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• W4284697893 endingPage "e1010110" @default.
• W4284697893 startingPage "e1010110" @default.
• W4284697893 abstract "Human immune deficiency virus (HIV) infection in the brain leads to chronic neuroinflammation due to the production of pro-inflammatory cytokines, which in turn promotes HIV transcription in infected microglial cells. However, powerful counteracting silencing mechanisms in microglial cells result in the rapid shutdown of HIV expression after viral reactivation to limit neuronal damage. Here we investigated whether the Nerve Growth Factor IB-like nuclear receptor Nurr1 (NR4A2), which is a repressor of inflammation in the brain, acts directly to restrict HIV expression. HIV silencing following activation by TNF-α, or a variety of toll-like receptor (TLR) agonists, in both immortalized human microglial cells (hμglia) and induced pluripotent stem cells (iPSC)-derived human microglial cells (iMG) was enhanced by Nurr1 agonists. Similarly, overexpression of Nurr1 led to viral suppression, while conversely, knock down (KD) of endogenous Nurr1 blocked HIV silencing. The effect of Nurr1 on HIV silencing is direct: Nurr1 binds directly to the specific consensus binding sites in the U3 region of the HIV LTR and mutation of the Nurr1 DNA binding domain blocked its ability to suppress HIV-1 transcription. Chromatin immunoprecipitation (ChIP) assays also showed that after Nurr1 binding to the LTR, the CoREST/HDAC1/G9a/EZH2 transcription repressor complex is recruited to the HIV provirus. Finally, transcriptomic studies demonstrated that in addition to repressing HIV transcription, Nurr1 also downregulated numerous cellular genes involved in inflammation, cell cycle, and metabolism, further promoting HIV latency and microglial homoeostasis. Nurr1 therefore plays a pivotal role in modulating the cycles of proviral reactivation by potentiating the subsequent proviral transcriptional shutdown. These data highlight the therapeutic potential of Nurr1 agonists for inducing HIV silencing and microglial homeostasis and ultimately for the amelioration of the neuroinflammation associated with HIV-associated neurocognitive disorders (HAND)." @default.
• W4284697893 created "2022-07-08" @default.
• W4284697893 creator A5009610277 @default.
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• W4284697893 creator A5028081311 @default.
• W4284697893 creator A5030223113 @default.
• W4284697893 creator A5048275392 @default.
• W4284697893 creator A5049581015 @default.
• W4284697893 creator A5068034550 @default.
• W4284697893 date "2022-07-07" @default.
• W4284697893 modified "2023-09-30" @default.
• W4284697893 title "Recruitment of the CoREST transcription repressor complexes by Nerve Growth factor IB-like receptor (Nurr1/NR4A2) mediates silencing of HIV in microglial cells" @default.
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