Frontiers in immunology · 2026
Distinct roles of dopamine receptors in HIV latency reversal in a myeloid cell model.
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Basova Liana V, Riley Tera, Delorme-Walker Violaine, de Siqueira-Lima Daniel, Milner Richard, Ellis Ronald J, Fox Howard, Marcondes Maria Cecilia Garibaldi
Аннотация
BACKGROUND: Currently, studies on the interactions between neurotransmitters and immune cells that are targets of HIV are limited by a focus on single pathways at a time. The latent myeloid reservoir cells in the brain are a source of virus responsive to changes in the levels of dopamine (DA), caused by stimulant drugs such as methamphetamine (Meth), which, in part, explains the poor control of brain viral load in models of chronic Meth exposure. Among the effects of DA, HIV latency reversal is observed in a proportion of latent cells that turn on the transcription of viral genes. In this study, our goal was to define the specific DA receptors and pathways involved in latency reversal by DA, under the hypothesis that downstream effects of DA activating HIV transcription can be learned and serve as targets for future therapeutic purposes.
METHODS: We focused on DA receptor (DRD)1 and DRD4, using the selective agonists SKF38393 hydrobromide and PD168077 maleate, which, like DA, increased levels of p24 in culture supernatants. A single-cell approach identified cells and enriched phenotypes associated with positive transcription of HIV genes.
RESULTS: Interestingly, we found very little overlap between DA and the individual receptor clusters, pathways, and upstream regulators, while the two receptors exhibited higher phenotypic cluster similarities and a higher number of perturbed genes indicating cross-regulation. Yet, between conditions, different pathways were convergent in isolated signatures and by their overall involvement in inflammation.
DISCUSSION: While Meth was a major contextual motivation for this work, the implications of these findings extend beyond stimulant use disorders, indicating that neuroimmune interactions are complex with resulting phenotypes derived from a combination of signaling pathways. The results suggest that latency reversal by DA in myeloid targets, especially in the brain, can occur with the contribution of DRDs' signaling via a diversity of inflammatory pathways that have cell activation as a common feature.
METHODS: We focused on DA receptor (DRD)1 and DRD4, using the selective agonists SKF38393 hydrobromide and PD168077 maleate, which, like DA, increased levels of p24 in culture supernatants. A single-cell approach identified cells and enriched phenotypes associated with positive transcription of HIV genes.
RESULTS: Interestingly, we found very little overlap between DA and the individual receptor clusters, pathways, and upstream regulators, while the two receptors exhibited higher phenotypic cluster similarities and a higher number of perturbed genes indicating cross-regulation. Yet, between conditions, different pathways were convergent in isolated signatures and by their overall involvement in inflammation.
DISCUSSION: While Meth was a major contextual motivation for this work, the implications of these findings extend beyond stimulant use disorders, indicating that neuroimmune interactions are complex with resulting phenotypes derived from a combination of signaling pathways. The results suggest that latency reversal by DA in myeloid targets, especially in the brain, can occur with the contribution of DRDs' signaling via a diversity of inflammatory pathways that have cell activation as a common feature.