HIV‐1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors
HIV‐1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors
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DOI：
10.1002/1531-8249(20010201)49:2
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发表时间：
2001-02
影响因子：
11.2
通讯作者：
J. Johnston;Kunyan Zhang;Cláudia Silva;D. Shalinsky;K. Conant;W. Ni;D. Corbett;V. Yong;C. Power
中科院分区：
文献类型：
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作者：
J. Johnston;Kunyan Zhang;Cláudia Silva;D. Shalinsky;K. Conant;W. Ni;D. Corbett;V. Yong;C. Power
HIV感染的脑巨噬细胞释放潜在的神经毒性分子，伴随着神经元的损伤和死亡，导致HIV相关性痴呆(HAD)的发生。在与HAD的发生有关的潜在神经毒素中，有一种是HIV-1反式激活蛋白TAT。为了探讨TAT导致神经毒性的机制，将非痴呆(TAT-ND)和痴呆(TAT-HAD)艾滋病患者的脑源性TAT序列在U937单核母细胞和原代人巨噬细胞中表达，这些序列主要在TAT的增强区存在差异。表达TAT-HAD蛋白的细胞表现为基质金属蛋白酶-2和-7的释放和活化增加，而表达TAT-ND的细胞没有表现出增强的基质金属蛋白酶表达。TAT-ND转染组的神经元死亡率(15.4±4.3%)显著高于未转染组(2.1±0.8%)和TAT-ND组(4.4±2.1%)。TAT-HAD的神经毒性可被抗MMP2或MMP7抗体抑制(p<；0.005)，但不能被抗MMP9或TAT抗体所抑制。类似地，接受TAT转基因细胞纹状植入的SCID/NOD小鼠表现出比接受TAT-ND或未转基因细胞的动物更严重的神经行为异常和神经元丢失(p<；0.005)，后者通过使用基质金属蛋白酶抑制剂PRIMOMASAT治疗而减少(p<；0.005)。这些发现表明，TAT通过一种间接机制导致神经元死亡，这种机制是TAT序列依赖的，涉及MMPs的诱导。Ann Neurol 2001；49：230-241
The release of potentially neurotoxic molecules by HIV‐infected brain macrophages is accompanied by neuronal injury and death that results in the development of HIV‐associated dementia (HAD). Among the potential neurotoxins implicated in the development of HAD is the HIV‐1 transactivating protein, Tat. To investigate the mechanism by which Tat causes neurotoxicity, brain‐derived Tat sequences from nondemented (Tat‐ND) and demented (Tat‐HAD) AIDS patients, which differed primarily in the augmenting region of Tat, were expressed in U937 monoblastoid cells and primary human macrophages. Cells expressing Tat‐HAD protein exhibited elevated matrix metalloproteinase (MMP)‐2 and ‐7 release and activation, but cells expressing Tat‐ND did not exhibit enhanced MMP expression. Conditioned media from Tat‐HAD–transfected cells caused significantly greater neuronal death (15.4 ± 4.3%) than did Tat‐ND (4.4 ± 2.1%) or nontransfected (2.1 ± 0.8%) cell‐derived conditioned media. The neurotoxicity induced by Tat‐HAD was inhibited by anti–MMP‐2 or ‐7 antibodies (p < 0.005) but not by antibodies against MMP‐9 or Tat. Similarly, scid/nod mice receiving striatal implants of Tat‐HAD–transfected cells exhibited greater neurobehavioral abnormalities and neuronal loss (p < 0.005) than did animals receiving Tat‐ND or nontransfected cells, which were reduced by treatment with the MMP inhibitor prinomastat (p < 0.005). These findings indicate that Tat causes neuronal death through an indirect mechanism that is Tat sequence dependent and involves the induction of MMPs. Ann Neurol 2001;49:230–241