Differential role of autophagy in CD4 T cells and macrophages during X4 and R5 HIV-1 infection.
Differential role of autophagy in CD4 T cells and macrophages during X4 and R5 HIV-1 infection.
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DOI：
10.1371/journal.pone.0005787
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发表时间：
2009-06-03
期刊：
影响因子：
3.7
通讯作者：
Biard-Piechaczyk M
中科院分区：
文献类型：
--
作者：
Espert L;Varbanov M;Robert-Hebmann V;Sagnier S;Robbins I;Sanchez F;Lafont V;Biard-Piechaczyk M
HIV-1可以在CD 4 T细胞和巨噬细胞中感染和复制。在这些细胞类型中，HIV-1进入是通过包膜糖蛋白（gp 120和gp 41，Env）与受体CD 4和辅助受体（主要是CCR 5或CXCR 4，取决于病毒株（分别为R5或X4））的结合介导的。未感染的CD 4 T细胞经历X4 Env介导的自噬，导致其凋亡，这是一种现在被认为是免疫缺陷的核心机制。我们在这里证明，自噬和细胞死亡也诱导在未感染的CD 4 T细胞的HIV-1 R5 Env，而自噬被抑制在生产性X4或R5感染的CD 4 T细胞。相比之下，未感染的巨噬细胞，在HIV-1感染期间保存的细胞群体，不经历X4或R5 Env介导的自噬。然而，自噬体存在于暴露于感染性HIV-1颗粒的巨噬细胞中，与辅助受体的使用无关。有趣的是，我们观察到两个群体的自噬细胞：一个高度自噬和其他弱自噬。令人惊讶的是，在弱自噬细胞中可以检测到病毒，但在高自噬细胞中却没有。此外，我们表明，巨噬细胞中自噬的触发是病毒复制所必需的，但加入巴弗洛霉素A1，它阻断了自噬的最后阶段，大大增加了生产性感染。总之，我们的数据表明，自噬通过调节病毒复制和靶细胞的命运在HIV病理学中起着复杂但重要的作用。
HIV-1 can infect and replicate in both CD4 T cells and macrophages. In these cell types, HIV-1 entry is mediated by the binding of envelope glycoproteins (gp120 and gp41, Env) to the receptor CD4 and a coreceptor, principally CCR5 or CXCR4, depending on the viral strain (R5 or X4, respectively). Uninfected CD4 T cells undergo X4 Env-mediated autophagy, leading to their apoptosis, a mechanism now recognized as central to immunodeficiency. We demonstrate here that autophagy and cell death are also induced in the uninfected CD4 T cells by HIV-1 R5 Env, while autophagy is inhibited in productively X4 or R5-infected CD4 T cells. In contrast, uninfected macrophages, a preserved cell population during HIV-1 infection, do not undergo X4 or R5 Env-mediated autophagy. Autophagosomes, however, are present in macrophages exposed to infectious HIV-1 particles, independently of coreceptor use. Interestingly, we observed two populations of autophagic cells: one highly autophagic and the other weakly autophagic. Surprisingly, viruses could be detected in the weakly autophagic cells but not in the highly autophagic cells. In addition, we show that the triggering of autophagy in macrophages is necessary for viral replication but addition of Bafilomycin A1, which blocks the final stages of autophagy, strongly increases productive infection. Taken together, our data suggest that autophagy plays a complex, but essential, role in HIV pathology by regulating both viral replication and the fate of the target cells.
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