{"doi":"10.3389/fimmu.2025.1628872","title":"Mu opioid receptor activation in microglia enhances HIV-1 infection and HIV-infection-induced inflammatory responses","abstract":"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 p24 Gag 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.","journal":"Frontiers in Immunology","year":2025,"id":534950,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1418090,"name":"Gabriel Sgambettera","orcid":"0009-0000-4172-162X","position":1,"is_corresponding":false},{"id":1246732,"name":"Aldana D. Gojanovich","orcid":null,"position":2,"is_corresponding":false},{"id":406161,"name":"Xianbao He","orcid":"0000-0003-2448-8437","position":3,"is_corresponding":false},{"id":1418577,"name":"D. H. Bryant","orcid":null,"position":4,"is_corresponding":false},{"id":1129950,"name":"Mengwei Yang","orcid":"0000-0002-4775-5406","position":5,"is_corresponding":false},{"id":1418091,"name":"Shreya Banerjee","orcid":"0000-0002-6405-7917","position":6,"is_corresponding":false},{"id":1160189,"name":"Andrés A. Quiñones-Molina","orcid":"0009-0004-4534-0524","position":7,"is_corresponding":false},{"id":331884,"name":"Hisashi Akiyama","orcid":"0000-0001-9228-0465","position":8,"is_corresponding":false},{"id":253657,"name":"Gustavo Mostoslavsky","orcid":"0000-0002-0784-2169","position":9,"is_corresponding":false},{"id":292062,"name":"Andrew J. Henderson","orcid":"0000-0002-9299-5302","position":10,"is_corresponding":false},{"id":69465,"name":"Suryaram Gummuluru","orcid":"0000-0002-8606-8481","position":11,"is_corresponding":false},{"id":1418576,"name":"Chelsey Skeete","orcid":null,"position":0,"is_corresponding":true}],"reference_count":128,"raw_metadata":null,"created_at":"2026-07-19T02:51:52.019261Z","pmid":"41122167","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}