Resistance to the Tat Inhibitor Didehydro-Cortistatin A Is Mediated by Heightened Basal HIV-1 Transcription

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) Tat binds the viral RNA structure transactivation-responsive element (TAR) and recruits transcriptional cofactors, amplifying viral mRNA expression. The Tat inhibitor didehydro-cortistatin A (dCA) promotes a state of persistent latency, refractory...

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Autores principales:	Guillaume Mousseau, Rachna Aneja, Mark A. Clementz, Sonia Mediouni, Noemia S. Lima, Alexander Haregot, Cari F. Kessing, Joseph A. Jablonski, Suzie Thenin-Houssier, Nisha Nagarsheth, Lydie Trautmann, Susana T. Valente
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	HIV promoter HIV transcription Nef Tat inhibitor Vpr drug resistance Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c4b6f2c1a0084651a181b6cce77eddfc
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spelling	oai:doaj.org-article:c4b6f2c1a0084651a181b6cce77eddfc2021-11-15T16:22:09ZResistance to the Tat Inhibitor Didehydro-Cortistatin A Is Mediated by Heightened Basal HIV-1 Transcription10.1128/mBio.01750-182150-7511https://doaj.org/article/c4b6f2c1a0084651a181b6cce77eddfc2019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01750-18https://doaj.org/toc/2150-7511ABSTRACT Human immunodeficiency virus type 1 (HIV-1) Tat binds the viral RNA structure transactivation-responsive element (TAR) and recruits transcriptional cofactors, amplifying viral mRNA expression. The Tat inhibitor didehydro-cortistatin A (dCA) promotes a state of persistent latency, refractory to viral reactivation. Here we investigated mechanisms of HIV-1 resistance to dCA in vitro. Mutations in Tat and TAR were not identified, consistent with the high level of conservation of these elements. Instead, viruses resistant to dCA developed higher Tat-independent basal transcription. We identified a combination of mutations in the HIV-1 promoter that increased basal transcriptional activity and modifications in viral Nef and Vpr proteins that increased NF-κB activity. Importantly, these variants are unlikely to enter latency due to accrued transcriptional fitness and loss of sensitivity to Tat feedback loop regulation. Furthermore, cells infected with these variants become more susceptible to cytopathic effects and immune-mediated clearance. This is the first report of viral escape to a Tat inhibitor resulting in heightened Tat-independent activity, all while maintaining wild-type Tat and TAR. IMPORTANCE HIV-1 Tat enhances viral RNA transcription by binding to TAR and recruiting activating factors. Tat enhances its own transcription via a positive-feedback loop. Didehydro-cortistatin A (dCA) is a potent Tat inhibitor, reducing HIV-1 transcription and preventing viral rebound. dCA activity demonstrates the potential of the “block-and-lock” functional cure approaches. We investigated the viral genetic barrier to dCA resistance in vitro. While mutations in Tat and TAR were not identified, mutations in the promoter and in the Nef and Vpr proteins promoted high Tat-independent activity. Promoter mutations increased the basal transcription, while Nef and Vpr mutations increased NF-κB nuclear translocation. This heightened transcriptional activity renders CD4+ T cells infected with these viruses more susceptible to cytotoxic T cell-mediated killing and to cell death by cytopathic effects. Results provide insights on drug resistance to a novel class of antiretrovirals and reveal novel aspects of viral transcriptional regulation.Guillaume MousseauRachna AnejaMark A. ClementzSonia MediouniNoemia S. LimaAlexander HaregotCari F. KessingJoseph A. JablonskiSuzie Thenin-HoussierNisha NagarshethLydie TrautmannSusana T. ValenteAmerican Society for MicrobiologyarticleHIV promoterHIV transcriptionNefTat inhibitorVprdrug resistanceMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	HIV promoter HIV transcription Nef Tat inhibitor Vpr drug resistance Microbiology QR1-502
spellingShingle	HIV promoter HIV transcription Nef Tat inhibitor Vpr drug resistance Microbiology QR1-502 Guillaume Mousseau Rachna Aneja Mark A. Clementz Sonia Mediouni Noemia S. Lima Alexander Haregot Cari F. Kessing Joseph A. Jablonski Suzie Thenin-Houssier Nisha Nagarsheth Lydie Trautmann Susana T. Valente Resistance to the Tat Inhibitor Didehydro-Cortistatin A Is Mediated by Heightened Basal HIV-1 Transcription
description	ABSTRACT Human immunodeficiency virus type 1 (HIV-1) Tat binds the viral RNA structure transactivation-responsive element (TAR) and recruits transcriptional cofactors, amplifying viral mRNA expression. The Tat inhibitor didehydro-cortistatin A (dCA) promotes a state of persistent latency, refractory to viral reactivation. Here we investigated mechanisms of HIV-1 resistance to dCA in vitro. Mutations in Tat and TAR were not identified, consistent with the high level of conservation of these elements. Instead, viruses resistant to dCA developed higher Tat-independent basal transcription. We identified a combination of mutations in the HIV-1 promoter that increased basal transcriptional activity and modifications in viral Nef and Vpr proteins that increased NF-κB activity. Importantly, these variants are unlikely to enter latency due to accrued transcriptional fitness and loss of sensitivity to Tat feedback loop regulation. Furthermore, cells infected with these variants become more susceptible to cytopathic effects and immune-mediated clearance. This is the first report of viral escape to a Tat inhibitor resulting in heightened Tat-independent activity, all while maintaining wild-type Tat and TAR. IMPORTANCE HIV-1 Tat enhances viral RNA transcription by binding to TAR and recruiting activating factors. Tat enhances its own transcription via a positive-feedback loop. Didehydro-cortistatin A (dCA) is a potent Tat inhibitor, reducing HIV-1 transcription and preventing viral rebound. dCA activity demonstrates the potential of the “block-and-lock” functional cure approaches. We investigated the viral genetic barrier to dCA resistance in vitro. While mutations in Tat and TAR were not identified, mutations in the promoter and in the Nef and Vpr proteins promoted high Tat-independent activity. Promoter mutations increased the basal transcription, while Nef and Vpr mutations increased NF-κB nuclear translocation. This heightened transcriptional activity renders CD4+ T cells infected with these viruses more susceptible to cytotoxic T cell-mediated killing and to cell death by cytopathic effects. Results provide insights on drug resistance to a novel class of antiretrovirals and reveal novel aspects of viral transcriptional regulation.
format	article
author	Guillaume Mousseau Rachna Aneja Mark A. Clementz Sonia Mediouni Noemia S. Lima Alexander Haregot Cari F. Kessing Joseph A. Jablonski Suzie Thenin-Houssier Nisha Nagarsheth Lydie Trautmann Susana T. Valente
author_facet	Guillaume Mousseau Rachna Aneja Mark A. Clementz Sonia Mediouni Noemia S. Lima Alexander Haregot Cari F. Kessing Joseph A. Jablonski Suzie Thenin-Houssier Nisha Nagarsheth Lydie Trautmann Susana T. Valente
author_sort	Guillaume Mousseau
title	Resistance to the Tat Inhibitor Didehydro-Cortistatin A Is Mediated by Heightened Basal HIV-1 Transcription
title_short	Resistance to the Tat Inhibitor Didehydro-Cortistatin A Is Mediated by Heightened Basal HIV-1 Transcription
title_full	Resistance to the Tat Inhibitor Didehydro-Cortistatin A Is Mediated by Heightened Basal HIV-1 Transcription
title_fullStr	Resistance to the Tat Inhibitor Didehydro-Cortistatin A Is Mediated by Heightened Basal HIV-1 Transcription
title_full_unstemmed	Resistance to the Tat Inhibitor Didehydro-Cortistatin A Is Mediated by Heightened Basal HIV-1 Transcription
title_sort	resistance to the tat inhibitor didehydro-cortistatin a is mediated by heightened basal hiv-1 transcription
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/c4b6f2c1a0084651a181b6cce77eddfc
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Resistance to the Tat Inhibitor Didehydro-Cortistatin A Is Mediated by Heightened Basal HIV-1 Transcription

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