Blasi Elisabetta, Colombari Bruna, Orsi Carlotta Francesca, Pinti Marcello, Troiano Leonarda, Cossarizza Andrea, Esposito Roberto, Peppoloni Samuela, Mussini Cristina, Neglia Rachele
Dipartimento di Scienze Igienistiche, Microbiologiche e Biostatistiche, Via Campi 287, 41100 Modena, Italy.
FEMS Immunol Med Microbiol. 2004 Oct 1;42(2):187-95. doi: 10.1016/j.femsim.2004.05.001.
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.
高效抗逆转录病毒疗法（HAART），其中包括人类免疫缺陷病毒（HIV）蛋白酶抑制剂（PIs），已显示出显著疗效，包括对一些机会性感染有效。在本报告中，我们研究了PI茚地那韦对新型隐球菌蛋白酶活性的影响，新型隐球菌是一种机会性真菌病原体，可导致艾滋病患者反复发生脑膜脑炎。我们还测试了茚地那韦对其他参数的潜在影响，如真菌活力、生长能力以及对免疫效应细胞的敏感性。结果发现，茚地那韦以时间和剂量依赖性方式损害隐球菌蛋白酶活性。在ATCC/实验室菌株和临床分离株中均可类似地检测到这种现象。暴露于茚地那韦后，新型隐球菌的生长速率也显著降低，而真菌活力未受影响，也未检测到线粒体毒性。此外，通过体外感染模型评估，茚地那韦显著且持续地增强了新型隐球菌对小胶质细胞介导的吞噬作用和杀伤作用的敏感性。总体而言，这些数据首次证明茚地那韦直接影响新型隐球菌，为PIs的广谱疗效提供了新的体外见解，进一步证明了HAART对艾滋病患者机会性感染的临床相关性。
