The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency
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 w...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Microbiology
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495168/ https://www.ncbi.nlm.nih.gov/pubmed/26152583 http://dx.doi.org/10.1128/mBio.00465-15 |
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author | Mousseau, Guillaume Kessing, Cari F. Fromentin, Rémi Trautmann, Lydie Chomont, Nicolas Valente, Susana T. |
author_facet | Mousseau, Guillaume Kessing, Cari F. Fromentin, Rémi Trautmann, Lydie Chomont, Nicolas Valente, Susana T. |
author_sort | Mousseau, Guillaume |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4495168 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | American Society of Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-44951682015-07-14 The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency Mousseau, Guillaume Kessing, Cari F. Fromentin, Rémi Trautmann, Lydie Chomont, Nicolas Valente, Susana T. mBio Research Article 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. American Society of Microbiology 2015-07-07 /pmc/articles/PMC4495168/ /pubmed/26152583 http://dx.doi.org/10.1128/mBio.00465-15 Text en Copyright © 2015 Mousseau et al. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0/) , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Mousseau, Guillaume Kessing, Cari F. Fromentin, Rémi Trautmann, Lydie Chomont, Nicolas Valente, Susana T. The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency |
title | 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_short | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495168/ https://www.ncbi.nlm.nih.gov/pubmed/26152583 http://dx.doi.org/10.1128/mBio.00465-15 |
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