Dissimilar attenuation of Candida albicans virulence properties by human immunodeficiency virus type 1 protease inhibitors.
The secreted aspartyl proteinase (Sap) of Candida albicans, which is believed to represent an important virulence factor of this opportunistic yeast, and the human immunodeficiency virus type 1 (HIV-1) protease, which is obligatory for the production of infectious virions, both belong to the same family of aspartyl proteinases. We have previously shown that the HIV-1 protease inhibitor Indinavir directly inhibits secretion and proteinase activity of Sap in a dose-dependent manner. Furthermore, at very high concentrations, viability of C. albicans is markedly reduced by Indinavir, indicating that HIV-1 protease inhibitors may possess antifungal activity. We thus proposed that these drugs may add to the resolution of mucosal candidiasis in HIV-1 infected subjects. We have now compared three different HIV-1 protease inhibitors. The rank order of Sap inhibition, already significant at 0.1 mg/ml for all protease inhibitors, was Ritonavir > Indinavir > Saquinavir. However, the cross-reactivity of Ritonavir to pepsin was also more pronounced compared with the other two. Indinavir did not affect Candida viability at concentrations up to 1 mg/ml, in line with our previous study. In contrast, at this concentration Saquinavir was even fungicidal as assessed by three different viability assays (colony formation assay, MTT assay, propidium iodide staining) whereas Ritonavir significantly affected the mitochondrial activity only (MTT assay). No influence on Candida viability was observed for any of the three at concentrations of 0.1 mg/ml or lower. It remains to be examined whether HIV-1 protease inhibitors or derivatives thereof may be suitable for in vivo therapy of subjects suffering from mucosal candidiasis resistant to current antimycotics.
Gruber
A
A
Institute for Hygiene, University of Innsbruck, and Ludwig-Bolzmann Institute for AIDS Research, Austria.
Berlit
J
J
Speth
C
C
Lass-Flörl
C
C
Kofler
G
G
Nagl
M
M
Borg-von Zepelin
M
M
Dierich
M P
MP
Würzner
R
R
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000472:pathogenicity; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1; D006801:Humans; D019469:Indinavir / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D019258:Saquinavir / Q000494:pharmacology*; D013552:Swine; D014774:Virulence
D000935:Antifungal Agents; D017320:HIV Protease Inhibitors; D019469:Indinavir; D016282:Aspartic Acid Endopeptidases; D019258:Saquinavir; D019438:Ritonavir