Persidsky Y, Buttini M, Limoges J, Bock P, Gendelman H E
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198-5215, USA.
J Neurovirol. 1997 Dec;3(6):401-16. doi: 10.3109/13550289709031186.
The human immunodeficiency virus type 1 (HIV)-associated dementia complex (ADC) is a neuroimmunological disorder fueled by viral replication in mononuclear phagocytes (MP) (brain macrophages and microglia). The elucidation of MP inflammatory factors involved in neurological dysfunction is pivotal for unraveling pathogenic mechanisms and in developing new therapies for this disease. Recent advances in animal model systems for ADC and its associated encephalitis have provided important insights into how virus-infected macrophages cause brain injury. Indeed, the stereotactic inoculation of HIV infected monocytes into the basal ganglia/cortex of mice with severe combined immunodeficiency disease (SCID) results in pathological features similar to those of human HIV-1 encephalitis (HIVE). We used this SCID model to study the roles of macrophage secretory factors in HIVE. The expression of interleukin-1 (IL-1 beta, IL-6, IL-10), tumor necrosis factors-alpha (TNF alpha), vascular endothelial growth factor (VEGF), and adhesion molecules (E-selectin, intracellular cell adhesion molecule (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1)) in encephalitic brains of mice and humans was evaluated by semi-quantitative polymerase chain reaction (PCR). In SCID mice with HIVE, human and mouse TNF alpha, and mouse IL-6, VEGF, VCAM-1 and E-selectin were expressed at high levels. These results paralleled, to a great extent, those in HIVE brain tissues. Laser scanning confocal microscopy performed to assess the associated neuronal damage showed that microtubule associated protein-2 (MAP-2) immunoreactive dendrites were significantly reduced in both the ipsilateral and contralateral hemispheres of encephalitic mice. These results demonstrate the importance of macrophage inflammatory products in the pathogenesis of HIVE and further validates this model of viral encephalitis in SCID mice.
1型人类免疫缺陷病毒（HIV）相关痴呆综合征（ADC）是一种神经免疫性疾病，由单核吞噬细胞（MP，即脑巨噬细胞和小胶质细胞）中的病毒复制引发。阐明参与神经功能障碍的MP炎症因子对于揭示致病机制和开发该疾病的新疗法至关重要。ADC及其相关脑炎动物模型系统的最新进展为病毒感染的巨噬细胞如何导致脑损伤提供了重要见解。事实上，将感染HIV的单核细胞立体定向接种到严重联合免疫缺陷病（SCID）小鼠的基底神经节/皮质中，会导致与人类HIV-1脑炎（HIVE）相似的病理特征。我们使用这个SCID模型来研究巨噬细胞分泌因子在HIVE中的作用。通过半定量聚合酶链反应（PCR）评估小鼠和人类脑炎脑中白细胞介素-1（IL-1β、IL-6、IL-10）、肿瘤坏死因子-α（TNFα）、血管内皮生长因子（VEGF）和黏附分子（E-选择素、细胞间黏附分子（ICAM-1）和血管细胞黏附分子-1（VCAM-1））的表达。在患有HIVE的SCID小鼠中，人类和小鼠的TNFα以及小鼠的IL-6、VEGF、VCAM-1和E-选择素均高表达。这些结果在很大程度上与HIVE脑组织中的结果相似。为评估相关神经元损伤而进行的激光扫描共聚焦显微镜检查显示，脑炎小鼠同侧和对侧半球中微管相关蛋白-2（MAP-2）免疫反应性树突均显著减少。这些结果证明了巨噬细胞炎症产物在HIVE发病机制中的重要性，并进一步验证了SCID小鼠中的这种病毒性脑炎模型。
