Persidsky Y, Zheng J, Miller D, Gendelman H E
Center for Neurovirology and Neurodegenerative Disorders, the Department of Pathology, University of Nebraska Medical Center, Omaha 68198-5215, USA.
J Leukoc Biol. 2000 Sep;68(3):413-22.
The neuropathogenesis of HIV-1 infection revolves around the production of secretory factors from immune-activated brain mononuclear phagocytes (MP). MP-secreted chemokines may play several roles in HIV-1 encephalitis (HIVE). These can promote macrophage brain infiltration, blood-brain barrier (BBB) and neuronal dysfunction during HIV-1-associated dementia. We investigate how HIV-1-infected MP regulates the production of chemokines and how they influence HIV-1 neuropathogenesis. We demonstrate that HIV-1-infected and immune-activated MP (for example, microglia) and astrocytes produce beta-chemokines in abundance, as shown in both laboratory assays and within infected brain tissue. HIV-1-infected microglia significantly modulate monocyte migration in a BBB model system and in brains of SCID mice with HIVE. HIV-1-infected MP down-regulate tight junction protein and special polarized transport systems on brain microvascular endothelial cells as shown in human autopsy brain tissue and in SCID mice with HIVE. Chemokines can damage neurons directly. Toxicity caused by binding of stromal-derived factor-1alpha to its receptor on neurons exemplifies such mechanism. In toto, these works underscore the diverse roles of chemokines in HIV-1 neuropathogenesis and lay the foundation for future therapeutic interventions.
HIV-1感染的神经发病机制围绕免疫激活的脑单核吞噬细胞（MP）分泌因子的产生展开。MP分泌的趋化因子可能在HIV-1脑炎（HIVE）中发挥多种作用。在与HIV-1相关的痴呆症中，这些趋化因子可促进巨噬细胞向脑内浸润、破坏血脑屏障（BBB）并导致神经元功能障碍。我们研究了HIV-1感染的MP如何调节趋化因子的产生以及它们如何影响HIV-1神经发病机制。我们证明，在实验室检测以及感染的脑组织中均显示，HIV-1感染且免疫激活的MP（如小胶质细胞）和星形胶质细胞会大量产生β趋化因子。在BBB模型系统以及患有HIVE的SCID小鼠的大脑中，HIV-1感染的小胶质细胞可显著调节单核细胞的迁移。在人类尸检脑组织以及患有HIVE的SCID小鼠中均显示，HIV-1感染的MP会下调脑微血管内皮细胞上的紧密连接蛋白和特殊的极化转运系统。趋化因子可直接损伤神经元。基质衍生因子-1α与其在神经元上的受体结合所导致的毒性就是这种机制的例证。总的来说，这些研究强调了趋化因子在HIV-1神经发病机制中的多种作用，并为未来的治疗干预奠定了基础。
