Synergistic antiviral action of ribonucleotide reductase inhibitors and 3′-azido-3′-deoxythymidine on HIV type 1 infection in vitro

Mauro Giacca, Stefania Borella, Francesca Calderazzo, Luigi Chieco Bianchi, Pierlanfranco D'Agaro, Chiara Rampazzo, Vera Bianchi, Peter Reichard

Research output: Contribution to journalArticlepeer-review

Abstract

Ribonucleotide reductase inhibitors reduce the cellular supply of DNA precursors (dNTP) by interfering with their de novo synthesis. A secondary effect is the stimulation of the uptake and phosphorylation of extracellular deoxynucleosides, including their analogs, e.g., 3′-azidothymidine (AZT). Both effects are relevant to HIV replication, which requires dNTP and is impaired by the triphosphate of AZT. Earlier we demonstrated that ribonucleotide reductase inhibitors - hydroxyurea, and two deoxycytidine analogs specifically active in lymphoid cells - increased the phosphorylation of AZT in CEM cells by prolonging the S phase of the cell cycle. Here we tested the effects of long-term treatments on HIV proliferation in CEM cells and stimulated human lymphocytes infected with HIV-1IIIB. Treatment with low doses of AZT (0.05-0.1 μM) and either hydroxyurea (25-100 μM) or 2′-azido-2′-deoxycytidine (0.25-4 μM) lasted 2 weeks, during which p24 in the culture medium was monitored. Noninfected CEM cells were treated in parallel to measure the inhibition of cell growth, distribution along the cell cycle, dNTP pool size, and level of tritiated AZT phosphorylation. A clear synergism between AZT and ribonucleotide reductase inhibitors was observed at nontoxic doses that in-duced only minor changes in the cellular parameters measured. The reductase inhibitors by themselves interfered with viral replication only at doses that inhibited cell proliferation.

Original languageEnglish
Pages (from-to)677-682
Number of pages6
JournalAIDS Research and Human Retroviruses
Volume12
Issue number8
Publication statusPublished - May 20 1996

ASJC Scopus subject areas

  • Immunology
  • Virology

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