PLATELET-ACTIVATING-FACTOR - A CANDIDATE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE 1-INDUCED NEUROTOXIN
PLATELET-ACTIVATING-FACTOR - A CANDIDATE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE 1-INDUCED NEUROTOXIN
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DOI：
10.1128/jvi.68.7.4628-4635.1994
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发表时间：
1994-07-01
影响因子：
5.4
通讯作者：
GENDELMAN, HE
中科院分区：
文献类型：
--
作者：
GELBARD, HA;NOTTET, HSLM;GENDELMAN, HE
人类免疫缺陷病毒 1 型 (HIV-1) 感染期间中枢神经系统疾病的发病机制与脑巨噬细胞和小胶质细胞的生产性病毒感染有关。皮质和皮质下灰质的神经元损失伴随着巨噬细胞感染。脑巨噬细胞的病毒感染最终如何导致中枢神经系统（CNS）病理的问题仍然没有答案。我们之前的工作证明，HIV 感染的单核细胞和星形胶质细胞可高水平产生肿瘤坏死因子 α、白细胞介素 1 β、花生四烯酸代谢物和血小板激活因子 (PAF)（H. E. Gendelman、P. Genis、M. Jett 和 H. S. L. M. Nottet，E. Major 编辑，神经系统艾滋病研究技术进展，出版中； P. Genis、M. Jett、E. W. Bernton、H. A. Gelbard、K. Dzenko、R. Keane、L. Resnick、D. J. Volsky、L. G. Epstein 和 H. E. Gendelmal、J. Exp。医学。 176：1703-1718，1992）。这些因素加在一起具有神经毒性。这些初始实验并未阐明每种候选神经毒素在 HIV-1 相关中枢神经系统功能障碍中的相对作用。我们现在报道 PAF 是在 HIV-1 感染的单核细胞与星形胶质细胞相互作用过程中产生的。在免疫抑制和中枢神经系统功能障碍的 HIV-1 感染患者的脑脊液中检测到高水平的 PAF。通过将 PAF 添加到原代人胎儿皮质或大鼠出生后视网膜神经节神经元的培养物中，确定了神经系统疾病结果的生物学意义。此处，浓度大于或等于 300 pg/ml 的 PAF 会导致神经元死亡。 N-甲基-D-天冬氨酸受体拮抗剂 MK-801 或美金刚可部分阻断 PAF 的神经毒性作用。 PAF 被鉴定为 HIV-1 诱导的神经毒素，为了解 HIV-1 如何导致神经损伤以及最终如何改善神经损伤提供了新的见解。
The pathogenesis of central nervous system disease during human immunodeficiency virus type 1 (HIV-1) infection revolves around productive viral infection of brain macrophages and microglia. Neuronal losses in the cortex and subcortical gray matter accompany macrophage infection. The question of how viral infection of brain macrophages ultimately leads to central nervous system (CNS) pathology remains unanswered. Our previous work demonstrated high-level production of tumor necrosis factor alpha, interleukin 1 beta, arachidonic acid metabolites, and platelet-activating factor (PAF) from HIV-infected monocytes and astroglia (H. E. Gendelman, P. Genis, M. Jett, and H. S. L. M. Nottet, in E. Major, ed., Technical Advances in AIDS Research in the Nervous System, in press; P. Genis, M. Jett, E. W. Bernton, H. A. Gelbard, K. Dzenko, R. Keane, L. Resnick, D. J. Volsky, L. G. Epstein, and H. E. Gendelmal, J. Exp. Med. 176:1703-1718, 1992). These factors, together, were neurotoxic. The relative role(s) of each of these candidate neurotoxins in HIV-1-related CNS dysfunction was not unraveled by these initial experiments. We now report that PAF is produced during HIV-1-infected monocyte-astroglia interactions. PAF was detected at high levels in CSF of HIV-1-infected patients with immunosuppression and signs of CNS dysfunction. The biologic significance of the results for neurological disease was determined by addition of PAF to cultures of primary human fetal cortical or rat postnatal retinal ganglion neurons. Here, PAF at concentrations of greater than or equal to 300 pg/ml produced neuronal death. The N-methyl-D-aspartate receptor antagonist MK-801 or memantine partially blocked the neurotoxic effects of PAF. The identification of PAF as an HIV-1-induced neurotoxin provides ne,v insights into how HIV-1 causes neurological impairment and how it may ultimately be ameliorated.