HIV-Related Neurotoxicity
HIV-Related Neurotoxicity
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DOI：
10.1111/j.1750-3639.1991.tb00659.x
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发表时间：
1991-04-01
期刊：
影响因子：
6.4
通讯作者：
Lipton, Stuart A.
中科院分区：
文献类型：
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作者：
Lipton, Stuart A.
AIDS的中枢神经系统表现最初被认为仅由白色物质病变组成，但最近的证据表明，也可能发生相当程度的神经元损失。这篇综述提供了HIV相关毒性因素的证据，这些因素可能至少部分地导致了这种新认识的神经元损伤。一种潜在的神经毒素是HIV-1包膜糖蛋白gp 120或该分子的片段。这种外壳蛋白由病毒脱落，并可能从HN感染的免疫细胞中释放出来。在啮齿动物神经元的组织培养实验中，gp 120产生细胞内钙浓度的早期上升，随后产生延迟发作的神经毒性。此外，HIV感染的巨噬细胞或小胶质细胞释放尚未确定的毒性因子，在体外杀死啮齿动物、鸡和人类神经元。目前尚不清楚这些巨噬细胞毒性因子之一是否可能代表gp 120片段，或者在没有HIV-1感染的情况下，gp 120是否能够激活巨噬细胞释放这些毒性因子。在至少一些神经元细胞类型中，gp 120诱导的神经毒性可以通过L型电压依赖性钙通道的拮抗剂或N-甲基-D-天冬氨酸（NMDA，谷氨酸受体的亚型）的拮抗剂来预防。内源性谷氨酸的降解也保护神经元免受gp 120相关的神经元损伤，这表明gp 120和谷氨酸作为协同效应物对于神经元细胞死亡都是必需的。作用于其他类型谷氨酸受体的拮抗剂（非NMDA拮抗剂）在提供gp 120保护方面无效。有趣的是，NMDA而非非NMDA拮抗剂也阻断巨噬细胞毒性因子的致死作用。药理学保护的相似特征可能反映了至少一种巨噬细胞毒性因子与gp 120相关的事实，如上所述。然而，分子筛和蛋白酶消化实验表明，巨噬细胞毒性因子（S）似乎不是完整的gp 120，虽然gp 120片段仍然是一种可能性。或者，巨噬细胞分泌几种不相关的神经毒性因子也是合理的。星形胶质细胞在介导HIV相关的神经毒性中也可能是重要的。例如，在某些神经元培养物中，gp 120诱导的毒性可以通过血管活性肠多肽（VIP）或具有序列同源性的五氨基酸物质肽T来预防。已发现VIP作用于星形胶质细胞，增加细胞内钙的振荡，并释放正常神经元生长和生存所需的因子。这些结果提高了gp 120可能与内源性VIP竞争受体的可能性，最有可能在星形胶质细胞上，这对神经元功能很重要。总之，来自HIV感染的人单核细胞样细胞的毒性因子可导致体外神经元损伤。目前尚不清楚这些因子是否包括gp 120片段，或者gp 120是否可能触发这些神经毒性因子的释放。基于体外研究，钙通道拮抗剂或NMDA拮抗剂可能代表保护神经元免受HIV相关损伤的有前景的药理学干预形式。在艾滋病患者的大脑中，神经元损伤可能由几个独立的途径介导，这些途径最有可能来自HIV感染的巨噬细胞释放的毒素。由于涉及生长因子，NMDA受体，和细胞内高水平的钙离子。
The central nervous system manifestations of AIDS were originally thought to consist solely of white matter lesions, but recent evidence has shown that a substantial degree of neuronal loss can also occur. This review presents evidence for HIV-related toxic factors that may account at least in part for this newly-recognized neuronal injury. One potential neurotoxin is the HIV-1 envelope glycoprotein gp120 or a fragment of this molecule. This coat protein is shed by the virus and potentially released from HN-infected immune cells. In tissue culture experiments on rodent neurons, gp120 produces an early rise in intracellular calcium concentration and, subsequently, delayed-onset neurotoxicity. In addition, HIV-infected macrophages or microglia release as yet undefined toxic factor(s) that kill rodent, chick, and human neurons in vitro. It is as yet unknown if one of these macrophage toxic factors might represent a gp120 fragment, or alternatively, if gp120, in the absence of HIV-1 infection, might be capable of activating macrophages to release these toxic factor(s). In at least some neuronal cell types, gp120-induced neurotoxicity can be prevented by antagonists of L-type voltage-dependent calcium channels or by antagonists of N-methyl-D-aspartate (NMDA, a subtype of glutamate receptor). Degradation of endogenous glutamate also protects neurons from gp120-related neuronal injury, suggesting that gp120 and glutamate are both necessary for neuronal cell death as synergistic effectors. Antagonists acting at the other types of glutamate receptors (non-NMDA antagonists) are ineffective in affording protection from gp120. Interestingly, NMDA, but not non-NMDA, antagonists also block the lethal effects of the macrophage toxic factor(s). The similar profile of pharmacological protection may possibly reflect the fact that at least one of the macrophage toxic factors is related to gp120, as suggested above. However, molecular-sieving and protease-digestion experiments suggest that the macrophage toxic factor(s) does not appear to be intact gp120, although a gp120 fragment remains a possibility. Alternatively, it is plausible that macrophages secrete several unrelated neurotoxic factors. Astrocytes may also be important in mediating HIV-related neurotoxicity. For example, in some neuronal cultures gp120-induced toxicity can be prevented by vasoactive intestinal polypeptide (VIP) or by a five amino acid substance with sequence homology, peptide T. VIP has been found to act on astrocytes to increase oscillations in intracellular calcium and to release factors necessary for normal neuronal outgrowth and survival. These results raise the possibility that gp120 may compete with endogenous VIP for a receptor, most likely on astrocytes, that is important for neuronal function. In summary, toxic factor(s) from HIV-infected human monocytoid cells may lead to neuronal damage in vitro. It is as yet unknown if these factors include a gp120 fragment or if gp120 may trigger the release of these neurotoxic factors. Based upon in vitro studies, calcium channel antagonists or NMDA antagonists may represent promising forms of pharmacological intervention to protect neurons from HIV-related injury. In the brains of AIDS patients, neuronal injury may be mediated by several separate pathways that most likely originate from toxins released by HIV-infected macrophages.Alternatively, there may be an intricate web of neurotoxic factors interacting with macrophages/microglia, astrocytes, and neurons; this complex may be amenable to pharmacotherapy because of common finalpathways of attack involving growth factors, NMDA receptors, and deleteriously high levels of intracellular calcium ions.