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NSC95397 is a Novel HIV Latency Reversing Agent

The latent viral reservoir represents one of the major barriers of curing HIV. Focus on the “kick and kill” approach, in which virus expression is reactivated then cells producing virus are selectively depleted, has led to the discovery of many latency reversing agents (LRAs) that can reactivate lat...

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Autores principales: Nichols Doyle, Randilea, Yang, Vivian, Damoiseaux, Robert, Fregoso, Oliver I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245985/
https://www.ncbi.nlm.nih.gov/pubmed/37293110
http://dx.doi.org/10.1101/2023.05.24.542213
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author Nichols Doyle, Randilea
Yang, Vivian
Damoiseaux, Robert
Fregoso, Oliver I.
author_facet Nichols Doyle, Randilea
Yang, Vivian
Damoiseaux, Robert
Fregoso, Oliver I.
author_sort Nichols Doyle, Randilea
collection PubMed
description The latent viral reservoir represents one of the major barriers of curing HIV. Focus on the “kick and kill” approach, in which virus expression is reactivated then cells producing virus are selectively depleted, has led to the discovery of many latency reversing agents (LRAs) that can reactivate latently integrated virus and further our understanding of the mechanisms driving HIV latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that can act in novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ~4250 compounds in J-Lat cell lines. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events. Cotreating cells with NSC95397 and known LRAs demonstrated that NSC95397 has the potential to synergize with different drugs, such prostratin, a PKC agonist, and SAHA, an HDAC inhibitor. By looking at multiple common markers of open chromatin, we show that NSC95397 does not increase open chromatin globally. Bulk RNA sequencing revealed that NSC95397 does not greatly change cellular transcription. Instead, NSC95397 downregulates many pathways key to metabolism, cell growth, and DNA repair – highlighting the potential of these pathways in regulating HIV latency. Overall, we identified NSC95397 as a novel LRA that does not alter global transcription, that shows potential for synergy with known LRAs, and that may act through novel pathways not previously recognized for their ability to modulate HIV latency.
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spelling pubmed-102459852023-06-08 NSC95397 is a Novel HIV Latency Reversing Agent Nichols Doyle, Randilea Yang, Vivian Damoiseaux, Robert Fregoso, Oliver I. bioRxiv Article The latent viral reservoir represents one of the major barriers of curing HIV. Focus on the “kick and kill” approach, in which virus expression is reactivated then cells producing virus are selectively depleted, has led to the discovery of many latency reversing agents (LRAs) that can reactivate latently integrated virus and further our understanding of the mechanisms driving HIV latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that can act in novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ~4250 compounds in J-Lat cell lines. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events. Cotreating cells with NSC95397 and known LRAs demonstrated that NSC95397 has the potential to synergize with different drugs, such prostratin, a PKC agonist, and SAHA, an HDAC inhibitor. By looking at multiple common markers of open chromatin, we show that NSC95397 does not increase open chromatin globally. Bulk RNA sequencing revealed that NSC95397 does not greatly change cellular transcription. Instead, NSC95397 downregulates many pathways key to metabolism, cell growth, and DNA repair – highlighting the potential of these pathways in regulating HIV latency. Overall, we identified NSC95397 as a novel LRA that does not alter global transcription, that shows potential for synergy with known LRAs, and that may act through novel pathways not previously recognized for their ability to modulate HIV latency. Cold Spring Harbor Laboratory 2023-05-25 /pmc/articles/PMC10245985/ /pubmed/37293110 http://dx.doi.org/10.1101/2023.05.24.542213 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Nichols Doyle, Randilea
Yang, Vivian
Damoiseaux, Robert
Fregoso, Oliver I.
NSC95397 is a Novel HIV Latency Reversing Agent
title NSC95397 is a Novel HIV Latency Reversing Agent
title_full NSC95397 is a Novel HIV Latency Reversing Agent
title_fullStr NSC95397 is a Novel HIV Latency Reversing Agent
title_full_unstemmed NSC95397 is a Novel HIV Latency Reversing Agent
title_short NSC95397 is a Novel HIV Latency Reversing Agent
title_sort nsc95397 is a novel hiv latency reversing agent
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245985/
https://www.ncbi.nlm.nih.gov/pubmed/37293110
http://dx.doi.org/10.1101/2023.05.24.542213
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