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Editor's Pick Research Article

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

Guillaume Mousseau, Cari F. Kessing, Rémi Fromentin, Lydie Trautmann, Nicolas Chomont, Susana T. Valente
Vicente Planelles, Invited Editor, Vinayaka R. Prasad, Editor
Guillaume Mousseau
Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA
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Cari F. Kessing
Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA
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Rémi Fromentin
Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA
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Lydie Trautmann
Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA
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Nicolas Chomont
Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA
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Susana T. Valente
Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA
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Vicente Planelles
University of Utah School of Medicine
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Vinayaka R. Prasad
Albert Einstein College of Medicine
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DOI: 10.1128/mBio.00465-15
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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.

  • Copyright © 2015 Mousseau et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency
Guillaume Mousseau, Cari F. Kessing, Rémi Fromentin, Lydie Trautmann, Nicolas Chomont, Susana T. Valente
mBio Jul 2015, 6 (4) e00465-15; DOI: 10.1128/mBio.00465-15

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The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency
Guillaume Mousseau, Cari F. Kessing, Rémi Fromentin, Lydie Trautmann, Nicolas Chomont, Susana T. Valente
mBio Jul 2015, 6 (4) e00465-15; DOI: 10.1128/mBio.00465-15
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