title: The human immunodeficiency virus (HIV) protease inhibitor indinavir directly affects the opportunistic fungal pathogen Cryptococcus neoformans.
abstract: Highly active antiretroviral therapy (HAART), that includes human immunodeficiency virus (HIV) protease inhibitors (PIs), has been remarkably efficacious including against some opportunistic infections. In this report we investigated the effect(s) of the PI indinavir on protease activity by Cryptococcus neoformans, an opportunistic fungal pathogen responsible for recurrent meningoencephalitis in AIDS patients. Indinavir was also tested for potential effects on other parameters, such as fungal viability, growth ability and susceptibility to immune effector cells. It was found that indinavir impaired cryptococcal protease activity in a time- and dose-dependent fashion. The phenomenon was similarly detectable in ATCC/laboratory strains and clinical isolates. C. neoformans growth rate was also significantly reduced upon exposure to indinavir, while fungal viability was not affected and mitochondrial toxicity not detected. Furthermore, as assessed by an in vitro infection model, indinavir significantly and consistently augmented C. neoformans susceptibility to microglial cell-mediated phagocytosis and killing. Overall, by providing the first evidence that indinavir directly affects C. neoformans, these data add new in vitro insights on the wide-spectrum efficacy of PIs, further arguing for the clinical relevance of HAART against opportunistic infections in AIDS.
authors.affiliation: Dipartimento di Scienze Igienistiche, Microbiologiche e Biostatistiche, Via Campi 287, 41100 Modena, Italy. blasi.elisabetta@unimore.it
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Blasi
authors.forename: Bruna
authors.initials: B
authors.lastname: Colombari
authors.forename: Carlotta Francesca
authors.initials: CF
authors.lastname: Orsi
authors.forename: Marcello
authors.initials: M
authors.lastname: Pinti
authors.forename: Leonarda
authors.initials: L
authors.lastname: Troiano
authors.forename: Andrea
authors.initials: A
authors.lastname: Cossarizza
authors.forename: Roberto
authors.initials: R
authors.lastname: Esposito
authors.forename: Samuela
authors.initials: S
authors.lastname: Peppoloni
authors.forename: Cristina
authors.initials: C
authors.lastname: Mussini
authors.forename: Rachele
authors.initials: R
authors.lastname: Neglia
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002460:Cell Line; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D017628:Microglia; D008928:Mitochondria / Q000502:physiology; D010447:Peptide Hydrolases / Q000378:metabolism*; D010587:Phagocytosis
chemical_list: D000935:Antifungal Agents; D017320:HIV Protease Inhibitors; D019469:Indinavir; D010447:Peptide Hydrolases