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首页> 外文期刊>Cellular Signalling >Toll-like receptor-3 mediates HIV-1 transactivation via NF kappa B and JNK pathways and histone acetylation, but prolonged activation suppresses Tat and HIV-1 replication
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Toll-like receptor-3 mediates HIV-1 transactivation via NF kappa B and JNK pathways and histone acetylation, but prolonged activation suppresses Tat and HIV-1 replication

机译：Toll样受体3通过NFκB和JNK途径以及组蛋白乙酰化介导HIV-1的反式激活，但是长时间的激活会抑制Tat和HIV-1的复制。

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摘要

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-Bl (NFKB1), 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 NF kappa B pathways. This was associated with epigenetic 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 that TLR3 can act 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. (C) 2015 Elsevier Inc All rights reserved.
机译：TLR3与多种病毒感染的发病机制有关，包括SIV和HIV-1引起的炎症和AIDS。然而，尚不清楚这些TLR3介导的作用的分子机制，也不清楚HIV是否与细胞TLR3相互作用以影响疾病过程。在这里，我们使用主要的人类巨噬细胞和包含HIV-1启动子整合拷贝的细胞研究TLR3配体对HIV-1反式激活的影响。我们证明TLR3激活诱导转录因子，例如c-Jun，CCAAT /增强子结合蛋白α（CEBPA），信号转导和转录激活因子（STAT）-1，STAT-2，RELB和核因子kappa- B1（NFKB1），其中大多数已知可调节HIV启动子的活性。我们还证明了TLR3激活通过-c-Jun N末端激酶（JNK）和NF kappa B途径增加了HIV -1反式激活。这与表观遗传修饰有关，包括降低的组蛋白脱乙酰基酶活性，增加的组蛋白乙酰转移酶（HAT）活性，以及​​在HIV-1启动子的0号核小体和1号核小体上的赖氨酸残基处的组蛋白H3和H4的乙酰化增加。但是，长时间的TLR3激活会降低HIV -1反式激活，降低HAT活性和Tat转录并抑制病毒复制。总体而言，数据表明TLR3可以作为病毒传感器来介导HIV感染人类的​​病毒反式激活，细胞信号传导，先天免疫应答和炎症。我们的研究为这些TLR3介导的作用的分子基础提供了新颖的见解。 （C）2015 Elsevier Inc保留所有权利。

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