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

作者: Wei Chen , Jerrold Sulcove , Ian Frank , Salman Jaffer , Hakan Ozdener

DOI: 10.1128/JVI.76.18.9407-9419.2002

关键词:

摘要: Neuronal apoptosis within the central nervous system (CNS) is a characteristic feature of AIDS dementia, and it represents common mechanism neuronal death induced by neurotoxins (e.g., glutamate) released from human immunodeficiency virus (HIV)-infected macrophages (HIV/macrophage-induced neurotoxicity). may result activation intrinsic (mitochondrial/bcl-2 regulated) or extrinsic (death receptor) pathways, although which pathway predominates in CNS HIV infection unknown. Apoptosis initiated typically blocked antiapoptosis Bcl-2 family proteins, such as Bcl-xL, but whether these can block HIV/macrophage-induced To determine potential role apoptosis, we developed unique vitro model, utilizing NT2 cell line, primary astrocytes macrophages, type 1 (HIV-1) isolates. We validated our model demonstrating that NT2.N neurons are protected against HIV-infected N-methyl-d-aspartate (NMDA) glutamate receptor antagonists, similar to effects seen neurons. then established stable lines overexpress Bcl-xL (NT2.N/bcl-2 NT2.N/bcl-xL, respectively) determined their sensitivity infected with R5, X4, R5/X4 HIV-1 found NT2.N/bcl-2 NT2.N/bcl-xL were resistant either isolates resistance was abrogated antagonist. Thus, NMDA receptor/bcl-2-regulated apoptotic contributes significantly proteins protect spectrum Modulation bcl-2 gene expression therefore offer adjunctive neuroprotection development dementia.

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