Acquired immunodeficiency syndrome (AIDS) is a progressively fatal disease that is believed to be the result of infection by the lymphotrophic virus HIV. Hundreds of drugs have been screened for activity against the HIV, and the ones that have been found effective in vitro are all members of the dideoxynucleosides. It has recently come to the attention of researchers that the intracellular anabolism of these nucleosides into active nucleotides (triphosphates) has different efficiencies in different cell types and showed varying degrees of competition with the endogenous metabolites. We have recently demonstrated that dipyridamole, a potent membrane nucleoside transport inhibitor, can augment the anti-tumor activity of a nucleoside analog cytarabine (araC) if administered in a sequential regimen. The mechanism of synergy resides in the ability of dipyridamole to increase cellular exposure to the active metabolite araCTP by preventing araC efflux. We plan to test the applicability of this type of sequential regiment in augmenting the anti-viral activity of a prototype anti-=viral nucleoside 2',3' -dideoxycytidine. Since the HIV has been shown to replicate in lymphocytes, macrophages, and bone marrow cells, we plan to use these cells as our experimental models. Our plan of action includes; a) demonstrating that their is a specific nucleoside transport system in each of the cell types; b) showing that such a nucleoside transport system is responsible for 2'3' -dideoxycytidine uptake into these immune effector cells; c) proving that this membrane nucleoside transport system is inhibitable by dipyridamole; d) confirming that dipyridamole can trap high concentrations of 2'3' -dideoxycytidine and its triphosphate within the immune effector cells for extended periods; and e) showing that prolonged entrapment of 2'3' -dideoxycytidine within cells is associated with improved anti-viral activity. Dipyridamole is a good drug to use because it has already been shown to be well tolerated in cardiac patients requiring anti-platelet therapy. In addition to the important therapeutic implications, this study will also provide valuable information on nucleoside metabolism in immune cells which is important in certain autoimmune diseases.
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