DISPARATE ACTIONS OF HYDROXYUREA IN POTENTIATION OF PURINE AND PYRIMIDINE 2',3'-DIDEOXYNUCLEOSIDE ACTIVITIES AGAINST REPLICATION OF HUMAN-IMMUNODEFICIENCY-VIRUS

We and other groups have recently reported the potentiation by ribonuc leotide reductase inhibitors such as hydroxyurea of the anti-human imm unodeficiency virus type 1 (HIV-1) activity of purine and pyrimidine 2 ',3'-dideoxynucleosides in both resting and phytohemagglutinin-stimula ted peripheral blood mononuclear cells. Little agreement prevails, how ever, as to the mechanism of the synergistic effects described. We rep ort here that in phytophemagglutinin-stimulated peripheral blood monon uclear cells, two mechanisms exist for the potentiation of the anti-HI V-1 activity by low-dose hydroxyurea of the purine-based dideoxynucleo side 2',3'-dideoxyinosine and the pyrimidine-based dideoxynucleosides 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine. For 2',3'-dideox yinosine, the enhancement arises from a specific depletion of dATP by hydroxyurea, resulting in a favorable shift of the 2',3'-dideoxyadenos ine 5'-triphosphate/dATP ratio. For the pyrimidine dideoxynucleosides 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine, the more modest anti-HIV enhancement results from hydroxyurea-induced increases of pyr imidine kinase activities in the salvage pathway and, hence, increased 5'-phosphorylation of these drugs, while depletion of the correspondi ng deoxynucleoside 5'-triphosphates (dTTP and dCTP) plays no significa nt role.