV is an enveloped virus with a linear double-stranded genome of approximately 125,000 base pairs (bp). The complete genomic nucleotide sequence of VZV has been determined and predicts approximately 70 unique genes. The expression of VZV genes appear to be temporally regulated and three putative kinetic classes have been defined for VZV genes; namely immediate early, early and late. Evolving evidence suggest that the putative immediate early gene product of ORF62 (IE62) to be the dominant regulatory protein in VZV. In addition, the ORF62 gene has been shown to be transcriptionally active during the latent phase of VZV infection in ganglia, thus suggesting a potential role for this gene in the maintenance of latency. Current efforts focus on the structure-function analysis of IE62 regulatory protein using a variety of genetic approaches. In transient expression assays, the IE62 protein has been shown to be a potent promiscuous transactivator of both VZV genes and heterologous genes. The activation domain of the 1310-amino acid IE62 protein has been localized to a 75-amino acid region in the N-terminus of the molecule. Using saturation and site specific mutagenesis further dissection of the 75- amino acid activation domain has been undertaken to identify functionally critical residues within the activation domain. Furthermore, our recent studies have illustrated that the IE-62 -dependent activation of responsive promoters are mediated by a unique mechanism involving the TATA element of the promoter. Studies are in progress to delineate the interactions of IE62 with the transscriptional machinery of the Pol II promoters. In addition, the promoter functions of IE62 gene are being investigated. Preliminary findings indicate enhanced capable promoter activity in neuronal cells and a 80-bp region in the promoter has been identified as being capable of confering neuronal specificity to the ORF62 promoter. Isolation and identification of neuronal specific transcription factors that interact with the 80-bp promoter element are currently in progress.
