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The landscape of alternative splicing in HIV-1 infected CD4 T-cells

机译：HIV-1感染CD4 T细胞中替代剪接景观

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Elucidating molecular mechanisms that are altered during HIV-1 infection may provide a better understanding of the HIV-1 life cycle and how it interacts with infected T-cells. One such mechanism is alternative splicing (AS), which has been studied for HIV-1 itself, but no systematic analysis has yet been performed on infected T-cells. We hypothesized that AS patterns in infected T-cells may illuminate the molecular mechanisms underlying HIV-1 infection and identify candidate molecular markers for specifically targeting infected T-cells. We downloaded previously published raw RNA-seq data obtained from HIV-1 infected and non-infected T-cells. We estimated percent spliced in (PSI) levels for each AS exon, then identified differential AS events in the infected cells (FDR 0.1). We performed functional gene set enrichment analysis on the genes with differentially expressed AS exons to identify their functional roles. In addition, we used RT-PCR to validate differential alternative splicing events in cyclin T1 (CCNT1) as a case study. We identified 427 candidate genes with differentially expressed AS exons in infected T-cells, including 20 genes related to cell surface, 35 to kinases, and 121 to immune-related genes. In addition, protein-protein interaction analysis identified six essential subnetworks related to the viral life cycle, including Transcriptional regulation by TP53, Class I MHC mediated antigen, G2/M transition, and late phase of HIV life cycle. CCNT1 exon 7 was more frequently skipped in infected T-cells, leading to loss of the key Cyclin_N motif and affecting HIV-1 transcriptional elongation. Our findings may provide new insight into systemic host AS regulation under HIV-1 infection and may provide useful initial candidates for the discovery of new markers for specifically targeting infected T-cells.
机译：阐明在HIV-1感染期间改变的分子机制可以更好地了解HIV-1生命周期以及它如何与感染的T细胞相互作用。一种这样的机制是替代的剪接（AS），已经研究了HIV-1本身，但在感染的T细胞上没有进行系统分析。我们假设作为感染的T细胞的模式可以照亮HIV-1感染的分子机制，并确定特异性靶向感染的T细胞的候选分子标记。我们下载了先前发表的原始RNA-SEQ数据从HIV-1感染和未感染的T细胞获得。我们估计百分比（PSI）水平的百分比为外显子，然后将差异作为感染细胞中的事件（FDR 0.1）鉴定为事件。我们对差异表达为外显子的基因进行了功能基因，以鉴定其功能作用。此外，我们使用RT-PCR验证Cyclin T1（CCNT1）中的差异替代剪接事件，如案例研究。我们确定了427个候选基因，其差异表达为感染的T细胞的外显子，其中包含与细胞表面相关的20个基因，35-激酶，121-免疫相关基因。此外，蛋白质 - 蛋白质相互作用分析确定了与病毒生命周期有关的六个基本网络，包括通过TP53，I类MHC介导的抗原，G2 / M转变和HIV生命周期晚期的转录调节。 CCNT1 EXON 7更频繁地跳过受感染的T细胞，导致关键细胞周期蛋白酶损失并影响HIV-1转录伸长率。我们的调查结果可以在HIV-1感染下的调节中提供新的洞察力，并且可以为发现专门针对受感染的T细胞的新标记提供有用的初始候选者。

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