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

Biswajit Das, Curtis Dobrowolski, Benjamin Luttge, Saba Valadkhan, Nicolas Chomont, Rowena Johnston, Peter Bacchetti, Rebecca Hoh, Monica Gandhi, Steven G. Deeks, Eileen Scully, Jonathan Karn

Research output: Contribution to journalArticle

Abstract

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 phar-macologically attractive target that can be exploited in the design of therapeutic strategies for latency reversal.

Original languageEnglish (US)
Pages (from-to)E7795-E7804
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number33
DOIs
Publication statusPublished - Aug 14 2018

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Keywords

  • Estrogen receptor
  • HIV-1 latency
  • HIV-1 reservoir
  • Latency-reversing agents
  • Selective estrogen receptor modulators

ASJC Scopus subject areas

  • General

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