The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency

ABSTRACT Antiretroviral therapy (ART) inhibits HIV-1 replication, but the virus persists in latently infected resting memory CD4+ T cells susceptible to viral reactivation. The virus-encoded early gene product Tat activates transcription of the viral genome and promotes exponential viral production....

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Autores principales:	Guillaume Mousseau, Cari F. Kessing, Rémi Fromentin, Lydie Trautmann, Nicolas Chomont, Susana T. Valente
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6842f7e80f224a9ebc119c819dd92917
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spelling	oai:doaj.org-article:6842f7e80f224a9ebc119c819dd929172021-11-15T15:41:27ZThe Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency10.1128/mBio.00465-152150-7511https://doaj.org/article/6842f7e80f224a9ebc119c819dd929172015-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00465-15https://doaj.org/toc/2150-7511ABSTRACT Antiretroviral therapy (ART) inhibits HIV-1 replication, but the virus persists in latently infected resting memory CD4+ T cells susceptible to viral reactivation. The virus-encoded early gene product Tat activates transcription of the viral genome and promotes exponential viral production. Here we show that the Tat inhibitor didehydro-cortistatin A (dCA), unlike other antiretrovirals, reduces residual levels of viral transcription in several models of HIV latency, breaks the Tat-mediated transcriptional feedback loop, and establishes a nearly permanent state of latency, which greatly diminishes the capacity for virus reactivation. Importantly, treatment with dCA induces inactivation of viral transcription even after its removal, suggesting that the HIV promoter is epigenetically repressed. Critically, dCA inhibits viral reactivation upon CD3/CD28 or prostratin stimulation of latently infected CD4+ T cells from HIV-infected subjects receiving suppressive ART. Our results suggest that inclusion of a Tat inhibitor in current ART regimens may contribute to a functional HIV-1 cure by reducing low-level viremia and preventing viral reactivation from latent reservoirs. IMPORTANCE Antiretroviral therapy (ART) reduces HIV-1 replication to very low levels, but the virus persists in latently infected memory CD4+ T cells, representing a long-lasting source of resurgent virus upon ART interruption. Based on the mode of action of didehydro-cortistatin A (dCA), a Tat-dependent transcription inhibitor, our work highlights an alternative approach to current HIV-1 eradication strategies to decrease the latent reservoir. In our model, dCA blocks the Tat feedback loop initiated after low-level basal reactivation, blocking transcriptional elongation and hence viral production from latently infected cells. Therefore, dCA combined with ART would be aimed at delaying or halting ongoing viral replication, reactivation, and replenishment of the latent viral reservoir. Thus, the latent pool of cells in an infected individual would be stabilized, and death of the long-lived infected memory T cells would result in a continuous decay of this pool over time, possibly culminating in the long-awaited sterilizing cure.Guillaume MousseauCari F. KessingRémi FromentinLydie TrautmannNicolas ChomontSusana T. ValenteAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 4 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Guillaume Mousseau Cari F. Kessing Rémi Fromentin Lydie Trautmann Nicolas Chomont Susana T. Valente The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency
description	ABSTRACT Antiretroviral therapy (ART) inhibits HIV-1 replication, but the virus persists in latently infected resting memory CD4+ T cells susceptible to viral reactivation. The virus-encoded early gene product Tat activates transcription of the viral genome and promotes exponential viral production. Here we show that the Tat inhibitor didehydro-cortistatin A (dCA), unlike other antiretrovirals, reduces residual levels of viral transcription in several models of HIV latency, breaks the Tat-mediated transcriptional feedback loop, and establishes a nearly permanent state of latency, which greatly diminishes the capacity for virus reactivation. Importantly, treatment with dCA induces inactivation of viral transcription even after its removal, suggesting that the HIV promoter is epigenetically repressed. Critically, dCA inhibits viral reactivation upon CD3/CD28 or prostratin stimulation of latently infected CD4+ T cells from HIV-infected subjects receiving suppressive ART. Our results suggest that inclusion of a Tat inhibitor in current ART regimens may contribute to a functional HIV-1 cure by reducing low-level viremia and preventing viral reactivation from latent reservoirs. IMPORTANCE Antiretroviral therapy (ART) reduces HIV-1 replication to very low levels, but the virus persists in latently infected memory CD4+ T cells, representing a long-lasting source of resurgent virus upon ART interruption. Based on the mode of action of didehydro-cortistatin A (dCA), a Tat-dependent transcription inhibitor, our work highlights an alternative approach to current HIV-1 eradication strategies to decrease the latent reservoir. In our model, dCA blocks the Tat feedback loop initiated after low-level basal reactivation, blocking transcriptional elongation and hence viral production from latently infected cells. Therefore, dCA combined with ART would be aimed at delaying or halting ongoing viral replication, reactivation, and replenishment of the latent viral reservoir. Thus, the latent pool of cells in an infected individual would be stabilized, and death of the long-lived infected memory T cells would result in a continuous decay of this pool over time, possibly culminating in the long-awaited sterilizing cure.
format	article
author	Guillaume Mousseau Cari F. Kessing Rémi Fromentin Lydie Trautmann Nicolas Chomont Susana T. Valente
author_facet	Guillaume Mousseau Cari F. Kessing Rémi Fromentin Lydie Trautmann Nicolas Chomont Susana T. Valente
author_sort	Guillaume Mousseau
title	The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency
title_short	The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency
title_full	The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency
title_fullStr	The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency
title_full_unstemmed	The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency
title_sort	tat inhibitor didehydro-cortistatin a prevents hiv-1 reactivation from latency
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/6842f7e80f224a9ebc119c819dd92917
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The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency

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