Hydroxyurea: mechanisms of HIV-1 inhibition

Hydroxyurea inhibits cellular ribonucleotide reductase, resulting in decreased pools of dNTPs and thus inhibition of DNA synthesis. Studies in vitro have shown that hydroxyurea reduces dNTP pools in cells infected with human immunodeficiency virus type 1 (HIV-1), inhibiting HIV-1 DNA synthesis in infected quiescent and activated primary human lymphocytes and macrophages. Hydroxyurea also potentiates the activity of nucleoside reverse transcriptase inhibitors (NRTIs): the activated triphosphate forms of NRTIs compete with naturally occurring dNTPs for incorporation into nascent viral DNA during reverse transcription. A synergistic effect is observed between hydroxyurea and didanosine (2',3'-dideoxyinosine; DDI). This combination exerts persistent suppression of HIV-1 replication without evidence of viral rebound for over 1 year in HIV-1-infected patients. Didanosine-resistant HIV-1 mutants retain sensitivity to didanosine in the presence of hydroxyurea. The incorporation of didanosine triphosphate by resistant reverse transcriptase is increased in the context of the hydroxyurea-induced depletion of dATP. Although hydroxyurea has a reduced effect on dNTPs competing with the triphosphate forms of pyrimidine NRTIs, it appears to augment the anti-HIV-1 activity of these agents by increasing their intracellular phosphorylation; this may be of particular interest for salvage strategies given recent data indicating disruption of NRTI phosphorylation with specific NRTI treatment regimens. Finally, by exerting a cytostatic effect on CD4 and CD8 T lymphocytes, hydroxyurea may (i) reduce HIV-1 replication by decreasing CD4 T cell proliferation; and (ii) prevent the exhaustion of CD8 T cell populations that may occur as a result of excessive activation in the context of HIV-1 infection.