5-Amino-4-imidazolecarboxamide riboside potentiates the metabolism and anti-human immunodeficiency virus activity of 2',3'-dideoxyinosine

Abstract

The antiviral activity of the purine dideoxynucleosides 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) is dependent on their conversion into ddA triphosphate in vivo. 5-Amino-4-imidazolecarboxamide riboside (AICA riboside), a natural metabolite in purine biosynthetic pathways, is converted into IMP, a substrate for the biosynthesis of adenine and guanine nucleotides, and enhances the intracellular purine nucleotide pools. Because IMP also serves as a phosphate donor in the anabolic phosphorylation of ddI (and ddA) into ddI monophosphate by the cytosolic enzyme 5'-nucleotidase, we investigated the effects of AICA riboside on the phosphorylation and antiretroviral activity of these purine nucleoside analogs. At an AICA riboside concentration of 0.5 mM, there was a approximately 2-fold increase in the intracellular ATP and GTP levels, whereas a nearly 8-fold increase was observed for the phosphorylation of ddA (or ddI). A marked reduction in intracellular pools of the pyrimidine nucleotides CTP and UTP was observed in AICA riboside-treated cells and inhibited cell proliferation. However, this growth inhibition was prevented by the addition of uridine to the cultures. Cells pretreated with AICA riboside and ddI were less susceptible to human immunodeficiency virus (HIV) infection and synthesized reduced levels of HIV proviral DNA. A 10-fold potentiation of the effectiveness of ddI against both wild-type HIV (HIVIIIB) and a ddI-resistant variant HIV was observed in the presence of 0.5 mM AICA riboside. These results show that AICA riboside modulates the anabolism and antiviral activity of ddI, and they have implications for possible therapies with dideoxynucleosides.