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Article Dans Une Revue mBio Année : 2019

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

Guillaume Mousseau
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Rachna Aneja
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Mark A Clementz
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Sonia Mediouni
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Noemia S Lima
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Alexander Haregot
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Cari F Kessing
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Joseph A Jablonski
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Nisha Nagarsheth
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Lydie Trautmann
Susana T Valente
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Résumé

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.
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Dates et versions

hal-04372239 , version 1 (04-01-2024)

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Guillaume Mousseau, Rachna Aneja, Mark A Clementz, Sonia Mediouni, Noemia S Lima, et al.. Resistance to the Tat Inhibitor Didehydro-Cortistatin A Is Mediated by Heightened Basal HIV-1 Transcription. mBio, 2019, 10 (4), ⟨10.1128/mBio.01750-18⟩. ⟨hal-04372239⟩
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