Human cytomegalovirus (HCMV), a member of the herpesvirus family, is the leading viral cause of birth defects and causes significant morbidity and mortality in immunosuppressed individuals. The multiple pathogenic effects of HCMV are likely manifested through a complex interplay of viral gene products and induced and repressed cellular functions. HCMV immediate early (IE) and early gene expression clearly play a pivotal role in this scheme. A major part of our research has been directed towards determining the cis-acting regulatory elements and the cellular and viral factors involved in the regulation of HCMV early gene expression, with primary focus on the promoter for the ULI 12-113 RNAs. We have also studied in great depth the functional properties of the major viral transactivator of these genes, 1E2 86, and have developed a way to generate viruses with mutations in the 1E2 86 gene. In this renewal application, we propose to continue our studies on 1E2 86 function and on the cellular and viral factors governing HCMV early gene expression. The approach is to couple functional in vivo genetic analyses with biochemical and molecular assays to achieve the following aims: 1) determination of the function of the 1E2 86 protein in the context of the viral genome; 2) elucidation of 1E2 86-mediated effects on expression of cellular genes with focus on genes involved in cell cycle control, transcriptional regulation, apoptosis, and tumor suppression; and 3) determination of the mechanism of regulation of early viral gene expression by viral and cellular factors, using the UL1 12-113 gene as a model. The long range goals of this research are to define at the molecular level the mechanisms which operate to control HCMV gene expression, thus providing an important foundation for understanding how the complex interactions of viral and host functions relate to the pathogenesis of the virus.
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