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Identification of celastrol as a novel HIV-1 latency reversal agent by an image-based screen

Although current antiretroviral therapies (ART) are successful in controlling HIV-1 infection, a stable viral reservoir reactivates when ART is discontinued. Consequently, there is a major research effort to develop approaches to disrupt the latent viral reservoir and enhance the immune system’s abi...

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Autores principales: Liu, Hongbing, Hu, Pei-Wen, Dubrulle, Julien, Stossi, Fabio, Nikolai, Bryan C., Mancini, Michael A., Rice, Andrew P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084242/
https://www.ncbi.nlm.nih.gov/pubmed/33914760
http://dx.doi.org/10.1371/journal.pone.0244771
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author Liu, Hongbing
Hu, Pei-Wen
Dubrulle, Julien
Stossi, Fabio
Nikolai, Bryan C.
Mancini, Michael A.
Rice, Andrew P.
author_facet Liu, Hongbing
Hu, Pei-Wen
Dubrulle, Julien
Stossi, Fabio
Nikolai, Bryan C.
Mancini, Michael A.
Rice, Andrew P.
author_sort Liu, Hongbing
collection PubMed
description Although current antiretroviral therapies (ART) are successful in controlling HIV-1 infection, a stable viral reservoir reactivates when ART is discontinued. Consequently, there is a major research effort to develop approaches to disrupt the latent viral reservoir and enhance the immune system’s ability to clear HIV-1. A number of small molecules, termed latency reversal agents (LRAs), have been identified which can reactivate latent HIV-1 in cell lines and patients’ cells ex vivo. However, clinical trials have suggested that combinations of LRAs will be required to efficiently reactivate HIV-1 in vivo, especially LRAs that act synergistically by functioning through distinct pathways. To identify novel LRAs, we used an image-based assay to screen a natural compound library for the ability to induce a low level of aggregation of resting primary CD4(+) T cells from healthy donors. We identified celastrol as a novel LRA. Celastrol functions synergistically with other classes of LRA to reactivate latent HIV-1 in a Jurkat cell line, suggesting a novel mechanism in its LRA activity. Additionally, celastrol does not appear to activate resting CD4(+) T cells at levels at which it can reactivate latent HIV-1. Celastrol appears to represent a novel class of LRAs and it therefore can serve as a lead compound for LRA development.
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spelling pubmed-80842422021-05-06 Identification of celastrol as a novel HIV-1 latency reversal agent by an image-based screen Liu, Hongbing Hu, Pei-Wen Dubrulle, Julien Stossi, Fabio Nikolai, Bryan C. Mancini, Michael A. Rice, Andrew P. PLoS One Research Article Although current antiretroviral therapies (ART) are successful in controlling HIV-1 infection, a stable viral reservoir reactivates when ART is discontinued. Consequently, there is a major research effort to develop approaches to disrupt the latent viral reservoir and enhance the immune system’s ability to clear HIV-1. A number of small molecules, termed latency reversal agents (LRAs), have been identified which can reactivate latent HIV-1 in cell lines and patients’ cells ex vivo. However, clinical trials have suggested that combinations of LRAs will be required to efficiently reactivate HIV-1 in vivo, especially LRAs that act synergistically by functioning through distinct pathways. To identify novel LRAs, we used an image-based assay to screen a natural compound library for the ability to induce a low level of aggregation of resting primary CD4(+) T cells from healthy donors. We identified celastrol as a novel LRA. Celastrol functions synergistically with other classes of LRA to reactivate latent HIV-1 in a Jurkat cell line, suggesting a novel mechanism in its LRA activity. Additionally, celastrol does not appear to activate resting CD4(+) T cells at levels at which it can reactivate latent HIV-1. Celastrol appears to represent a novel class of LRAs and it therefore can serve as a lead compound for LRA development. Public Library of Science 2021-04-29 /pmc/articles/PMC8084242/ /pubmed/33914760 http://dx.doi.org/10.1371/journal.pone.0244771 Text en © 2021 Liu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Liu, Hongbing
Hu, Pei-Wen
Dubrulle, Julien
Stossi, Fabio
Nikolai, Bryan C.
Mancini, Michael A.
Rice, Andrew P.
Identification of celastrol as a novel HIV-1 latency reversal agent by an image-based screen
title Identification of celastrol as a novel HIV-1 latency reversal agent by an image-based screen
title_full Identification of celastrol as a novel HIV-1 latency reversal agent by an image-based screen
title_fullStr Identification of celastrol as a novel HIV-1 latency reversal agent by an image-based screen
title_full_unstemmed Identification of celastrol as a novel HIV-1 latency reversal agent by an image-based screen
title_short Identification of celastrol as a novel HIV-1 latency reversal agent by an image-based screen
title_sort identification of celastrol as a novel hiv-1 latency reversal agent by an image-based screen
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084242/
https://www.ncbi.nlm.nih.gov/pubmed/33914760
http://dx.doi.org/10.1371/journal.pone.0244771
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