Altered P-glycoprotein expression in AIDS patients with HIV encephalitis
Altered P-glycoprotein expression in AIDS patients with HIV encephalitis
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DOI：
10.1093/jnen/63.10.1038
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发表时间：
2004-10-01
影响因子：
3.2
通讯作者：
Masliah, E
中科院分区：
文献类型：
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作者：
Langford, D;Grigorian, A;Masliah, E
抗逆转录病毒药物进入中枢神经系统的渗透部分取决于 P-糖蛋白 (P-gp) 的活性，P-糖蛋白是一种 ATP 依赖性外排泵，参与限制亲脂性药物进入大脑。本研究描述了 AIDS 患者大脑中 P-gp 表达模式的特征，并探讨了其与 HIV 脑炎 (HIVE) 临床和神经病理学指标的关系。为此，我们分析了尸检时从 26 名有 HIV 病史的受试者（9 名没有 HIV 感染；17 名有 HIV 感染）身上收集的脑组织。对区域 P-gp 表达进行免疫细胞化学染色和蛋白质印迹分析，并将其水平与神经病理学指标和 HIV RNA 相关。使用针对星形胶质细胞 (GFAP)、内皮细胞 (CD31)、小胶质细胞 (CD45) 和神经元 (MAP2) 细胞标记物的抗体进行双标记实验。在 HIVE 阴性病例中，P-gp 免疫反应性主要与内皮细胞相关。 HIVE阳性病例显示星形胶质细胞和小胶质细胞的广泛免疫标记，但内皮细胞免疫标记相对较少。研究中任何病例的脑组织中均未检测到神经元 P-gp 免疫染色。在具有广泛星形胶质细胞标记的 HIVE 阳性病例中，在白质中检测到最强烈的免疫反应性。一部分 HIVE 阳性病例显示出与皮质血管密切相关的星形胶质细胞的强烈 P-gp 免疫染色。免疫细胞化学和蛋白质印迹分析均显示 P-gp 表达与 HIV RNA 水平之间存在显着相关性。总之，P-gp 免疫反应性主要在 HIVE 阳性患者组织中的神经胶质细胞中检测到。此外，在 HIVE 阳性患者中，脑病毒负荷和 P-gp 水平显着高于 HIVE 阴性患者。总而言之，我们的数据表明，P-gp 可能是介导 HIV 感染者大脑中病毒分区的中央通路的一部分，并且可能在 HIV 疾病的大脑进展中发挥重要作用。
Penetrance of anti-retroviral drugs into the CNS depends partly on the activity of P-glycoprotein (P-gp), an ATP-dependent efflux pump involved in restricting entry of lipophilic drugs into the brain. The present study characterizes the patterns of P-gp expression in the brains of AIDS patients and examines its relationship with clinical and neuropathological indicators of HIV encephalitis (HIVE). For this purpose, brain tissue collected at autopsy from 26 subjects with a history of HIV (9 without HIVE; 17 with HIVE) was analyzed. Immunocytochemical staining and Western blot analyses for regional P-gp expression were performed and levels were correlated with neuropathological indicators and with HIV RNA. Double labeling experiments were performed with antibodies against astroglial (GFAP), endothelial (CD31), microglial (CD45) and neuronal (MAP2) cell markers. In the HIVE-negative cases, P-gp immunoreactivity was associated primarily with endothelial cells. HIVE-positive cases showed extensive immunolabeling of astroglial and microglial cells, but relatively less endothelial cell immunolabeling. No neuronal P-gp immunostaining was detected in brain tissue from any cases in the study. In the HIVE-positive cases with extensive astroglial labeling, the most intense immunoreactivity was detected in white matter. A subset of HIVE-positive cases displayed intense P-gp immunostaining of astrocytes closely associated with blood vessels in the cortex. Both the immunocytochemical and Western blot analyses showed a significant correlation between P-gp expression and HIV RNA levels. In conclusion, P-gp immunoreactivity was detected largely in glial cells in tissue from HIVE-positive patients. Furthermore, in HIVE-positive patients, brain viral burden and P-gp levels were significantly higher than those in HIVE-negative patients. Taken together, our data suggest that P-gp may be part of a central pathway mediating viral the partmentalization in the brains of HIV-infected individuals and may play a significant part in HIV disease in the progression in the brain.