HIV‐Protease Inhibitors Contribute to P‐Glycoprotein Efflux Function Defect in Peripheral Blood Lymphocytes From HIV‐Positive Patients Receiving HAART
HIV‐Protease Inhibitors Contribute to P‐Glycoprotein Efflux Function Defect in Peripheral Blood Lymphocytes From HIV‐Positive Patients Receiving HAART
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HIV蛋白酶抑制剂导致接受HAART的HIV阳性患者外周血淋巴细胞P-糖蛋白流出功能缺陷
DOI：
10.1097/00042560-200108010-00001
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发表时间：
2001
期刊：
影响因子：
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通讯作者：
R. Cauda
中科院分区：
文献类型：
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作者：
M. Lucia;S. Rutella;G. Leone;S. Vella;R. Cauda
摘要：已发现P-糖蛋白（P-gp）在正常人体细胞中表达，如骨髓和外周血细胞。本研究的目的是研究HIV蛋白酶抑制剂（HIV PI）是否与正常人外周血淋巴细胞（PBL）和CD 34+祖细胞中的P-gp外排功能相互作用。此外，我们分析了HIV-PI对接受高效抗逆转录病毒治疗（HAART）的HIV感染患者PBL中P-gp功能的体内影响。我们发现HIV-PI（即，利托那韦、沙奎那韦、奈非那韦和茚地那韦）干扰正常PBL中的P‐gp功能，如罗丹明123（Rh 123）外排减少所证明。该效应具有剂量依赖性，并提示以下层次：利托那韦>沙奎那韦>奈非那韦>茚地那韦。我们进一步分析了HIV-PI对特定PBL亚群中P-gp功能的影响。我们的研究结果表明，HIV-PI-诱导的对CD 4+和CD 8 + T细胞亚群中P-gp功能的抑制，主要是由对CD 4+和CD 8 + T细胞的幼稚区室的影响引起的。在CD 34+造血祖细胞中发现了相同的抑制作用。关于HIV感染患者PBL中P-gp功能的体内评估，我们发现Rh 123外排水平降低，在接受HAART的艾滋病患者中达到最低值。我们得出结论，HIV-PI干扰HIV感染的主要细胞靶点（如CD 4 + T细胞和CD 34+祖细胞）中的P-gp功能。这种能力可能导致在HIV感染患者中发现的P-gp外排功能缺陷，并表明药物相互作用研究对于全面了解这一重要药物组的作用至关重要。
Summary: P‐glycoprotein (P‐gp) has been found expressed in normal human cells, such as bone marrow and peripheral blood cells. The aim of this study was to investigate whether HIV‐protease inhibitors (HIV‐PIs) interact with P‐gp efflux function in normal human peripheral blood lymphocytes (PBLs) and CD34+ progenitor cells. Moreover, we analyzed the in vivo effect of HIV‐PIs on P‐gp function in PBLs from HIV‐infected patients receiving highly active antiretroviral therapy (HAART). We found that HIV‐PIs (i.e., ritonavir, saquinavir, nelfinavir and indinavir) interfere with P‐gp function in normal PBLs as demonstrated by the reduced efflux of rhodamine 123 (Rh123). This effect was dose‐dependent and suggested the following hierarchy: ritonavir > saquinavir > nelfinavir > indinavir. We further analyzed the effect of HIV‐PIs on the P‐gp function in specific PBLs subsets. Our results show an HIV‐PI‐induced inhibition of P‐gp function in CD4+ and CD8+ T cell subsets, mostly caused by the effect on the naive compartment of both CD4+ and CD8+ T cells. The same inhibitory effect was found in CD34+ hematopoietic progenitor cells. With respect to the in vivo evaluation of P‐gp function in PBLs from HIV‐infected patients, we found reduced levels of Rh123 efflux that reached the lowest value in AIDS patients receiving HAART. We concluded that HIV‐PIs interfere with P‐gp function in major cellular targets for HIV infection, such as CD4+ T cells and CD34+ progenitor cells. This ability may contribute to P‐gp efflux function defect found in HIV‐infected patients and suggests that drug interaction studies are crucial to an overall understanding of the effects of this important group of drugs.