Hydroxyurea as an Inhibitor of Human Immunodeficiency Virus-Type 1 Replication

Abstract

Hydroxyurea, a drug widely used in therapy of several human diseases, inhibits deoxynucleotide synthesis--and, consequently, DNA synthesis--by blocking the cellular enzyme ribonucleotide reductase. Hydroxyurea inhibits human immunodeficiency virus-type 1 (HIV-1) DNA synthesis in activated peripheral blood lymphocytes by decreasing the amount of intracellular deoxynucleotides, thus suggesting that this drug has an antiviral effect. Hydroxyurea has now been shown to block HIV-1 replication in acutely infected primary human lymphocytes (quiescent and activated) and macrophages, as well as in blood cells infected in vivo obtained from individuals with acquired immunodeficiency syndrome (AIDS). The antiviral effect was achieved at nontoxic doses of hydroxyurea, lower than those currently used in human therapy. Combination of hydroxyurea with the nucleoside analog didanosine (2',3'-dideoxyinosine, or ddl) generated a synergistic inhibitory effect without increasing toxicity. In some instances, inhibition of HIV-1 by hydroxyurea was irreversible, even several weeks after suspension of drug treatment. The indirect inhibition of HIV-1 by hydroxyurea is not expected to generate high rates of escape mutants. Hydroxyurea therefore appears to be a possible candidate for AIDS therapy.

Induction of G 1 cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: A strategy to inhibit R5 HIV-1

“…To this end, ␤-chemokine production by activated PBMCs cultured in the presence of HU was investigated. HU is a cytostatic drug that, by depleting intracellular nucleotide pools, arrests cell cycle progression in late G 1 (9). Fig.…”

“…These data suggested that the antiviral effect observed was not due to inhibition of the virus reverse transcription step by HU-mediated depletion of nucleotide pools. Although it is known that HU exerts anti-HIV-1 activity by reducing the intracellular nucleotide pools (15), low concentrations of the drug (Յ100 M) are effective only when combined with nucleoside analog reverse transcription inhibitors (9). Therefore, our results showing little antiviral activity by 100 M HU when added to fresh culture medium agree with previous reports and indicate further that the increase in chemokine levels resulting from exposure to the drug is the likely explanation for the antiviral effect observed.…”

Measles virus inhibits human immunodeficiency virus type 1 reverse transcription and replication by blocking cell-cycle progression of CD4+ T lymphocytes

“…Thapsigargin, which blocks the cell cycle at G 0 , did not consistently reduce lymphoproliferation or p24 antigen production. Hydroxyurea inhibits HIV-1 replication (Lori et al, 1994) and has been used in combination with dideoxynucleoside reverse transcriptase inhibitors for the treatment of HIV-1 infection (Lori & Lisziewicz, 2000).…”

Early Detection of a Two-Long-Terminal-Repeat Junction Molecule in the Cytoplasm of Recombinant Murine Leukemia Virus-Infected Cells

“…In this case, the two-LTR circular form was not detected until 8 h after infection, when the majority of cells have passed through mitosis. Because HUand not aphidicolin-inhibits deoxynucleotide synthesis and consequently blocks HIV-1 DNA synthesis by decreasing the amount of intracellular deoxynucleotides (31), it is a reasonable explanation for the lack of two-LTR detection in this In support of this hypothesis is the fact that in vitro direct ligation of the ends of HIV-1 linear DNA molecule with cytoplasmic extracts is induced by incubation of the extracts in the presence of added deoxynucleoside triphosphates. To the contrary, no two-LTR junctions were detected when extracts were incubated in the absence of added deoxynucleoside triphosphates (15).…”