HIV gp41-induced apoptosis is mediated by caspase-3-dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir
HIV gp41-induced apoptosis is mediated by caspase-3-dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir
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DOI：
10.1189/jlb.0805430
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发表时间：
2006-02-01
影响因子：
5.5
通讯作者：
Blumenthal, Robert
中科院分区：
文献类型：
--
作者：
Garg, Himanshu;Blumenthal, Robert
CD4+ T 细胞的凋亡丧失被认为是人类免疫缺陷病毒 (HIV) 感染导致免疫缺陷的 T 细胞耗竭的机制。 Env 糖蛋白通过 gp120 与 CD4/CXC 趋化因子受体 4 结合以及 gp41 介导的融合/半融合过程参与未感染旁观者细胞的凋亡。使用表达 Env 的细胞作为效应器和 CD4+ T 细胞作为靶标的体外共培养模型，我们发现旁观者细胞中由 Env 糖蛋白介导的细胞凋亡实际上与 gp41 诱导的半融合相关。此外，这种相互作用引发的细胞凋亡途径涉及 caspase-3 依赖性线粒体去极化和活性氧的产生。 HIV gp41 诱导的线粒体去极化可被蛋白酶抑制剂奈非那韦抑制，但不能被其他 HIV 蛋白酶抑制剂或钙蛋白酶和组织蛋白酶抑制剂抑制。这种“死亡之吻”（半融合）信号通路独立于 p38 丝裂原激活蛋白激酶和 p53，使其与合胞体中看到的细胞凋亡不同。我们还表明，病毒颗粒诱导的细胞凋亡是 gp41 依赖性的。我们的研究结果为 HIV gp41 介导旁观细胞凋亡的机制提供了新的见解。
Apoptotic loss of CD4+ T cells has been proposed as a mechanism of T cell depletion in human immunodeficiency virus (HIV) infections resulting in immunodeficiency. The Env glycoprotein has been implicated in apoptosis of uninfected bystander cells via gp120 binding to CD4/CXC chemokine receptor 4 as well as the fusion/hemifusion process mediated by gp41. Using an in vitro model of coculture of Env-expressing cells as effectors and CD4+ T cells as targets, we find that apoptosis mediated by Env glycoprotein in bystander cells in fact correlates with gp41-induced hemifusion. Further, the apoptotic pathway initiated by this interaction involves caspase-3-dependent mitochondrial depolarization and reactive oxygen species production. HIV gp41-induced mitochondrial depolarization is inhibited by protease inhibitor nelfinavir but not by other HIV protease inhibitors or inhibitors of calpain and cathepsin. This "kiss of death" (hemifusion) signaling pathway is independent of p38 mitogen-activated protein kinase and p53, making it distinct from the apoptosis seen in syncytia. We also show that virion-induced apoptosis is gp41-dependent. Our findings provide new insights into the mechanism via which HIV gp41 mediates apoptosis in bystander cells.