The human herpesviruses cause a spectrum of clinically significant acute and life-long latent infections which can be life-threatening in immunocompromised individuals. Viral DNA replication is a pivotal event in the dual life cycles of all herpesviruses in that the onset of viral DNA replication signals both the commitment of acutely infected cells to ultimate lysis and the reactivation of virus from neuronal latency, whereas the absence of viral DNA replication is a hallmark of viability in latently infected neurons. Using the neurotropic herpesvirus, herpes simples virus type 1 (HSV-1) as a model, the objectives of this proposal are to determine the roles of viral and cellular proteins that bind to the two HSV-1 origins of replication, ori L and ori S, in origin-dependent DNA replication in cells of neural avid nonneural lineage. The composition of the protein complexes that bind to ori L and ori S in extracts of the two types of cells will also be determined. Whether origin-dependent DNA replication and transcription of origin flanking genes are linked in the two types of cells will be established. The roles of the virus specified proteins, OBP and OBPC, whose genes overlap in HSV- 1 DNA, will be determined by constructing and characterizing replication-defective adenovirus vectors that express either one protein or the other. The role of phosphorylation of OBP and OBPC in origin-dependent DNA replication and in transcription of origin flanking genes will also be determined. A better understanding of the mechanism involved in origin-dependent DNA replication and transcription of origin-flanking genes should shed light on the disease producing properties of herpesviruses and may provide novel molecular targets for intervention in the herpesvirus life-cycle.
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