Varicella-zoster virus (VZV) is s neurotropic human herpesvirus that causes two clinically distinct diseases: varicella (chickenpox) and zoster (shingles). The threat of disseminated, life-threatening VZV infections in leukemic children has led to the development of attenuated strains of VZV which are currently undergoing clinical evaluation. VZV replicates in a strongly cell-associated manner, and yields extremely low titers of infectious virus from cultured cells. Despite its importance as a human pathogen, we have only an incomplete understanding of the biology, biochemistry, and structure of VZV, but there are a number of aspects of VZV biology which are likely to be virion-envelope related. The long- term goals of this proposal are to analyze the biosynthesis and assembly of the VZV envelope and to determine the role(s) of the viral envelope components in infection and in the immune response to infection. The experiments described in this proposal are designed to: (1) test whether the unusual proteolytic cleavage of gpII is related to the low viral infectivity; (2) localize the epitopes on gpII that cross-react with herpes simplex virus (HSV) gB; (3) compare the kinetics of gpI synthesis and processing in infected and uninfected cells; (4) determine when targeting of the viral glycoproteins to the nuclear sites of virion envelope assembly begins; (5) locate the sites of the phosphorylation of gpI; (6) analyze the role of a predicted VZV protein kinase in the phosphorylation of gpI; (7) analyze the synthesis, processing and subcellular localization of the minor glycoprotein gpIV and of the predicted glycoprotein gpV. The techniques employed will include: preparation of monoclonal antibody resistant (MAR) mutants of VZV, preparation of heterotype VZV virions containing HSV gB, immunoprecipitation, SDS-PAGE, pulse-labelling, subcellular fractionation, DNA cloning and sequencing, peptide mapping, preparation of peptide-specific antibodies, Western immunoblotting, and preparation of HSV strains expressing non- HSV glycoproteins. These studies will yield reagents and information that are necessary for understanding the roles of the viral glycoproteins and their post-translational modifications in virion assembly and viral infection, for future analysis of the immune response to infection, and for possible development of a DNA-free subunit vaccine.
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