This is a resubmission of the second renewal application of the Virology Program Project of the University of North Carolina """"""""Virus Genomes, Oncogenesis, and Latency."""""""" The general objectives of the program are to characterize in molecular terms aspects of genome structure and function of the Epstein-Barr virus and other herpesviruses. The program focuses on virus and host-specific properties that relate to mechanisms of persistent infection, virus latency, and oncogenesis in human pathogenetic processes. In addition, the project brings together Dr. Y.C. Cheng's, Dr. Huang's, and Dr. J.S. Pagano's laboratories to provide virologic expertise for Herpes simplex viruses, cytomegalovirus, and Epstein-Barr virus to design and search for potent anti-herpes agents of low toxicity, especially against human CMV and EBV, and to elucidate their mode of action. There are five subprojects: 1) Identification of the Origin of Replication of the EBV Genome. This project will determine if regions of the EBV genome which can function as autonomous replicating sequences in yeast are involved in the replication of the EBV plasmid. 2) Analyses of Nasopharyngeal Carcinoma. The presence of EBV DNA and the pattern of expression within NPC tumor material will be correlated to histology and serology. Viral proteins encoded by the regions of the EBV genome which are expressed in NPC will be identified in EBV infected cell lines and in tumor material. 3) Herpesviruses Enzymes. The herpes simplex virus induced DNA uracil N-glycosidase and dUTP pyrophosphatase will be purified and characterized. The EBV-associated DNAse will be purifed and identified in NPC tissue. 4) Expression, Replication, Maturation, and Encapsidation of HSV type 1 DNA. This proposal will gather the structural, biochemical, and genetic data related to the replicative intermediate of HSV type 1 DNA. 5) Anti-herpesvirus compounds. Two groups of newly developed nucleoside analogs, 2'-fluoro-5-methyl derivatives of arabinosyl nucleoside analogs (FIAC, FMAC, FIAU and FMAU) and acyclovir derivative (BIOLF.62) will be studied for their antiviral effect against human CMV and EBV and for their mode of action. These projects concentrate on aspects of DNA structure and enzymatic functions which are essential for maintenance of latency or productive replication and are possibly involved in oncogenesis. This knowledge will facilitate the development of antiviral compounds.
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