Cellular transporter proteins have been identified as the receptors for retroviruses. The receptor for the amphotropic murine retroviruses and Gibbon ape leukemia virus are related phosphate transporters (RAM-1 and GLVR-1, respectively). The receptor for the ecotropic murine retrovirus is a basic amino acid transporter (CAT-1). The overall goal of these studies are to analyze the structure and dual functions of these receptors/transporters in order to understand their role in viral pathogenesis as well as to improve their use for gene delivery.
Five specific aims are proposed: 1) Understand the structures, post-translational modifications, cellular distributions, and mechanisms of function of the RAM-1 and GLVR-1 proteins. Of particular interest is the role of phosphorylation in enhancing the activities of the RAM-1 protein in both transport and infection. 2) Identify factors that functionally and/or physically interact with RAM-1 and study the functions of these interactions. 3) Pursue host cell factor(s) that could collaborate with receptors in a pathway that leads to fusion of the cell and viral membranes. A model is presented that the assembly of multivalent virus-receptor clusters may be necessary for completion of this pathway 4) Determine whether the antiviral drug, phosphate analog, forscarnet (phosphonoformate) inhibits the RAM-1 and GLVR-1 transporter activities. 5) Analyze the role of glycosylation in blocking infection of hamster cells by ecotropic and amphotropic mouse retroviruses.
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