Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4
Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4
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DOI：
10.1172/jci26185
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发表时间：
2006-08-01
影响因子：
15.9
通讯作者：
Biard-Piechaczyk, Martine
中科院分区：
文献类型：
--
作者：
Espert, Lucile;Denizot, Melanie;Biard-Piechaczyk, Martine
HIV-1包膜糖蛋白（Env）表达于细胞表面，诱导未感染的CD 4（+）T细胞凋亡，促进AIDS的发展。在这里，我们证明，独立于HIV复制，转染或HIV感染的细胞，表达Env诱导自噬和积累的Beclin 1在未感染的CD 4（+）T淋巴细胞通过CXCR 4。同样的现象发生在T细胞系和转染的HEK.293细胞中，这些细胞表达野生型CXCR 4和不能结合淋巴细胞特异性蛋白激酶Lck的截短形式的CD 4。Env介导的自噬是触发CD 4（+）T细胞凋亡所必需的，因为通过药物（3-甲基腺嘌呤和巴弗洛霉素A1）或Beclin 1/Atg 6和Atg 7基因特异性siRNA在不同步骤阻断自噬完全抑制了凋亡过程。此外，当凋亡被抑制时，CD 4（+）T细胞仍然经历Env介导的具有自噬特征的细胞死亡。这些结果表明，HIV感染的细胞可以通过Env与CXCR 4的接触诱导旁观者CD 4（+）T淋巴细胞的自噬，导致细胞凋亡，这是一种最有可能导致免疫缺陷的机制。
HIV-1 envelope glycoproteins (Env), expressed at the cell surface, induce apoptosis of uninfected CD4(+) T cells, contributing to the development of AIDS. Here we demonstrate that, independently of HIV replication, transfected or HIV-infected cells that express Env induced autophagy and accumulation of Beclin 1 in uninfected CD4(+) T lymphocytes via CXCR4. The same phenomena occurred in a T cell line and in transfected HEK.293 cells that expressed both wild-type CXCR4 and a truncated form of CD4 that is unable to bind the lymphocyte-specific protein kinase Lck. Env-mediated autophagy is required to trigger CD4(+) T cell apoptosis since blockade of autophagy at different steps, by either drugs (3-methyladenine and bafilomycin A1) or siRNAs specific for Beclin 1/Atg6 and Atg7 genes, totally inhibited the apoptotic process. Furthermore, CD4(+) T cells still underwent Env-mediated cell death with autophagic features when apoptosis was inhibited. These results suggest that HIV-infected cells can induce autophagy in bystander CD4(+) T lymphocytes through contact of Env with CXCR4, leading to apoptotic cell death, a mechanism most likely contributing to immunodeficiency.