Herpes simplex viruses (HSV) belong to a family of oncogenic viruses. They cause moderate to severe disease, particularly in neonates, infection or drug induced immunologically deficient individuals including cancer patients and are associated as co- factors with human cancer of the cervix. A key property is their ability to remain latent in sensory or autonomic neurons and to cause recurrent lesions after spontaneous or induced activation of viral replication. This application consolidates four long standing interdigitated projects centering on the molecular biology of these viruses. The key components of these projects are as follows: (i) The HSV genome consists of two covalently linked double stranded DNA components flanked by inverted repeats. The terminal a sequence shared by both components contains the cis sites for the inversion of the two components relative to each other, for the excision of the genome from multimeric head to tail concatemers, for packaging of the DNA into capsids, and for the circularization of the DNA. The a sequence contains the transcription initiation site and the promoter of a gene whose coding sequence are in the repeats of the long component. These studies will be continued to identify the viral trans-acting factors that specifically bind to the a sequence and to determine their function by mutage- nesis of their genes and of their cis-acting sites. (ii) Technology has been developed and applied to demonstrate that all but one gene mapping in the unique sequences of the small (S) component are dispensable with respect to viral growth in cell culture. The intent is to continue the analyses of the viral genome for dispensable genes, to determine their function, and to determine the function of a new essential gene which contain in its domain the S component origins of DNA synthesis. (iii) HSV genes form three major groups alpha, beta, and gamma whose expression is regulated in a cascade fashion. The alpha genes are induced by a structural component of the virion but that the cis-acting site required for the induction of the alpha genes binds two host proteins. The plan is to continue to characterize the interaction of the viral factor with these proteins and to determine the role of these proteins in the induction of alpha genes, as well as the role of the major regulatory protein, alpha 4, in the regulation of beta and gamma genes. (iv) Only a subset of viral genes in expressed during latent infection of neurons. The objectives are to genetically engineer novel genomes to determine why the full complement of viral genes is not expressed during latency.
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