In vitro and in vivo anticandidal activity of human immunodeficiency virusprotease inhibitors

Highly active antiretroviral therapy that includes human immunodeficiency v irus (HIV) aspartyl protease inhibitors (PIs) causes a decline in the incid ence of some opportunistic infections in AIDS, and this decline is currentl y attributed to the restoration of specific immunity. The effect of two PIs (indinavir and ritonavir) on the enzymatic activity of a secretory asparty l protease (Sap) of Candida albicans (a major agent of mucosal disease in H IV-infected subjects) and on growth and experimental pathogenicity of this fungus was evaluated. Both PIs strongly (greater than or equal to 90%) and dose dependently (0.1-10 mu M) inhibited Sap activity and production. They also significantly reduced Candida growth in a nitrogen-limited, Sap expres sion-dependent growth medium and exerted a therapeutic effect in an experim ental model of vaginal candidiasis, with an efficacy comparable to that of fluconazole. Thus, besides the expected immunorestoration, patients receivi ng PI therapy may benefit from a direct anticandidal activity of these drug s.