Background:Leflunomide inhibitsde novopyrimidine synthesis by inhibiting the activity of dihydroorotic acid dehydrogenase and has other immunomodulatory properties that make it a promising candidate for an anti-HIV drug.Objectives:To compare the anti-HIV activity of leflunomide with that of the immunomodulatory drugs hydroxyurea and mycophenolic acid; to assess whether there is an additive or synergistic effect when leflunomide is used in conjunction with mycophenolic acid; and to characterize the molecular mechanism of the anti-HIV activity of leflunomide.Methods:Anti-HIV activity was examined in peripheral blood mononuclear cells. CD4 cell survival was examined in tonsillar lymphocytes by fluorescence-activating cell sorting.Results:Leflunomide decreased HIV replication by approximately 75% at concentrations that can be obtained with conventional dosing. This activity was similar to that of hydroxyurea but superior to mycophenolic acid. Leflunomide and mycophenolic acid together have modest additive anti-HIV effects. Restoration of HIV replication by uridine indicates that leflunomide's primary mechanism at lower concentrations is inhibition of dihydroorotic acid dehydrogenase while at higher concentrations additional mechanisms may be involved.Conclusions:Leflunomide's anti-HIV activity and clinical profile make it an attractive candidate for further study of its effects. Since HIV RNA levels are an effective predictor of AIDS-free survival, leflunomide's partial suppression of HIV RNA may be valuable in certain patients.