DYRK1A Controls HIV-1 Replication at a Transcriptional Level in an NFAT Dependent Manner

BackgroundTranscription of the HIV-1 provirus is regulated by both viral and host proteins and is very important in the context of viral latency. In latently infected cells, viral gene expression is inhibited as a result of the sequestration of host transcription factors and epigenetic modifications.ResultsIn our present study we analyzed the effect of host factor dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) on HIV-1 replication. We show that DYRK1A controls HIV-1 replication by regulating provirus transcription. Downregulation or inhibition of DYRK1A increased LTR-driven transcription and viral replication in cell lines and primary PBMC. Furthermore, inhibition of DYRK1A resulted in reactivation of latent HIV-1 provirus to a similar extent as two commonly used broad-spectrum HDAC inhibitors. We observed that DYRK1A regulates HIV-1 transcription via the Nuclear Factor of Activated T-cells (NFAT) by promoting its translocation from the nucleus to the cytoplasm. Therefore, inhibition of DYRK1A results in increased nuclear levels of NFAT and increased NFAT binding to the viral LTR and thus increasing viral transcription.ConclusionsOur data indicate that host factor DYRK1A plays a role in the regulation of viral transcription and latency. Therefore, DYRK1A might be an attractive candidate for therapeutic strategies targeting the viral reservoir.背景：人类免疫缺陷病毒1型（HIV-1）前病毒的转录受病毒蛋白与宿主蛋白共同调控，在病毒潜伏状态下具有关键意义。在潜伏感染的细胞中，由于宿主转录因子被隔离以及表观遗传修饰的作用，病毒基因的表达会受到抑制。 结果：本研究分析了宿主因子双特异性酪氨酸磷酸化调节激酶1A（dual specificity tyrosine-phosphorylation-regulated kinase 1A，DYRK1A）对HIV-1复制的影响。研究证实，DYRK1A通过调控前病毒转录来控制HIV-1的复制。下调或抑制DYRK1A的表达，可增强细胞系与原代外周血单个核细胞（peripheral blood mononuclear cell，PBMC）中长末端重复序列（long terminal repeat，LTR）介导的转录活性以及病毒复制能力。此外，抑制DYRK1A可使潜伏的HIV-1前病毒重新激活，其效果与两种常用的广谱组蛋白去乙酰化酶（histone deacetylase，HDAC）抑制剂相当。研究发现，DYRK1A通过活化T细胞核因子（Nuclear Factor of Activated T-cells，NFAT）调控HIV-1的转录：它可促进NFAT从细胞核向细胞质转运。因此，抑制DYRK1A会使细胞核内的NFAT水平升高，增强NFAT与病毒LTR的结合，进而提升病毒的转录活性。 结论：本研究数据表明，宿主因子DYRK1A参与调控病毒的转录与潜伏过程。因此，DYRK1A可作为靶向病毒储存库的治疗策略的潜在候选靶点。