Langford Dianne, Grigorian Aline, Hurford Rosemary, Adame Anthony, Ellis Ronald J, Hansen Lawrence, Masliah Eliezer
Department of Pathology, University of California San Diego, La Jolla, CA 92093-0624, USA.
J Neuropathol Exp Neurol. 2004 Oct;63(10):1038-47. doi: 10.1093/jnen/63.10.1038.
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 compartmentalization in the brains of HIV-infected individuals and may play a significant part in HIV disease progression in the brain.
抗逆转录病毒药物进入中枢神经系统的程度部分取决于P-糖蛋白（P-gp）的活性，P-糖蛋白是一种依赖ATP的外排泵，参与限制亲脂性药物进入大脑。本研究描述了艾滋病患者大脑中P-糖蛋白的表达模式，并研究了其与HIV脑炎（HIVE）的临床和神经病理学指标之间的关系。为此，对26例有HIV病史的受试者（9例无HIVE；17例有HIVE）尸检时采集的脑组织进行了分析。进行了区域P-糖蛋白表达的免疫细胞化学染色和蛋白质印迹分析，其水平与神经病理学指标和HIV RNA相关。用抗星形胶质细胞（GFAP）、内皮细胞（CD31）、小胶质细胞（CD45）和神经元（MAP2）细胞标志物的抗体进行了双重标记实验。在无HIVE的病例中，P-糖蛋白免疫反应主要与内皮细胞有关。有HIVE的病例显示星形胶质细胞和小胶质细胞有广泛的免疫标记，但内皮细胞免疫标记相对较少。在本研究的任何病例的脑组织中均未检测到神经元P-糖蛋白免疫染色。在有广泛星形胶质细胞标记的有HIVE的病例中，在白质中检测到最强的免疫反应。一部分有HIVE的病例在皮质中显示与血管紧密相关的星形胶质细胞有强烈的P-糖蛋白免疫染色。免疫细胞化学和蛋白质印迹分析均显示P-糖蛋白表达与HIV RNA水平之间存在显著相关性。总之，在有HIVE的患者组织中，P-糖蛋白免疫反应主要在胶质细胞中检测到。此外，在有HIVE的患者中，脑病毒载量和P-糖蛋白水平显著高于无HIVE的患者。综上所述，我们的数据表明，P-糖蛋白可能是介导HIV感染个体大脑中病毒分隔的中心途径的一部分，并且可能在大脑中HIV疾病进展中起重要作用。
