ORIGINAL RESEARCH article
Front. Immunol.
Sec. Viral Immunology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1628872
Mu Opioid Receptor Activation in Microglia Enhances HIV-1 Infection and HIV-infection-induced inflammatory responses
Provisionally accepted
Chelsey Skeete1
Gabriel Sgambettera1Aldana Gojanovich1Xianbao He2
Daniel Bryant2Mengwei Yang1Shreya Banjeree1
Andrés A Quiñones-Molina1
Hisashi Akiyama1
Gustavo Mostoslavsky1
Andrew J Henderson1
Suryaram Gummuluru1*- 1Chobanian & Avedisian School of Medicine, Boston University, Boston, United States
- 2BMC, Boston, United States
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People living with HIV-1 (PWH) and chronically using opioids have elevated risks of developing HIV-associated neurological disorders (HAND) that are often correlated with persistent inflammation. Microglia, innate immune cells in the brain, are the principal HIV-1 reservoir in the central nervous system and regulate neuroinflammation. Our group previously showed that HIV-1 infection of induced pluripotent stem cell (iPSC)-derived microglia and viral intron-containing RNA (icRNA) expression triggers inflammatory responses. Microglia express μ opioid receptor, MOR, yet the immunomodulatory effects of opioids on HIV-1 infection in microglia are unclear. Here, we report that MOR activation impacts HIV-1 infection establishment and HIV-1-induced innate responses in microglia. Morphine pretreatment enhanced reverse transcription (RT), integration, viral transcription, and p24Gag secretion in HIV-1-infected iPSC-derived microglia, which was blocked by treatment with naloxone, a MOR antagonist. In contrast, morphine treatment did not impact HIV-1 infection in MOR-deficient monocyte-derived macrophages, although, induced exogenous expression of MOR in macrophages conferred morphine-mediated enhancement of HIV-1 infection. Interestingly, viral transcriptome analysis by digital-drop PCR revealed selective enhancement of HIV-1 icRNA expression in morphine-exposed iPSC-derived microglia, which correlated with enhanced HIV-1 icRNA-induced secretion of IP-10 in MOR+ cells. Further, PI3K inhibitor, wortmannin, blocked morphine-mediated enhancement of HIV-1 replication and HIV-1 icRNA-induced IP-10 secretion, suggesting that MOR signaling and HIV-1 icRNA expression synergistically activate the PI3K-Akt signaling pathway in microglia to exacerbate virus-induced inflammatory responses.
Keywords: HIV-1, Opioids, Inflammation, Microglia, µ-opioid receptor
Received: 14 May 2025; Accepted: 22 Sep 2025.
Copyright: © 2025 Skeete, Sgambettera, Gojanovich, He, Bryant, Yang, Banjeree, Quiñones-Molina, Akiyama, Mostoslavsky, Henderson and Gummuluru. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Suryaram Gummuluru, rgummulu@bu.edu
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