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

Abstract

SignificanceThe molecular mechanisms leading to the creation and maintenance of the latent HIV reservoir remain incompletely understood. Unbiased shRNA screens showed that the estrogen receptor acts as a potent repressor of proviral reactivation in T cells. Antagonists of ESR-1 activate latent HIV-1 proviruses while agonists, including β-estradiol, potently block HIV reactivation. Using a well-matched set of male and female donors, we found that ESR-1 plays an important role in regulating HIV transcription in both sexes. However, women are much more responsive to estrogen and appear to harbor smaller inducible RNA reservoirs. Accounting for the impact of estrogen on HIV viral reservoirs will therefore be critical for devising curative therapies for women, a group representing 51% of global HIV infections.

Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

“…We observed an enrichment of proteins coordinating RNA transport/quality control, DNA replication, and the cell cycle, all of which are important for the reactivation of HIV-1 (64,65). Importantly, levels of estrogen signaling proteins involved in induction of mitochondrial ROS and HIV-1 reactivation are enriched in M. tuberculosis exosomes (66,67). HIF-1 signaling plays an important role in HIV-1 pathogenesis by facilitating viral replication and promoting lymphocyte and macrophage-mediated inflammatory responses (68).…”

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

“…It has been further demonstrated by several groups, including ours, that targeting a single mechanism might not be efficient enough to reactivate the majority of latent proviruses and that combinations of LRAs acting on several HIV-1 silencing molecular mechanisms are needed to obtain synergistic viral reactivations and achieve a more significant decrease in the size of the reservoirs (Reuse et al, 2009;Bouchat et al, 2012Bouchat et al, , 2016Darcis et al, 2015;Jiang et al, 2015;Laird et al, 2015;Pache et al, 2015;Tripathy et al, 2015;Abdel-Mohsen et al, 2016;Chen et al, 2017;Rochat et al, 2017;Das et al, 2018). Moreover, when LRAs are used in combination, lower concentrations are effective, thereby reducing the toxicity of each LRA.…”

Histone deacetylase inhibitors induce complex host responses that contribute to differential potencies of these compounds in HIV reactivation

“…The ESR1 gene encoding estrogen receptor 1 was down-regulated by RMD 24.3-fold, by TCR 25.6-fold, and much less strongly by SAHA (8-fold). ESR1 is required to maintain HIV provirus in a latent state (27); thus, its down-regulation by these treatments probably represents one of the secondary mechanisms of action by which latency is reversed. Interestingly, among genes modulated by RMD and not by SAHA, 17 were found to be members of the estrogen signaling pathway, consistent with the possibility that the specific effect on this pathway contributes to greater potency of RMD, compared with SAHA.…”