Tat-induced FOXO3a is a key mediator of apoptosis in HIV-1-infected human CD4+ T lymphocytes.
Tat-induced FOXO3a is a key mediator of apoptosis in HIV-1-infected human CD4+ T lymphocytes.
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DOI：
10.4049/jimmunol.181.12.8460
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发表时间：
2008-12-15
期刊：
影响因子：
--
通讯作者：
Aldovini A
中科院分区：
文献类型：
--
作者：
Dabrowska A;Kim N;Aldovini A
HIV的高突变率与表达功能改变的蛋白质的病毒的产生有关，其对疾病进展的影响尚不清楚。我们研究了缺乏Env、Vpr和Nef的HIV-1病毒如何影响CD4+ T细胞的存活。我们发现，在缺乏这些蛋白的情况下，HIV-1感染的CD4+原代T细胞进展到细胞周期的G0期和细胞死亡，这表明表达这些蛋白失活形式的病毒可以像野生型病毒一样导致CD4+ T细胞衰退，这表明其他HIV蛋白负责诱导细胞凋亡。这些细胞的凋亡是由Egr1-PTEN-Akt（10号染色体上缺失的早期生长反应-1/磷酸和紧张素同源物）和p53通路的改变引发的，这些通路汇聚在FOXO3a（叉头盒转录因子O类3a）转录激活子上。参与外源性凋亡通路的FOXO3a靶基因Fas配体和TRAIL，以及参与内源性凋亡通路的PUMA、Noxa和Bim也上调，表明HIV感染通过参与多种凋亡通路导致细胞凋亡。rnai介导的Egr1和FOXO3a敲低导致hiv感染的HeLa和CD4+ T细胞凋亡减少，进一步证明了它们在hiv诱导的细胞凋亡和G0阻滞中的关键作用。我们测试了Tat对这些突变病毒观察到的T细胞凋亡负责的可能性。在单独由Tat转导的Jurkat细胞中观察到Egr1和FOXO3a及其靶基因的诱导作用。Egr1-PTEN-FOXO3a通路的tat依赖性激活为hiv -1相关CD4+ T细胞死亡提供了一种机制。
The high mutation rate of HIV is linked to the generation of viruses expressing proteins with altered function whose impact on disease progression is unknown. We investigated how HIV-1 viruses lacking Env, Vpr, and Nef affect CD4+ T cell survival. We found that in the absence of these proteins, HIV-1-infected CD4+ primary T cells progress to the G0 phase of the cell cycle and to cell death, indicating that viruses expressing inactive forms of these proteins can contribute to the CD4+ T cell decline as the wild-type virus, suggesting that other HIV proteins are responsible for inducing apoptosis. Apoptosis in these cells is triggered by the alteration of the Egr1-PTEN-Akt (early growth response-1/phosphate and tensin homolog deleted on chromosome 10/Akt) and p53 pathways, which converge on the FOXO3a (Forkhead box transcription factor O class 3a) transcriptional activator. The FOXO3a target genes Fas ligand and TRAIL, involved in the extrinsic apoptotic pathway, and PUMA, Noxa, and Bim, which are part of the intrinsic apoptotic pathway, were also up-regulated, indicating that HIV infection leads to apoptosis by the engagement of multiple apoptotic pathways. RNAi-mediated knockdown of Egr1 and FOXO3a resulted in reduced apoptosis in HIV-infected HeLa and CD4+ T cells, providing further evidence for their critical role in HIV-induced apoptosis and G0 arrest. We tested the possibility that Tat is responsible for the T cell apoptosis observed with these mutant viruses. The induction of Egr1 and FOXO3a and its target genes was observed in Jurkat cells transduced by Tat alone. Tat-dependent activation of the Egr1-PTEN-FOXO3a pathway provides a mechanism for HIV-1-associated CD4+ T cell death.
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