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Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir

Unbiased shRNA library screens revealed that the estrogen receptor-1 (ESR-1) is a key factor regulating HIV-1 latency. In both Jurkat T cells and a Th17 primary cell model for HIV-1 latency, selective estrogen receptor modulators (SERMs, i.e., fulvestrant, raloxifene, and tamoxifen) are weak provira...

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Autores principales: Das, Biswajit, Dobrowolski, Curtis, Luttge, Benjamin, Valadkhan, Saba, Chomont, Nicolas, Johnston, Rowena, Bacchetti, Peter, Hoh, Rebecca, Gandhi, Monica, Deeks, Steven G., Scully, Eileen, Karn, Jonathan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099847/
https://www.ncbi.nlm.nih.gov/pubmed/30061382
http://dx.doi.org/10.1073/pnas.1803468115
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author Das, Biswajit
Dobrowolski, Curtis
Luttge, Benjamin
Valadkhan, Saba
Chomont, Nicolas
Johnston, Rowena
Bacchetti, Peter
Hoh, Rebecca
Gandhi, Monica
Deeks, Steven G.
Scully, Eileen
Karn, Jonathan
author_facet Das, Biswajit
Dobrowolski, Curtis
Luttge, Benjamin
Valadkhan, Saba
Chomont, Nicolas
Johnston, Rowena
Bacchetti, Peter
Hoh, Rebecca
Gandhi, Monica
Deeks, Steven G.
Scully, Eileen
Karn, Jonathan
author_sort Das, Biswajit
collection PubMed
description Unbiased shRNA library screens revealed that the estrogen receptor-1 (ESR-1) is a key factor regulating HIV-1 latency. In both Jurkat T cells and a Th17 primary cell model for HIV-1 latency, selective estrogen receptor modulators (SERMs, i.e., fulvestrant, raloxifene, and tamoxifen) are weak proviral activators and sensitize cells to latency-reversing agents (LRAs) including low doses of TNF-α (an NF-κB inducer), the histone deacetylase inhibitor vorinostat (soruberoylanilide hydroxamic acid, SAHA), and IL-15. To probe the physiologic relevance of these observations, leukapheresis samples from a cohort of 12 well-matched reproductive-age women and men on fully suppressive antiretroviral therapy were evaluated by an assay measuring the production of spliced envelope (env) mRNA (the EDITS assay) by next-generation sequencing. The cells were activated by T cell receptor (TCR) stimulation, IL-15, or SAHA in the presence of either β-estradiol or an SERM. β-Estradiol potently inhibited TCR activation of HIV-1 transcription, while SERMs enhanced the activity of most LRAs. Although both sexes responded to SERMs and β-estradiol, females showed much higher levels of inhibition in response to the hormone and higher reactivity in response to ESR-1 modulators than males. Importantly, the total inducible RNA reservoir, as measured by the EDITS assay, was significantly smaller in the women than in the men. We conclude that concurrent exposure to estrogen is likely to limit the efficacy of viral emergence from latency and that ESR-1 is a pharmacologically attractive target that can be exploited in the design of therapeutic strategies for latency reversal.
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spelling pubmed-60998472018-08-21 Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir Das, Biswajit Dobrowolski, Curtis Luttge, Benjamin Valadkhan, Saba Chomont, Nicolas Johnston, Rowena Bacchetti, Peter Hoh, Rebecca Gandhi, Monica Deeks, Steven G. Scully, Eileen Karn, Jonathan Proc Natl Acad Sci U S A PNAS Plus Unbiased shRNA library screens revealed that the estrogen receptor-1 (ESR-1) is a key factor regulating HIV-1 latency. In both Jurkat T cells and a Th17 primary cell model for HIV-1 latency, selective estrogen receptor modulators (SERMs, i.e., fulvestrant, raloxifene, and tamoxifen) are weak proviral activators and sensitize cells to latency-reversing agents (LRAs) including low doses of TNF-α (an NF-κB inducer), the histone deacetylase inhibitor vorinostat (soruberoylanilide hydroxamic acid, SAHA), and IL-15. To probe the physiologic relevance of these observations, leukapheresis samples from a cohort of 12 well-matched reproductive-age women and men on fully suppressive antiretroviral therapy were evaluated by an assay measuring the production of spliced envelope (env) mRNA (the EDITS assay) by next-generation sequencing. The cells were activated by T cell receptor (TCR) stimulation, IL-15, or SAHA in the presence of either β-estradiol or an SERM. β-Estradiol potently inhibited TCR activation of HIV-1 transcription, while SERMs enhanced the activity of most LRAs. Although both sexes responded to SERMs and β-estradiol, females showed much higher levels of inhibition in response to the hormone and higher reactivity in response to ESR-1 modulators than males. Importantly, the total inducible RNA reservoir, as measured by the EDITS assay, was significantly smaller in the women than in the men. We conclude that concurrent exposure to estrogen is likely to limit the efficacy of viral emergence from latency and that ESR-1 is a pharmacologically attractive target that can be exploited in the design of therapeutic strategies for latency reversal. National Academy of Sciences 2018-08-14 2018-07-30 /pmc/articles/PMC6099847/ /pubmed/30061382 http://dx.doi.org/10.1073/pnas.1803468115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Das, Biswajit
Dobrowolski, Curtis
Luttge, Benjamin
Valadkhan, Saba
Chomont, Nicolas
Johnston, Rowena
Bacchetti, Peter
Hoh, Rebecca
Gandhi, Monica
Deeks, Steven G.
Scully, Eileen
Karn, Jonathan
Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir
title Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir
title_full Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir
title_fullStr Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir
title_full_unstemmed Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir
title_short Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir
title_sort estrogen receptor-1 is a key regulator of hiv-1 latency that imparts gender-specific restrictions on the latent reservoir
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099847/
https://www.ncbi.nlm.nih.gov/pubmed/30061382
http://dx.doi.org/10.1073/pnas.1803468115
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