Zheng J, Thylin M R, Persidsky Y, Williams C E, Cotter R L, Zink W, Ryan L, Ghorpade A, Lewis K, Gendelman H E
The Center for Neurovirology and Neurodegenerative Disorders, Department of Pathology and Microbiology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA.
Neurotox Res. 2001 Oct;3(5):461-84. doi: 10.1007/BF03033204.
Secretory products from HIV-1-infected immune-competent mononuclear phagocytes (MP) damage neuronal dendritic arbor (Zheng et al., 2001). The mechanism behind neuronal injury and whether it is species and/or viral strain dependent is not fully understood. To these ends, we investigated whether HIV-1-infected and lipopolysaccharide (LPS)-activated MDM elicit neuronal injury in primary human neurons. Neuronal damage was compared to that seen in rat neurons. Utilizing a spectrum of HIV-1 strains to infect human monocyte-derived macrophages (MDM), productive viral replication proved necessary, but not sufficient, for neuronal injury. Neuronal demise was induced by virion-free HIV-1-infected and immune-activated MDM culture supernatants. Maximal alterations in glutamate mediated neuronal signaling, resulted from exposure to secretory products from HIV-1-infected and immune-activated MDM. Apoptosis was the predominant mechanism of cell death induced by HIV-1-infected and LPS-treated MDM. Importantly, neuronal injury and increases in calcium influx mediated by HIV-1-infected and immune-activated MDM culture supernatants was partially blocked by the N-methyl D-aspartate (NMDA) receptor antagonist, MK 801. These data support a primary role for immune-activation in MP neurotoxic activities. The upregulation of NMDA receptor sensitive soluble factors and neuronal apoptosis by HIV-1-infected and immune-activated MDM provide unique insights into links between soluble factors, produced as a consequence of MP immunity, and neuronal demise in HAD.
来自感染HIV-1的免疫活性单核吞噬细胞(MP)的分泌产物会损害神经元树突(Zheng等人,2001年)。神经元损伤背后的机制以及它是否依赖于物种和/或病毒株尚不完全清楚。为此,我们研究了感染HIV-1和脂多糖(LPS)激活的MDM是否会在原代人神经元中引发神经元损伤。将神经元损伤与在大鼠神经元中观察到的损伤进行比较。利用一系列HIV-1毒株感染人单核细胞衍生的巨噬细胞(MDM),结果表明有活性的病毒复制对于神经元损伤是必要的,但不是充分的。无病毒颗粒的感染HIV-1和免疫激活的MDM培养上清液可诱导神经元死亡。暴露于感染HIV-1和免疫激活的MDM的分泌产物会导致谷氨酸介导的神经元信号传导发生最大变化。凋亡是由感染HIV-1和LPS处理的MDM诱导的细胞死亡的主要机制。重要的是,感染HIV-1和免疫激活MDM培养上清液介导的神经元损伤和钙内流增加被N-甲基-D-天冬氨酸(NMDA)受体拮抗剂MK 801部分阻断。这些数据支持免疫激活在MP神经毒性活动中的主要作用。感染HIV-1和免疫激活的MDM对NMDA受体敏感的可溶性因子的上调和神经元凋亡为MP免疫产生的可溶性因子与HAD中的神经元死亡之间的联系提供了独特的见解。