Human immunodeficiency virus type 1 envelope-mediated neuronal death: uncoupling of viral replication and neurotoxicity.
Human immunodeficiency virus type 1 envelope-mediated neuronal death: uncoupling of viral replication and neurotoxicity.
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人类免疫缺陷病毒 1 型包膜介导的神经元死亡：病毒复制和神经毒性的解偶联。
DOI：
10.1128/jvi.77.12.6899-6912.2003
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发表时间：
2003
影响因子：
5.4
通讯作者：
Power,Christopher
中科院分区：
文献类型：
--
作者：
Zhang,Kunyan;Rana,Farazana;Silva,Claudia;Ethier,Julie;Wehrly,Kathy;Chesebro,Bruce;Power,Christopher
虽然人类免疫缺陷病毒(HIV)和/或艾滋病患者的脑组织一直被HIV-1(HIV-1)感染，但只有20%到30%的患者表现出脑损伤的临床或神经病理学证据。大脑中存在着广泛的HIV-1序列多样性，这可能在一定程度上解释了艾滋病毒引起的脑部疾病发生的多样性。HIV-1引起的神经损伤直接由神经毒性病毒蛋白介导，或通过感染或激活的神经胶质细胞过度产生宿主分子间接介导。为了阐明HIV-1感染与神经元死亡的关系，我们检测了表达重组HIV-1病毒粒子或含有来自非B分支脑源性HIV-1序列的V1V3或C2V3包膜区的gp120蛋白的人293T细胞或巨噬细胞的培养上清的神经毒性作用。神经毒性分别以凋亡或全部神经元死亡来衡量，根据个别病毒的不同，凋亡占观察到的总神经元死亡的30%至80%。此外，神经毒性依赖于HIV-1gp120的表达，并可被抗gp120抗体以及人类CCR5和CXCR4趋化因子受体抗体所阻断。尽管重组包膜区(V1V3或C2V3)具有广泛的序列多样性，但293T细胞的培养上清液诱导的神经毒性变异有限。相反，受感染巨噬细胞的上清会引起更广泛的神经毒性水平，这取决于每种病毒，与病毒的复制能力无关。这些发现强调了HIV-1包膜蛋白在与HIV引起的脑部疾病相关的神经毒性途径中表达的重要性，并强调了包膜作为神经保护性治疗干预的靶点。
Although brain tissue from patients with human immunodeficiency virus (HIV) and/or AIDS is consistently infected by HIV type 1 (HIV-1), only 20 to 30% of patients exhibit clinical or neuropathological evidence of brain injury. Extensive HIV-1 sequence diversity is present in the brain, which may account in part for the variability in the occurrence of HIV-induced brain disease. Neurological injury caused by HIV-1 is mediated directly by neurotoxic viral proteins or indirectly through excess production of host molecules by infected or activated glial cells. To elucidate the relationship between HIV-1 infection and neuronal death, we examined the neurotoxic effects of supernatants from human 293T cells or macrophages expressing recombinant HIV-1 virions or gp120 proteins containing the V1V3 or C2V3 envelope region from non-clade B, brain-derived HIV-1 sequences. Neurotoxicity was measured separately as apoptosis or total neuronal death, with apoptosis representing 30 to 80% of the total neuron death observed, depending on the individual virus. In addition, neurotoxicity was dependent on expression of HIV-1 gp120 and could be blocked by anti-gp120 antibodies, as well as by antibodies to the human CCR5 and CXCR4 chemokine receptors. Despite extensive sequence diversity in the recombinant envelope region (V1V3 or C2V3), there was limited variation in the neurotoxicity induced by supernatants from transfected 293T cells. Conversely, supernatants from infected macrophages caused a broader range of neurotoxicity levels that depended on each virus and was independent of the replicative ability of the virus. These findings underscore the importance of HIV-1 envelope protein expression in neurotoxic pathways associated with HIV-induced brain disease and highlight the envelope as a target for neuroprotective therapeutic interventions.