The Virology Program Project continues its focus on the identification of interactions between viral and cellular proteins in herpesvirus infection and the effects of viral infection on cellular growth control. The program encompasses diverse approaches to these questions that include detailed basic analyses of protein/DNA interactions and the development and analysis of biologic models of pathogenesis. In project l, Dr. Jack Griffith will continue his studies of herpes simplex virus (HSV) replication proteins, visualizing the UL-9 and ICP8 proteins to determine how they bind and open the lytic origin of replication. An in vitro HSV replication system will be reconstituted for detailed study and three-dimensional imaging of HSV protein/DNA complexes will be obtained. In project 2, Dr. Shannon Kenney will pursue her studies of the Epstein Barr virus (EBV) lytic origin of replication. She has previously shown that EBV BMRF1, the EBV polymerase processivity factor, functions as a transactivator and binds the downstream essential component in orilyt. In this project, she will identify cellular proteins that interact with BMRF1 and use an in vitro replication system to determine if transcriptional transactivation is coupled to replication. Working with Dr. Griffith, she will analyze the orilyt protein/DNA structure using electron microscopy. Dr. Steven Bachenheimer will, in Project 3, determine if HSV infection affects cell cycle progression by affecting cyclin dependent kinase activity and analyze viral infection in genetically altered rodent fibroblasts that lack the retinoblastoma protein. He will also determine the role of viral proteins in regulating E2F and cyclin kinase activity. In Project 4, Dr. Joseph Pagano, will analyze the relationship between the cell cycle and EBV expression during latent infection. This project will determine and identify viral proteins that are expressed in a cell cycle dependent fashion. The phosphorylation state of specific proteins and the effects of phosphorylation on protein function and protein/protein interactions will be determined. Dr. Eng Shang Huang will, in project 5, continue his studies of the effects of human cytomegalovirus (HCMV) on endothelial and monocyte cell function. He has previously shown that HCMV induces expression of interleukin 1beta, NFkappaB, and SP1, and that many of these effects are mediated by binding glycoprotein B (gB) to a cellular receptor. In these studies, he will determine the effects of virus infection and gB binding on expression of cytokine and adhesion molecules and determine if infected cells secrete factors that affect endothelial cell function. He will also clone the gB receptor and define the signaling process that is upregulated by gB binding. In project 6, Dr. Nancy Raab- Traub, P.I., will characterize EBV latent membrane protein LMP1-induced transformation in transgenic mice and in rodent fibroblasts. She will analyze the molecular interactions of LMP1 with cellular proteins, determine which cellular pathways mediate LMP1 transformation, and identify complementing pathways that contribute to oncogenesis. Overall, the program project will continue to dissect the viral/cellular molecular interactions that occur during viral infection and determine how specific molecular events underlie herpes virus pathogenesis.
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