Unexpected Mutations in HIV-1 That Confer Resistance to the Tat Inhibitor Didehydro-Cortistatin A

ABSTRACT Didehydro-cortistatin A (dCA) is a human immunodeficiency virus type 1 (HIV-1) Tat inhibitor that functions by selectively binding to the RNA binding domain of Tat. In addition to inhibiting viral replication, dCA can drive HIV-1 into a state of “deep latency” in which latent viruses are re...

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Autor principal:	Andrew P. Rice
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	didehydro-cortistatin A HIV-1 Tat deep latency latency Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2155958c270a45ffb27fc1864c1f61ec
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spelling	oai:doaj.org-article:2155958c270a45ffb27fc1864c1f61ec2021-11-15T16:22:11ZUnexpected Mutations in HIV-1 That Confer Resistance to the Tat Inhibitor Didehydro-Cortistatin A10.1128/mBio.01547-192150-7511https://doaj.org/article/2155958c270a45ffb27fc1864c1f61ec2019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01547-19https://doaj.org/toc/2150-7511ABSTRACT Didehydro-cortistatin A (dCA) is a human immunodeficiency virus type 1 (HIV-1) Tat inhibitor that functions by selectively binding to the RNA binding domain of Tat. In addition to inhibiting viral replication, dCA can drive HIV-1 into a state of “deep latency” in which latent viruses are refractory to reactivation. Mousseau et al. (G. Mousseau, R. Aneja, M. A. Clementz, S. Mediouni, et al., mBio 10:e01750-18, 2019, https://doi.org/10.1128/mBio.01750-18) have now selected dCA-resistant (dCAr) viruses in vitro. Remarkably, dCAr viruses do not contain mutations in Tat or the viral transactivation-responsive element (TAR) RNA element that is targeted by Tat. Rather, the viruses contain a combination of mutations in the viral long terminal repeat (LTR) and Nef and Vpr proteins that result in an increase in basal RNA polymerase II (Pol II) transcription of integrated HIV-1. Interestingly, dCAr viruses may be deficient in the establishment of latent infection because of their elevated basal Pol II transcription. dCA holds promise for strategies to achieve a functional cure of HIV-1 infection and justifies efforts to develop additional Tat inhibitors.Andrew P. RiceAmerican Society for Microbiologyarticledidehydro-cortistatin AHIV-1Tatdeep latencylatencyMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	didehydro-cortistatin A HIV-1 Tat deep latency latency Microbiology QR1-502
spellingShingle	didehydro-cortistatin A HIV-1 Tat deep latency latency Microbiology QR1-502 Andrew P. Rice Unexpected Mutations in HIV-1 That Confer Resistance to the Tat Inhibitor Didehydro-Cortistatin A
description	ABSTRACT Didehydro-cortistatin A (dCA) is a human immunodeficiency virus type 1 (HIV-1) Tat inhibitor that functions by selectively binding to the RNA binding domain of Tat. In addition to inhibiting viral replication, dCA can drive HIV-1 into a state of “deep latency” in which latent viruses are refractory to reactivation. Mousseau et al. (G. Mousseau, R. Aneja, M. A. Clementz, S. Mediouni, et al., mBio 10:e01750-18, 2019, https://doi.org/10.1128/mBio.01750-18) have now selected dCA-resistant (dCAr) viruses in vitro. Remarkably, dCAr viruses do not contain mutations in Tat or the viral transactivation-responsive element (TAR) RNA element that is targeted by Tat. Rather, the viruses contain a combination of mutations in the viral long terminal repeat (LTR) and Nef and Vpr proteins that result in an increase in basal RNA polymerase II (Pol II) transcription of integrated HIV-1. Interestingly, dCAr viruses may be deficient in the establishment of latent infection because of their elevated basal Pol II transcription. dCA holds promise for strategies to achieve a functional cure of HIV-1 infection and justifies efforts to develop additional Tat inhibitors.
format	article
author	Andrew P. Rice
author_facet	Andrew P. Rice
author_sort	Andrew P. Rice
title	Unexpected Mutations in HIV-1 That Confer Resistance to the Tat Inhibitor Didehydro-Cortistatin A
title_short	Unexpected Mutations in HIV-1 That Confer Resistance to the Tat Inhibitor Didehydro-Cortistatin A
title_full	Unexpected Mutations in HIV-1 That Confer Resistance to the Tat Inhibitor Didehydro-Cortistatin A
title_fullStr	Unexpected Mutations in HIV-1 That Confer Resistance to the Tat Inhibitor Didehydro-Cortistatin A
title_full_unstemmed	Unexpected Mutations in HIV-1 That Confer Resistance to the Tat Inhibitor Didehydro-Cortistatin A
title_sort	unexpected mutations in hiv-1 that confer resistance to the tat inhibitor didehydro-cortistatin a
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/2155958c270a45ffb27fc1864c1f61ec
work_keys_str_mv	AT andrewprice unexpectedmutationsinhiv1thatconferresistancetothetatinhibitordidehydrocortistatina
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Unexpected Mutations in HIV-1 That Confer Resistance to the Tat Inhibitor Didehydro-Cortistatin A

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