{"doi":"10.1172/jci187663","title":"The macrophage-intrinsic MDA5/IRF5 axis drives HIV-1 intron-containing RNA-induced inflammatory responses","abstract":"Despite effective antiretroviral therapy, transcriptionally competent HIV-1 reservoirs remain and contribute to persistent immune activation in people living with HIV (PWH). HIV-1-infected macrophages are important mediators of chronic innate immune activation, though the mechanisms remain unclear. We previously reported that nuclear export and cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) activates mitochondrial antiviral signaling (MAVS) protein-mediated type I IFN responses in macrophages. In this study, we demonstrate an essential role of melanoma differentiation-associated protein 5 (MDA5) in sensing HIV-1 icRNA and promoting MAVS-dependent interferon regulatory factor 5 (IRF5) activation in macrophages. Suppression of MDA5 but not retinoic acid-inducible gene I expression nor disruption of the endosomal TLR pathway abrogated HIV-1 icRNA-induced type I IFN responses and IP-10 expression in macrophages. Furthermore, induction of IP-10 in macrophages upon HIV-1 icRNA sensing by MDA5 was dependent on IRF5. Additionally, monocytes and monocyte-derived macrophages (MDMs) from older (>50 years) individuals exhibited constitutively higher levels of IRF5 expression compared with younger (<35 years) individuals, and HIV-1 icRNA-induced IP-10 expression was significantly enhanced in older macrophages, which was attenuated upon ablation of IRF5 expression, suggesting that IRF5 functions as a major mediator of proinflammatory response downstream of MDA5-dependent HIV-1 icRNA sensing, dysregulation of which might contribute to chronic inflammation in older PWH.","journal":"Journal of Clinical Investigation","year":2025,"id":530779,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"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":331884,"name":"Hisashi Akiyama","orcid":"0000-0001-9228-0465","position":1,"is_corresponding":false},{"id":551221,"name":"Jacob Berrigan","orcid":null,"position":2,"is_corresponding":false},{"id":1160189,"name":"Andrés A. Quiñones-Molina","orcid":"0009-0004-4534-0524","position":3,"is_corresponding":false},{"id":296035,"name":"Alex Olson","orcid":"0000-0002-3371-3213","position":4,"is_corresponding":false},{"id":242994,"name":"Yunhan Chen","orcid":"0000-0002-6891-6715","position":5,"is_corresponding":false},{"id":519030,"name":"Yanmei Liang","orcid":"0000-0002-8846-391X","position":6,"is_corresponding":false},{"id":292062,"name":"Andrew J. Henderson","orcid":"0000-0002-9299-5302","position":7,"is_corresponding":false},{"id":446832,"name":"Archana Asundi","orcid":"0000-0003-3910-909X","position":8,"is_corresponding":false},{"id":231606,"name":"Manish Sagar","orcid":"0000-0001-9803-6594","position":9,"is_corresponding":false},{"id":69465,"name":"Suryaram Gummuluru","orcid":"0000-0002-8606-8481","position":10,"is_corresponding":false},{"id":863190,"name":"Sita Ramaswamy","orcid":"0000-0003-1479-6954","position":0,"is_corresponding":true}],"reference_count":113,"raw_metadata":null,"created_at":"2026-07-19T02:51:10.077559Z","pmid":"40493408","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":[]}