Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation

Abstract Current antiretroviral therapy (ART) for HIV/AIDS slows disease progression by reducing viral loads and increasing CD4 counts. Yet ART is not curative due to the persistence of CD4+ T-cell proviral reservoirs that chronically resupply active virus. Elimination of these reservoirs through th...

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Autores principales:	Brice J. Albert, Austin Niu, Rashmi Ramani, Garland R. Marshall, Paul A. Wender, Robert M. Williams, Lee Ratner, Alexander B. Barnes, George B. Kyei
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/51c1c2571b74471db5299a641c3986a0
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spelling	oai:doaj.org-article:51c1c2571b74471db5299a641c3986a02021-12-02T16:05:58ZCombinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation10.1038/s41598-017-07814-42045-2322https://doaj.org/article/51c1c2571b74471db5299a641c3986a02017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07814-4https://doaj.org/toc/2045-2322Abstract Current antiretroviral therapy (ART) for HIV/AIDS slows disease progression by reducing viral loads and increasing CD4 counts. Yet ART is not curative due to the persistence of CD4+ T-cell proviral reservoirs that chronically resupply active virus. Elimination of these reservoirs through the administration of synergistic combinations of latency reversing agents (LRAs), such as histone deacetylase (HDAC) inhibitors and protein kinase C (PKC) modulators, provides a promising strategy to reduce if not eradicate the viral reservoir. Here, we demonstrate that largazole and its analogues are isoform-targeted histone deacetylase inhibitors and potent LRAs. Significantly, these isoform-targeted HDAC inhibitors synergize with PKC modulators, namely bryostatin-1 analogues (bryologs). Implementation of this unprecedented LRA combination induces HIV-1 reactivation to unparalleled levels and avoids global T-cell activation within resting CD4+ T-cells.Brice J. AlbertAustin NiuRashmi RamaniGarland R. MarshallPaul A. WenderRobert M. WilliamsLee RatnerAlexander B. BarnesGeorge B. KyeiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Brice J. Albert Austin Niu Rashmi Ramani Garland R. Marshall Paul A. Wender Robert M. Williams Lee Ratner Alexander B. Barnes George B. Kyei Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation
description	Abstract Current antiretroviral therapy (ART) for HIV/AIDS slows disease progression by reducing viral loads and increasing CD4 counts. Yet ART is not curative due to the persistence of CD4+ T-cell proviral reservoirs that chronically resupply active virus. Elimination of these reservoirs through the administration of synergistic combinations of latency reversing agents (LRAs), such as histone deacetylase (HDAC) inhibitors and protein kinase C (PKC) modulators, provides a promising strategy to reduce if not eradicate the viral reservoir. Here, we demonstrate that largazole and its analogues are isoform-targeted histone deacetylase inhibitors and potent LRAs. Significantly, these isoform-targeted HDAC inhibitors synergize with PKC modulators, namely bryostatin-1 analogues (bryologs). Implementation of this unprecedented LRA combination induces HIV-1 reactivation to unparalleled levels and avoids global T-cell activation within resting CD4+ T-cells.
format	article
author	Brice J. Albert Austin Niu Rashmi Ramani Garland R. Marshall Paul A. Wender Robert M. Williams Lee Ratner Alexander B. Barnes George B. Kyei
author_facet	Brice J. Albert Austin Niu Rashmi Ramani Garland R. Marshall Paul A. Wender Robert M. Williams Lee Ratner Alexander B. Barnes George B. Kyei
author_sort	Brice J. Albert
title	Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation
title_short	Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation
title_full	Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation
title_fullStr	Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation
title_full_unstemmed	Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation
title_sort	combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent hiv without global t-cell activation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/51c1c2571b74471db5299a641c3986a0
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Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation

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