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Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation

The presence of latent HIV-1 in infected individuals represents a major barrier preventingviral eradication. For that reason, reactivation of latent viruses in the presence of antiretroviral regimens has been proposed as a therapeutic strategy to achieve remission. We screened for small molecules an...

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Autores principales: Bosque, Alberto, Nilson, Kyle A., Macedo, Amanda B., Spivak, Adam M., Archin, Nancie M., Van Wagoner, Ryan M., Martins, Laura J., Novis, Camille L., Szaniawski, Matthew A., Ireland, Chris M., Margolis, David M., Price, David H., Planelles, Vicente
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461578/
https://www.ncbi.nlm.nih.gov/pubmed/28147284
http://dx.doi.org/10.1016/j.celrep.2017.01.022
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author Bosque, Alberto
Nilson, Kyle A.
Macedo, Amanda B.
Spivak, Adam M.
Archin, Nancie M.
Van Wagoner, Ryan M.
Martins, Laura J.
Novis, Camille L.
Szaniawski, Matthew A.
Ireland, Chris M.
Margolis, David M.
Price, David H.
Planelles, Vicente
author_facet Bosque, Alberto
Nilson, Kyle A.
Macedo, Amanda B.
Spivak, Adam M.
Archin, Nancie M.
Van Wagoner, Ryan M.
Martins, Laura J.
Novis, Camille L.
Szaniawski, Matthew A.
Ireland, Chris M.
Margolis, David M.
Price, David H.
Planelles, Vicente
author_sort Bosque, Alberto
collection PubMed
description The presence of latent HIV-1 in infected individuals represents a major barrier preventingviral eradication. For that reason, reactivation of latent viruses in the presence of antiretroviral regimens has been proposed as a therapeutic strategy to achieve remission. We screened for small molecules and identified several benzotriazole derivatives with the ability to reactivate latent HIV-1. In the presence of IL-2, benzotriazoles reactivated and reduced the latent reservoir in primary cells, and, remarkably, viral reactivation was achieved without inducing cell proliferation, T cell activation, or cytokine release. Mechanistic studies showed that benzotriazoles block SUMOylation of phosphorylated STAT5, increasing STAT5’s activity and occupancy of the HIV-1 LTR. Our results identify benzotriazoles as latency reversing agents and STAT5 signaling and SUMOylation as targets for HIV-1 eradication strategies. These compounds represent a different direction in the search for “shock and kill” therapies.
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spelling pubmed-54615782017-06-07 Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation Bosque, Alberto Nilson, Kyle A. Macedo, Amanda B. Spivak, Adam M. Archin, Nancie M. Van Wagoner, Ryan M. Martins, Laura J. Novis, Camille L. Szaniawski, Matthew A. Ireland, Chris M. Margolis, David M. Price, David H. Planelles, Vicente Cell Rep Article The presence of latent HIV-1 in infected individuals represents a major barrier preventingviral eradication. For that reason, reactivation of latent viruses in the presence of antiretroviral regimens has been proposed as a therapeutic strategy to achieve remission. We screened for small molecules and identified several benzotriazole derivatives with the ability to reactivate latent HIV-1. In the presence of IL-2, benzotriazoles reactivated and reduced the latent reservoir in primary cells, and, remarkably, viral reactivation was achieved without inducing cell proliferation, T cell activation, or cytokine release. Mechanistic studies showed that benzotriazoles block SUMOylation of phosphorylated STAT5, increasing STAT5’s activity and occupancy of the HIV-1 LTR. Our results identify benzotriazoles as latency reversing agents and STAT5 signaling and SUMOylation as targets for HIV-1 eradication strategies. These compounds represent a different direction in the search for “shock and kill” therapies. 2017-01-31 /pmc/articles/PMC5461578/ /pubmed/28147284 http://dx.doi.org/10.1016/j.celrep.2017.01.022 Text en http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Bosque, Alberto
Nilson, Kyle A.
Macedo, Amanda B.
Spivak, Adam M.
Archin, Nancie M.
Van Wagoner, Ryan M.
Martins, Laura J.
Novis, Camille L.
Szaniawski, Matthew A.
Ireland, Chris M.
Margolis, David M.
Price, David H.
Planelles, Vicente
Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation
title Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation
title_full Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation
title_fullStr Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation
title_full_unstemmed Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation
title_short Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation
title_sort benzotriazoles reactivate latent hiv-1 through inactivation of stat5 sumoylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461578/
https://www.ncbi.nlm.nih.gov/pubmed/28147284
http://dx.doi.org/10.1016/j.celrep.2017.01.022
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