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

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

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

AIDS Res Hum Retroviruses. 1996 May 20;12(8):677-82. Unique Identifier : AIDSLINE MED/96303586
Giacca M; Borella S; Calderazzo F; Bianchi LC; D'Agaro P; Rampazzo C; Bianchi V; Reichard P; International Centre for Genetic Engineering and Biotechnology,; Padriciano, Trieste, Italy.

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 microM) and either hydroxyurea (25-100 microM) or 2'-azido-2'-deoxycytidine (0.25-4 microM) 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 induced only minor changes in the cellular parameters measured. The reductase inhibitors by themselves interfered with replication only at doses that inhibited cell proliferation.

Keywords: Antiviral Agents/*PHARMACOLOGY Cell Cycle Cytidine/*ANALOGS & DERIVATIVES/PHARMACOLOGY Drug Synergism Enzyme Inhibitors/*PHARMACOLOGY Human Hydroxyurea/*PHARMACOLOGY HIV Core Protein p24/ANALYSIS HIV-1/*DRUG EFFECTS/PHYSIOLOGY Leukocytes, Mononuclear/CYTOLOGY/DRUG EFFECTS Phosphorylation Reverse Transcriptase Inhibitors/*PHARMACOLOGY Ribonucleotide Reductases/*ANTAGONISTS & INHIB Support, Non-U.S. Gov't Thymine Nucleotides/BIOSYNTHESIS Tumor Cells, Cultured Virus Replication/DRUG EFFECTS Zidovudine/*PHARMACOLOGY JOURNAL ARTICLE
961230
M96C0638

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