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A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter

The principal barrier to the eradication of HIV/AIDS is the existence of latent viral reservoirs. One strategy to overcome this barrier is to use latency-reversing agents (LRAs) to reactivate the latent proviruses, which can then be eliminated by effective anti-retroviral therapy. Although a number...

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Autores principales: Wu, Jun, Ao, Ming-tao, Shao, Rui, Wang, Hui-ru, Yu, Diao, Fang, Mei-juan, Gao, Xiang, Wu, Zhen, Zhou, Qiang, Xue, Yu-hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587564/
https://www.ncbi.nlm.nih.gov/pubmed/28878233
http://dx.doi.org/10.1038/s41598-017-10728-w
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author Wu, Jun
Ao, Ming-tao
Shao, Rui
Wang, Hui-ru
Yu, Diao
Fang, Mei-juan
Gao, Xiang
Wu, Zhen
Zhou, Qiang
Xue, Yu-hua
author_facet Wu, Jun
Ao, Ming-tao
Shao, Rui
Wang, Hui-ru
Yu, Diao
Fang, Mei-juan
Gao, Xiang
Wu, Zhen
Zhou, Qiang
Xue, Yu-hua
author_sort Wu, Jun
collection PubMed
description The principal barrier to the eradication of HIV/AIDS is the existence of latent viral reservoirs. One strategy to overcome this barrier is to use latency-reversing agents (LRAs) to reactivate the latent proviruses, which can then be eliminated by effective anti-retroviral therapy. Although a number of LRAs have been found to reactivate latent HIV, they have not been used clinically due to high toxicity and poor efficacy. In this study, we report the identification of a chalcone analogue called Amt-87 that can significantly reactivate the transcription of latent HIV provirses and act synergistically with known LRAs such as prostratin and JQ1 to reverse latency. Amt-87 works by activating the human transcriptional elongation factor P-TEFb, a CDK9-cyclin T1 heterodimer that is part of the super elongation complex (SEC) used by the viral encoded Tat protein to activate HIV transcription. Amt-87 does so by promoting the phosphorylation of CDK9 at the T-loop, liberating P-TEFb from the inactive 7SK snRNP, and inducing the formation of the Tat-SEC complex at the viral promoter. Together, our data reveal chalcones as a promising category of compounds that should be further explored to identify effective LRAs for targeted reversal of HIV latency.
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spelling pubmed-55875642017-09-13 A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter Wu, Jun Ao, Ming-tao Shao, Rui Wang, Hui-ru Yu, Diao Fang, Mei-juan Gao, Xiang Wu, Zhen Zhou, Qiang Xue, Yu-hua Sci Rep Article The principal barrier to the eradication of HIV/AIDS is the existence of latent viral reservoirs. One strategy to overcome this barrier is to use latency-reversing agents (LRAs) to reactivate the latent proviruses, which can then be eliminated by effective anti-retroviral therapy. Although a number of LRAs have been found to reactivate latent HIV, they have not been used clinically due to high toxicity and poor efficacy. In this study, we report the identification of a chalcone analogue called Amt-87 that can significantly reactivate the transcription of latent HIV provirses and act synergistically with known LRAs such as prostratin and JQ1 to reverse latency. Amt-87 works by activating the human transcriptional elongation factor P-TEFb, a CDK9-cyclin T1 heterodimer that is part of the super elongation complex (SEC) used by the viral encoded Tat protein to activate HIV transcription. Amt-87 does so by promoting the phosphorylation of CDK9 at the T-loop, liberating P-TEFb from the inactive 7SK snRNP, and inducing the formation of the Tat-SEC complex at the viral promoter. Together, our data reveal chalcones as a promising category of compounds that should be further explored to identify effective LRAs for targeted reversal of HIV latency. Nature Publishing Group UK 2017-09-06 /pmc/articles/PMC5587564/ /pubmed/28878233 http://dx.doi.org/10.1038/s41598-017-10728-w Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wu, Jun
Ao, Ming-tao
Shao, Rui
Wang, Hui-ru
Yu, Diao
Fang, Mei-juan
Gao, Xiang
Wu, Zhen
Zhou, Qiang
Xue, Yu-hua
A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter
title A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter
title_full A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter
title_fullStr A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter
title_full_unstemmed A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter
title_short A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter
title_sort chalcone derivative reactivates latent hiv-1 transcription through activating p-tefb and promoting tat-sec interaction on viral promoter
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587564/
https://www.ncbi.nlm.nih.gov/pubmed/28878233
http://dx.doi.org/10.1038/s41598-017-10728-w
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