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首页> 外文OA文献 >Development of a Human Neuronal Cell Model for Human Immunodeficiency Virus (HIV)-Infected Macrophage-Induced Neurotoxicity: Apoptosis Induced by HIV Type 1 Primary Isolates and Evidence for Involvement of the Bcl-2/Bcl-xL-Sensitive Intrinsic Apoptosis Pathway
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Development of a Human Neuronal Cell Model for Human Immunodeficiency Virus (HIV)-Infected Macrophage-Induced Neurotoxicity: Apoptosis Induced by HIV Type 1 Primary Isolates and Evidence for Involvement of the Bcl-2/Bcl-xL-Sensitive Intrinsic Apoptosis Pathway

机译：人类免疫缺陷病毒（HIV）感染的巨噬细胞诱导的神经毒性的人类神经元细胞模型的发展：由HIV 1型主要分离株诱导的细胞凋亡和参与Bcl-2 / Bcl-xL敏感内在凋亡途径的证据。

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Neuronal apoptosis within the central nervous system (CNS) is a characteristic feature of AIDS dementia, and it represents a common mechanism of neuronal death induced by neurotoxins (e.g., glutamate) released from human immunodeficiency virus (HIV)-infected macrophages (HIV/macrophage-induced neurotoxicity). Neuronal apoptosis may result from activation of the intrinsic (mitochondrial/bcl-2 regulated) or extrinsic (death receptor) pathways, although which pathway predominates in CNS HIV infection is unknown. Apoptosis initiated by the intrinsic pathway is typically blocked by antiapoptosis Bcl-2 family proteins, such as Bcl-2 and Bcl-xL, but whether these can block HIV/macrophage-induced neuronal apoptosis is unknown. To determine the potential role of the Bcl-2 family in HIV/macrophage-induced neuronal apoptosis, we developed a unique in vitro model, utilizing the NT2 neuronal cell line, primary astrocytes and macrophages, and primary CNS HIV type 1 (HIV-1) isolates. We validated our model by demonstrating that NT2.N neurons are protected against HIV-infected macrophages by N-methyl-d-aspartate (NMDA) glutamate receptor antagonists, similar to effects seen in primary neurons. We then established stable NT2.N neuronal lines that overexpress Bcl-2 or Bcl-xL (NT2.N/bcl-2 and NT2.N/bcl-xL, respectively) and determined their sensitivity to macrophages infected with primary R5, X4, and R5/X4 HIV-1 isolates. We found that NT2.N/bcl-2 and NT2.N/bcl-xL neurons were resistant to apoptosis induced by either R5, X4, or R5/X4 isolates and that resistance was abrogated by a Bcl-2 antagonist. Thus, the NMDA receptor/bcl-2-regulated apoptotic pathway contributes significantly to HIV/macrophage-induced neuronal apoptosis, and Bcl-2 family proteins protect neurons against the spectrum of primary HIV-1 isolates. Modulation of bcl-2 gene expression may therefore offer adjunctive neuroprotection against development of AIDS dementia.
机译：中枢神经系统（CNS）中的神经元凋亡是AIDS痴呆的特征，它代表由感染人类免疫缺陷病毒（HIV）的巨噬细胞（HIV /巨噬细胞）释放的神经毒素（例如谷氨酸）诱导的神经元死亡的常见机制。 -诱导的神经毒性）。神经元凋亡可能是由内源性（线粒体/ bcl-2调控）或外源性（死亡受体）途径的激活引起的，尽管尚不清楚CNS HIV感染中该途径占主导地位。由内在途径引发的细胞凋亡通常被抗细胞凋亡的Bcl-2家族蛋白（例如Bcl-2和Bcl-xL）阻断，但是这些蛋白是否可以阻断HIV /巨噬细胞诱导的神经元凋亡尚不清楚。为了确定Bcl-2家族在HIV /巨噬细胞诱导的神经元凋亡中的潜在作用，我们开发了一个独特的体外模型，利用NT2神经元细胞系，原代星形胶质细胞和巨噬细胞以及原发性CNS HIV 1型（HIV-1 ）分离物。我们通过证明NT2.N神经元受到N-甲基-d-天冬氨酸（NMDA）谷氨酸受体拮抗剂的保护，免受HIV感染的巨噬细胞的影响，从而验证了我们的模型。然后，我们建立了过表达Bcl-2或Bcl-xL（分别为NT2.N / bcl-2和NT2.N / bcl-xL）的稳定NT2.N神经元系，并确定了它们对感染原发性R5，X4，和R5 / X4 HIV-1分离株。我们发现NT2.N / bcl-2和NT2.N / bcl-xL神经元对R5，X4或R5 / X4分离株诱导的凋亡具有抗性，而Bcl-2拮抗剂则消除了这种抗性。因此，NMDA受体/ bcl-2调节的凋亡途径大大促进了HIV /巨噬细胞诱导的神经元凋亡，而Bcl-2家族蛋白保护神经元免受主要HIV-1分离株的侵害。因此，bcl-2基因表达的调节可能会提供辅助性的神经保护作用，以抵抗AIDS痴呆症的发展。

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