Toll-like receptor-3 mediates HIV-1 transactivation via NFκB and JNK pathways and histone acetylation, but prolonged activation suppresses Tat and HIV-1 replication.
Toll-like receptor-3 mediates HIV-1 transactivation via NFκB and JNK pathways and histone acetylation, but prolonged activation suppresses Tat and HIV-1 replication.
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DOI：
10.1016/j.cellsig.2015.11.005
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发表时间：
2016-02
影响因子：
4.8
通讯作者：
Kanmogne GD
中科院分区：
文献类型：
--
作者：
Bhargavan B;Woollard SM;Kanmogne GD
TLR3与多种病毒感染的发病机制有关，包括SIV和hiv -1诱导的炎症和艾滋病。然而，这些TLR3介导作用的分子机制尚不清楚，也不清楚HIV是否与细胞TLR3相互作用影响疾病过程。在这里，我们使用原代人巨噬细胞和含有HIV-1启动子整合拷贝的细胞来研究TLR3配体对HIV-1转激活的影响。我们证明，TLR3激活诱导转录因子上调，如c-Jun、CCAAT/增强子结合蛋白α (CEBPA)、转录信号换能器和激活因子(STAT)-1、STAT-2、RELB和核因子κ b1 (NFκB1)，其中大多数已知调节HIV启动子活性。我们还证明了TLR3的激活通过c-Jun n末端激酶（JNK）和NFκB途径增加了HIV-1的转激活。这与表观遗传学修饰有关，包括组蛋白去乙酰化酶活性降低，组蛋白乙酰转移酶（HAT）活性增加，以及HIV-1启动子核小体0和核小体1赖氨酸残基上组蛋白H3和H4乙酰化增加。然而，延长TLR3激活可降低HIV-1反式激活，降低HAT活性和Tat转录，并抑制病毒复制。总的来说，数据表明TLR3可以作为病毒传感器介导hiv感染者的病毒转激活、细胞信号传导、先天免疫反应和炎症。我们的研究为这些tlr3介导作用的分子基础提供了新的见解。
TLR3 has been implicated in the pathogenesis of several viral infections, including SIV- and HIV-1-induced inflammation and AIDS. However the molecular mechanisms of these TLR3-mediated effects are not known, and it is not known whether HIV interacts with cellular TLR3 to affect disease process. Here we investigate the effects of TLR3 ligands on HIV-1 transactivation using both primary human macrophages and cells containing integrated copies of the HIV-1 promoter. We demonstrate that TLR3 activation induced upregulation of transcription factors such as c-Jun, CCAAT/enhancer-binding protein alpha (CEBPA), signal transducer and activator of transcription (STAT)-1, STAT-2, RELB, and nuclear factor kappa-B1 (NFκB1), most of which are known to regulate the HIV promoter activity. We also demonstrate that TLR3 activation increased HIV-1 transactivation via the c-Jun N-terminal kinase (JNK) and NFκB pathways. This was associated with epigenetics modifications, including decreased histone deacetylase activity, increased histone acetyl transferase (HAT) activity, and increased acetylation of histones H3 and H4 at lysine residues in the nucleosome-0 and nucleosome-1 of the HIV-1 promoter. However, prolonged TLR3 activation decreased HIV-1 transactivation, decreased HAT activity and Tat transcription, and suppressed viral replication. Overall, data suggests TLR3 can acts as viral sensor to mediate viral transactivation, cellular signaling, innate immune response, and inflammation in HIV-infected humans. Our study provides novel insights into the molecular basis for these TLR3-mediated effects.