Catani M V, Corasaniti M T, Navarra M, Nisticò G, Finazzi-Agrò A, Melino G
Biochemistry Laboratory, IDI-IRCCS, c/o Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.
J Neurochem. 2000 Jun;74(6):2373-9. doi: 10.1046/j.1471-4159.2000.0742373.x.
To infect target cells, the human immunodeficiency virus (HIV) type I (HIV-1) must engage not only the well-known CD4 molecule, but it also requires one of several recently described coreceptors. In particular, the CXCR4 (LESTR/fusin) receptor allows fusion and entry of T-tropic strains of HIV, whereas CCR5 is the major coreceptor used by primary HIV-1 strains that infect macrophages and CD4(+) T-helper cells (M-tropic viruses). In addition, the alpha chemokine SDF1alpha and the beta chemokines MIP1alpha, MIP1beta, and RANTES, natural ligands of CXCR4 and CCR5, respectively, are potent soluble inhibitors of HIV infection by blocking the binding between the viral envelope glycoprotein gp120 and the coreceptors. Approximately two-thirds of individuals with acquired immunodeficiency syndrome (AIDS) show neurologic complications, which are referred to a syndrome called AIDS dementia complex or HIV-1-associated cognitive/motor complex. The HIV-1 coat glycoprotein gp120 has been proposed as the major etiologic agent for neuronal damage, mediating both direct and indirect effects on the CNS. Furthermore, recent findings showing the presence of chemokine receptors on the surface of different cell types resident in the CNS raise the possibility that the association of gp120 with these receptors may contribute to the pathogenesis of neurological dysfunction. Here, we address the possible role of alpha and beta chemokines in inhibiting gp120-mediated neurotoxicity using the human neuroblastoma CHP100 cell line as an experimental model. We have previously shown that, in CHP100 cells, picomolar concentrations of gp120 produce a significant increase in cell death, which seems to proceed through a Ca(2+) - and NMDA receptor-dependent cascade. In this study, we gained insight into the mechanism(s) of neurotoxicity elicited by the viral glycoprotein. We found that CHP100 cells constitutively express both CXCR4 and CCR5 receptors and that stimulation with phorbol 12-myristate 13-acetate down-regulates their expression, thus preventing gp120-induced cell death. Furthermore, all the natural ligands of these receptors exerted protective effects against gp120-mediated neuronal damage, although with different efficiencies. These findings, together with our previous reports, suggest that the neuronal injury observed in HIV-1 infection could be due to direct (or indirect) interactions between the viral protein gp120 and chemokine and/or NMDA receptors.
为了感染靶细胞，I型人类免疫缺陷病毒（HIV-1）不仅必须与众所周知的CD4分子结合，还需要几种最近描述的共受体之一。特别是，CXCR4（LESTR/融合素）受体允许T嗜性HIV毒株融合并进入细胞，而CCR5是感染巨噬细胞和CD4(+) T辅助细胞的原发性HIV-1毒株（M嗜性病毒）使用的主要共受体。此外，α趋化因子SDF1α和β趋化因子MIP1α、MIP1β和RANTES分别是CXCR4和CCR5的天然配体，通过阻断病毒包膜糖蛋白gp120与共受体之间的结合，是HIV感染的有效可溶性抑制剂。大约三分之二的获得性免疫缺陷综合征（AIDS）患者出现神经并发症，这些并发症被称为AIDS痴呆综合征或HIV-1相关认知/运动综合征。HIV-1包膜糖蛋白gp120被认为是神经元损伤的主要病因，对中枢神经系统产生直接和间接影响。此外，最近的研究发现显示中枢神经系统中不同类型驻留细胞表面存在趋化因子受体，这增加了gp120与这些受体的结合可能导致神经功能障碍发病机制的可能性。在这里，我们以人类神经母细胞瘤CHP100细胞系作为实验模型，探讨α和β趋化因子在抑制gp120介导的神经毒性中的可能作用。我们之前已经表明，在CHP100细胞中，皮摩尔浓度的gp120会导致细胞死亡显著增加，这似乎是通过钙（Ca(2+)）和N-甲基-D-天冬氨酸（NMDA）受体依赖性级联反应进行的。在这项研究中，我们深入了解了病毒糖蛋白引发神经毒性的机制。我们发现CHP100细胞组成性表达CXCR4和CCR5受体，用佛波酯12-肉豆蔻酸酯13-乙酸酯刺激会下调它们的表达，从而防止gp120诱导的细胞死亡。此外，这些受体的所有天然配体都对gp120介导的神经元损伤发挥了保护作用，尽管效率不同。这些发现，连同我们之前的报告，表明在HIV-1感染中观察到的神经元损伤可能是由于病毒蛋白gp120与趋化因子和/或NMDA受体之间的直接（或间接）相互作用。
