The human immunodeficiency virus (HIV) protease inhibitor indinavir directly affects the opportunistic fungal pathogen Cryptococcus neoformans.
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.
Blasi
Elisabetta
E
Dipartimento di Scienze Igienistiche, Microbiologiche e Biostatistiche, Via Campi 287, 41100 Modena, Italy. blasi.elisabetta@unimore.it
Colombari
Bruna
B
Orsi
Carlotta Francesca
CF
Pinti
Marcello
M
Troiano
Leonarda
L
Cossarizza
Andrea
A
Esposito
Roberto
R
Peppoloni
Samuela
S
Mussini
Cristina
C
Neglia
Rachele
R
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
D000935:Antifungal Agents; D017320:HIV Protease Inhibitors; D019469:Indinavir; D010447:Peptide Hydrolases