This proposal bring together a group of investigators who work on neurotropic viruses around the common theme of the role of viral receptors and cellular entry in the pathogenesis of central nervous system infections. The program has 7 major components: 4 projects and 3 cores, including an administrative core. Dr. Gonzalez-Scarano project will study the role of virus binding, entry and fusion in the neurotropism of La Crosse virus, and develop a system for reverse genetics; Dr. Gaulton project I will study infection with a neurotropic isolate of murine leukemia virus, elucidate the cell biology of env-receptor interactions, and determine the impact of retrovirus infection on endothelial cell function; Dr. Weiss project will study the pathogenesis of murine coronaviruses (MHV), which cause demyelination, with a focus on mapping the sequences responsible for demyelination through the construction of recombinant viruses and delineating the virus-receptor interactions in viruses with mutations in the receptor-binding domains of the S protein; Dr. Eisenberg project will study the interaction between herpes simplex virus glycoproteins and recently isolated HSV receptors, hPRR1, and hPRR2, determine the relationship between binding to these receptors and infection of neuronal and non-neuronal cells, and analyze the distribution of these receptors in the human brain. A neuropathology core will be used for pathogenesis studies in projects II and III, and for analysis of receptor distribution in project IV. A baculovirus expression core will be use to prepare recombinant glycoproteins for all of the projects, and recombinant receptor molecules where appropriate. The findings of each of these component projects will enhance our understanding of neurologic dysfunction mediated by viruses, and will have applicability to the study of viral encephalitis, multiple sclerosis, and retroviral infections of the nervous system.
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