The objectives of this component of the program project grant are several fold: First the project will generate a library of HSV-2 deletion mutants, focusing primarily on several genes previously shown in HSV-1 genomes to affect the capacity of the virus to replicate in CNS tissues. This approach is dictated by the concern that HSV infection can result in encephalitis, with its attendant mortality and morbidity. Studies on HSV-1 have previously shown that deletion mutants incapable of replicating in the CNS of highly susceptible animals can be constructed. At the molecular level, the desirable mutants are those that are avirulent, yet produce vast amounts of virion structural proteins properly displayed on the surfaces of infected cells. Each mutant will be tested in Project 3 for its phenotypic behavior in mice. The second objective of the project is to insert appropriate HSV-1 glycoprotein genes into the suitable candidate vaccine strain(s) selected from the screens described above, in order to enhance immunity against HSV- 1 infection. A number of potential sites for insertion of the HSV-1 genes are available and will be tested. The third objective of this project is to screen the replicative capacity of the deletion mutants in a variety of cell lines and strains, but particularly in cells like the MRC-5 cell strain which has been licensed and approved for viral vaccine production. The fourth objective is to construct and test under appropriate promoters viruses carrying genes that express factors involved in enhancement of mucosal immunity. While such vaccines might well be construed to being in the category of the """"""""next generation"""""""", the currently evolving technology of tailoring promoters to required level of expression will be tested using genes specifying particular interleukins. In all of these projects, the design and ultimate structure of the vaccine candidate strains will take cognizance of and rest on the results of studies in Projects 2 and 3.
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