Mele R, Gomez Morales M A, Tosini F, Pozio E
Laboratory of Parasitology, Istituto Superiore di Sanità, viale Regina Elena 299, 00161 Rome, Italy.
Int J Parasitol. 2003 Jul;33(7):757-64. doi: 10.1016/s0020-7519(03)00093-6.
The use of highly active antiretroviral therapy in persons with acquired immunodeficiency syndrome has reduced the prevalence of infection with Cryptosporidium parvum and the length and severity of its clinical course. This effect has in most cases been attributed to the recovery of the host immunity; however, some works suggest that human immunodeficiency virus protease inhibitors, indinavir in particular, which is one of the human immunodeficiency virus protease inhibitors used in highly active antiretroviral therapy, may be capable of controlling Microsporidia and Cryptosporidium infections, which are refractory to other treatments. The objective of the present study was to investigate the effect of human immunodeficiency virus protease inhibitors on C. parvum infections. Since preliminary experiments using ritonavir, saquinavir, and indinavir showed a drastic reduction of C. parvum infection both in vivo (neonatal Balb/c mice) and in vitro (human ileocecal adenocarcinoma tumour cell line) models, indinavir alone was tested in successive experiments. In vitro, the treatment of the sporulated oocysts with different concentrations of indinavir reduced the percentage of human ileocecal adenocarcinoma tumour cell line infected cells in a dose-dependent manner. For established infection, the treatment with 50 microM of indinavir decreased the percentage of infected cells in a time-dependent manner. In vivo, mice treated with indinavir at the same time they were infected with the oocysts showed a 93% reduction in the number of oocysts present in the entire intestinal contents and a 91% reduction in the number of intracellular parasites in the ileum. For established infection, indinavir treatment reduced the number of oocysts in the entire intestinal content by about 50% and the number of intracellular parasites in the ileum by about 70%. These data show that indinavir directly interferes with the cycle of C. parvum, resulting in a marked reduction in oocyst shedding and in the number of intracellular parasites. Protease inhibitors could be considered as good candidates for the treatment of cyptosporidiosis in immunosuppressed persons.
在获得性免疫缺陷综合征患者中使用高效抗逆转录病毒疗法，已降低了微小隐孢子虫感染的患病率及其临床病程的长度和严重程度。在大多数情况下，这种效果归因于宿主免疫力的恢复；然而，一些研究表明，人类免疫缺陷病毒蛋白酶抑制剂，特别是茚地那韦，它是高效抗逆转录病毒疗法中使用的人类免疫缺陷病毒蛋白酶抑制剂之一，可能能够控制对其他治疗难治的微孢子虫和隐孢子虫感染。本研究的目的是调查人类免疫缺陷病毒蛋白酶抑制剂对微小隐孢子虫感染的影响。由于使用利托那韦、沙奎那韦和茚地那韦的初步实验显示，在体内（新生Balb/c小鼠）和体外（人回盲部腺癌肿瘤细胞系）模型中微小隐孢子虫感染均大幅减少，因此在后续实验中单独测试了茚地那韦。在体外，用不同浓度的茚地那韦处理孢子化卵囊，以剂量依赖的方式降低了人回盲部腺癌肿瘤细胞系感染细胞的百分比。对于已建立的感染，用50微摩尔茚地那韦处理以时间依赖的方式降低了感染细胞的百分比。在体内，在感染卵囊的同时用茚地那韦治疗的小鼠，整个肠道内容物中存在的卵囊数量减少了93%，回肠中细胞内寄生虫的数量减少了91%。对于已建立的感染，茚地那韦治疗使整个肠道内容物中的卵囊数量减少了约50%，回肠中细胞内寄生虫的数量减少了约70%。这些数据表明，茚地那韦直接干扰微小隐孢子虫的周期，导致卵囊排出和细胞内寄生虫数量显著减少。蛋白酶抑制剂可被视为免疫抑制人群隐孢子虫病治疗的良好候选药物。
