In the current study, scientists from Case Western Reserve University investigated potential targets for new therapies for HIV-infected patients who could develop HIV-associated neurocognitive disorders (HAND). Due to microglial cells’ life span and ability to support the HIV replication, microglial cells could continue to latently carry the virus in human patients. This is cause for concern because the inflammation-prone environment of the brain is prone to induce the reactivation of transcription in HIV-infected microglial cells, as was discussed by the authors previously (here). To target the factors that triggered HIV reactivation (and more broadly the origin of HAND), researchers investigated Nerve Growth Factor IB-like nuclear receptor Nurr1’s role in silencing active HIV within microglia.
HIV-infected Microglial Cells Significance – A Recap
As previously mentioned, microglial cells are viable hosts of HIV-infection due to their ability to maintain latent infections. In this study, it was discovered that reactivation of HIV is related to central nervous system (CNS) inflammation rather than viral load. When inflammation occurs, consequential neuronal damage alters the ability of microglial cells to silence HIV. In other words, healthy neurons and neurotransmitters activate microglia to induce HIV-silencing, while inflammation-damaged neurons induce HIV expression in microglia. This demonstrates the importance of exploring therapeutics able to target genes that will silence HIV expression.
Researchers investigated Nurr1 (also known as NR4A2), which is a Nerve Growth Factor IB-like receptor that is proposed to mediate HIV silencing in microglial cells. Nerve Growth Factor IB-like nuclear receptors are critical in protecting neurons from neurodegenerative diseases. More specifically, these nuclear receptors function as negative transcriptional regulators in microglia cells.
What did researchers find?
This paper’s findings suggested that Nurr1 agonists have the potential to induce HIV silencing and microglial homeostasis. Nurr1 agonists were plated with iPSC-derived microglial (Tempo-iMG™) cells that enhanced HIV-silencing by targeting specific receptors in real-time. Furthermore, overexpression of Nurr1 caused silencing, while the knockdown of Nurr1 blocked silencing.
Why are these results significant?
These results are significant because new therapies could be developed to specifically target and enhance Nurr1 receptor function which would aid HIV patients with HAND. 6-MP and AQ, Nurr1 agonists, deactivate HIV-infected microglial cells and protect dopaminergic neurons. Future studies are necessary to investigate whether additional Nurr1 agonists have similar effects on HIV infected microglia.
Where does Tempo-iMG™ fit in? Why is this relevant?
To test that Nurr1 was critical for HIV silencing, researchers utilized Tempo-iMG™ cells, which are reprogrammed from human iPSCs. In this study, iMG cells were effectively infected with HIV and therefore demonstrated the effectiveness of Nurr1 agonists. These cells were also infected with EGFP HIV-1 reporter virus and then treated with 6-MP and amodiaquine (AQ), two Nurr1 agonists. After treatment, the number of infected cells decreased and the level of HIV-unspliced transcripts also decreased, which suggested that the Nurr1 agonists silenced active HIV transcription. Immortalized cell lines, as opposed to iMG, did not accurately reflect phenotypes found in human cell models.
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