The long term goal of the studies described in this proposal is to develop methods by which retroviruses and retroviral vectors may be targeted to specific cell types. These investigations are of medical significance because of the potential therapeutic value of employing targeted retroviral vectors for the treatment of genetically determined birth defects. Moreover, these studies should yield detailed information as to the mechanisms by which the Moloney murine leukemia virus (Mo-MuLV) envelope (env) proteins become incorporated into viral particles, the structure/function relationships of the Mo-MuLV env proteins, and the putative association of the env proteins with the Mo-MuLV core (gag) proteins. The model system described is ideal for the elucidation of general mechanisms of viral assembly and of cell surface and cytoplasmic protein interaction.
The specific aims are as follows: 1. We will undertake studies of mutant Mo-MuLV env proteins (the gp70/p15E complex) with respect to their subcellular localization, ability to be incorporated into viral particles, and facilitation of viral entry into cells. 2. Non-retroviral """"""""targeting"""""""" proteins, or fusions of such proteins with the Mo-MuLV envelope proteins will be examined to determine the factors which permit incorporation of heterologous proteins into retroviral particles. 3. Mutations in Mo-MuLV gag genes which may affect the incorporation of env proteins into virions will be generated and analyzed. Gag gene sequences responsible for directing the Pr65gag polyprotein to cell membranes and viral particles will be identified by analysis of gag gene fusions to indicator genes.
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