Herpes simplex virus type 1 (HSV-1) establishes life-long infections of the human host characterized by productive infection of actively cycling epithelial cells and fibroblasts at the site of primary infection, and non productive latent infection of growth-arrested sensory neurons. The ability of the virus to express productive cycle genes at high levels in some cells but not in others lies at the heart of the pathogenic mechanism of the clinically important virus. We have recently demonstrated that transcription and replication HSV-1 requires the activities of cyclin-dependent kinases recently demonstrated that transcription and replication of HSV-1 requires the activities of cyclin-dependent kinases (cdks), a family of cellular proteins whose phosphorylating activities are expressed differentially in mammalian cells as a function of cell type and growth-status. Using cdk inhibitors and HSV-1 mutant viruses, we will test the hypothesis that specific cdks together with well-characterized viral regulatory proteins, VP16, and immediate-early proteins ICPs 0, 4, 22, 27, mediate the distinct programs of viral gene expression characteristic of productive infection and latency. More specifically, we propose 1) to determine whether cdks- 1,-2 and/or -3 are required for HSV-1 transcription and replication in cells of neural and non-neural lineage, 2) to identify HSV-1 infection- related factors that activate cdks in cells of neural and non-neural lineage, 3) to determine whether the transactivating activities of VP16, ICPO and the CTAs cells of neural and non-neural lineage, 4) to examine the effects of the cdks and ICPO on the post-translational modification of IE regulatory proteins in cells of neural and non-neural lineage, 5) to determine whether the activities of cdks -1, -2 and/or -5 are essential for reactivation of HSV-1 from neuronal latency and if so, to establish the order of viral gene expression that occurs in latently infected neurons after reversal of a drug-induced block in the activities of these cdks, and 6) To assess the effect of the continuous expression of ICPO on the establishment, maintenance and reactivation of latency in vivo. Knowledge of the molecular basis for the dual cycle- cycle of HSV-1 generated in these studies will provide the means to develop successful strategies for the prevention and control of diseases caused by HIV-1 and other neurotropic herpesviruses.
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