Benos D J, Hahn B H, Bubien J K, Ghosh S K, Mashburn N A, Chaikin M A, Shaw G M, Benveniste E N
Department of Physiology and Biophysics, University of Alabama at Birmingham 35294.
Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):494-8. doi: 10.1073/pnas.91.2.494.
Infection by human immunodeficiency virus type 1 (HIV-1) is often complicated by a variety of neurological abnormalities. The most common clinical syndrome, termed acquired immunodeficiency syndrome (AIDS) dementia complex, presents as a subcortical dementia with cognitive, motor, and behavioral disturbances and is unique to HIV-1 infection. The pathogenesis of this syndrome is poorly understood but is believed to involve interactions among virally infected macrophages/microglia, astrocytes, and neurons. In this study, we show that exposure of primary rat and human astrocytes to heat-activated HIV-1 virions, or to eukaryotically expressed HIV-1 and HIV-2 envelope glycoproteins (gp120) stimulates amiloride-sensitive Na+/H+ antiport, potassium conductance, and glutamate efflux. These effects are blocked specifically by amiloride, an inhibitor of Na+/H+ antiport and by the selective removal of gp120 with immobilized monoclonal antibody. As a result of modulation of astrocytic function by gp120, the ensuing neuronal depolarization and glutamate exposure could activate both voltage-gated and N-methyl-D-aspartate-regulated Ca2+ channels, leading to increases in intraneuronal Ca2+ and neuronal death. These findings implicate the astrocyte directly in the pathogenesis of AIDS dementia complex.
1型人类免疫缺陷病毒（HIV-1）感染常常伴有多种神经功能异常。最常见的临床综合征，即所谓的获得性免疫缺陷综合征（AIDS）痴呆综合征，表现为一种伴有认知、运动和行为障碍的皮质下痴呆，是HIV-1感染所特有的。该综合征的发病机制尚不清楚，但据信涉及病毒感染的巨噬细胞/小胶质细胞、星形胶质细胞和神经元之间的相互作用。在本研究中，我们发现原代大鼠和人类星形胶质细胞暴露于热激活的HIV-1病毒体，或真核表达的HIV-1和HIV-2包膜糖蛋白（gp120）会刺激氨氯地平敏感的Na+/H+反向转运、钾电导和谷氨酸外流。这些效应被氨氯地平（一种Na+/H+反向转运抑制剂）以及用固定化单克隆抗体选择性去除gp120所特异性阻断。由于gp120对星形胶质细胞功能的调节，随后的神经元去极化和谷氨酸暴露可激活电压门控性和N-甲基-D-天冬氨酸调节性Ca2+通道，导致神经元内Ca2+增加和神经元死亡。这些发现表明星形胶质细胞直接参与了AIDS痴呆综合征的发病机制。
