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Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-κB pathway
Integration of HIV-1 linear DNA into host chromatin is required for high levels of viral expression, and constitutes a key therapeutic target. Unintegrated viral DNA (uDNA) can support only limited transcription but may contribute to viral propagation, persistence and/or treatment escape under speci...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863372/ https://www.ncbi.nlm.nih.gov/pubmed/27167871 http://dx.doi.org/10.1038/srep25678 |
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author | Thierry, Sylvain Thierry, Eloïse Subra, Frédéric Deprez, Eric Leh, Hervé Bury-Moné, Stéphanie Delelis, Olivier |
author_facet | Thierry, Sylvain Thierry, Eloïse Subra, Frédéric Deprez, Eric Leh, Hervé Bury-Moné, Stéphanie Delelis, Olivier |
author_sort | Thierry, Sylvain |
collection | PubMed |
description | Integration of HIV-1 linear DNA into host chromatin is required for high levels of viral expression, and constitutes a key therapeutic target. Unintegrated viral DNA (uDNA) can support only limited transcription but may contribute to viral propagation, persistence and/or treatment escape under specific situations. The molecular mechanisms involved in the differential expression of HIV uDNA vs integrated genome (iDNA) remain to be elucidated. Here, we demonstrate, for the first time, that the expression of HIV uDNA is mainly supported by 1-LTR circles, and regulated in the opposite way, relatively to iDNA, following NF-κB pathway modulation. Upon treatment activating the NF-κB pathway, NF-κB p65 and AP-1 (cFos/cJun) binding to HIV LTR iDNA correlates with increased iDNA expression, while uDNA expression decreases. On the contrary, inhibition of the NF-κB pathway promotes the expression of circular uDNA, and correlates with Bcl-3 and AP-1 binding to its LTR region. Finally, this study identifies NF-κB subunits and Bcl-3 as transcription factors binding the HIV promoter differently depending on viral genome topology, and opens new insights on the potential roles of episomal genomes during the HIV-1 latency and persistence. |
format | Online Article Text |
id | pubmed-4863372 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-48633722016-05-23 Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-κB pathway Thierry, Sylvain Thierry, Eloïse Subra, Frédéric Deprez, Eric Leh, Hervé Bury-Moné, Stéphanie Delelis, Olivier Sci Rep Article Integration of HIV-1 linear DNA into host chromatin is required for high levels of viral expression, and constitutes a key therapeutic target. Unintegrated viral DNA (uDNA) can support only limited transcription but may contribute to viral propagation, persistence and/or treatment escape under specific situations. The molecular mechanisms involved in the differential expression of HIV uDNA vs integrated genome (iDNA) remain to be elucidated. Here, we demonstrate, for the first time, that the expression of HIV uDNA is mainly supported by 1-LTR circles, and regulated in the opposite way, relatively to iDNA, following NF-κB pathway modulation. Upon treatment activating the NF-κB pathway, NF-κB p65 and AP-1 (cFos/cJun) binding to HIV LTR iDNA correlates with increased iDNA expression, while uDNA expression decreases. On the contrary, inhibition of the NF-κB pathway promotes the expression of circular uDNA, and correlates with Bcl-3 and AP-1 binding to its LTR region. Finally, this study identifies NF-κB subunits and Bcl-3 as transcription factors binding the HIV promoter differently depending on viral genome topology, and opens new insights on the potential roles of episomal genomes during the HIV-1 latency and persistence. Nature Publishing Group 2016-05-11 /pmc/articles/PMC4863372/ /pubmed/27167871 http://dx.doi.org/10.1038/srep25678 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Thierry, Sylvain Thierry, Eloïse Subra, Frédéric Deprez, Eric Leh, Hervé Bury-Moné, Stéphanie Delelis, Olivier Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-κB pathway |
title | Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-κB pathway |
title_full | Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-κB pathway |
title_fullStr | Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-κB pathway |
title_full_unstemmed | Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-κB pathway |
title_short | Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-κB pathway |
title_sort | opposite transcriptional regulation of integrated vs unintegrated hiv genomes by the nf-κb pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863372/ https://www.ncbi.nlm.nih.gov/pubmed/27167871 http://dx.doi.org/10.1038/srep25678 |
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