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

• Published in: Science (American Association for the Advancement of Science) 1994-11, Vol.266 (5186), p.801-805
• Main Authors: Lori, Franco, Malykh, Andrei, Cara, Andrea, Sun, Daisy, Weinstein, John N., Lisziewicz, Julianna, Gallo, Robert C.
• Format: Article
• Language: English
• Subjects: Acquired Immunodeficiency Syndrome - drug therapy; Acquired Immunodeficiency Syndrome - immunology; Acquired Immunodeficiency Syndrome - virology; AIDS; Antivirals; Cell Survival - drug effects; Didanosine - pharmacology; DNA; DNA Replication - drug effects; DNA, Viral - analysis; DNA, Viral - biosynthesis; Dosage; Dose-Response Relationship, Drug; Drug Synergism; HIV 1; HIV antigens; HIV Core Protein p24 - analysis; HIV-1 - drug effects; HIV-1 - physiology; human immunodeficiency virus 1; Humans; Hydroxyurea; Hydroxyurea - pharmacology; Infections; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - virology; Lymphocyte Activation; Lymphocytes; Macrophage Activation; Macrophages; Macrophages - drug effects; Macrophages - virology; Polymerase chain reaction; Virus Replication - drug effects; Viruses; Zidovudine - pharmacology
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.7973634

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.