HYDROXYUREA AS AN INHIBITOR OF HUMAN IMMUNODEFICIENCY VIRUS-TYPE-1 REPLICATION

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 in hibits human immunodeficiency virus-type 1 (HIV-1) DNA synthesis in ac tivated peripheral blood lymphocytes by decreasing the amount of intra cellular deoxynucleotides, thus suggesting that this drug has an antiv iral effect. Hydroxyurea has now been shown to block HIV-1 replication in acutely infected primary human lymphocytes (quiescent and activate d) and macrophages, as well as in brood cells infected in vivo obtaine d 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 hydroxyure a 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 irreversib le, even several weeks after suspension of drug treatment. The indirec t inhibition of HIV-1 by hydroxyurea is not expected to generate high rates of escape mutants. Hydroxyurea therefore appears to be a possibl e candidate for AIDS therapy.