{"doi":"10.1371/journal.pbio.3003320","title":"Expression of intron-containing HIV-1 RNA induces NLRP1 inflammasome activation in myeloid cells","abstract":"Despite the success of antiretroviral therapy in suppressing plasma viremia in people living with human immunodeficiency virus type-1 (HIV-1), persistent viral RNA expression in tissue reservoirs is observed and can contribute to HIV-1-induced immunopathology and comorbidities. Infection of long-lived innate immune cells, such as tissue-resident macrophages and microglia may contribute to persistent viral RNA production and chronic inflammation. We recently reported that de novo cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) in macrophages and microglia leads to MDA5 and MAVS-dependent innate immune sensing and induction of type I IFN responses, demonstrating that HIV icRNA is a pathogen-associated molecular pattern (PAMP). In this report, we show that cytoplasmic expression of HIV-1 icRNA also induces NLRP1 inflammasome activation and IL-1β secretion in macrophages and microglia in an RLR- and endosomal TLR-independent manner. Infection of both macrophages and microglia with either replication-competent or single-cycle HIV-1 induced IL-1β secretion, which was attenuated when cytoplasmic expression of viral icRNA was prevented. While IL-1β secretion was blocked by treatment with caspase-1 inhibitors or knockdown of NLRP1 or caspase-1 expression in HIV-infected macrophages, overexpression of NLRP1 significantly enhanced IL-1β secretion in an HIV-icRNA-dependent manner. Immunoprecipitation analysis revealed interaction of HIV-1 icRNA, but not multiply-spliced HIV-1 RNA, with NLRP1, suggesting that HIV-1 icRNA sensing by NLRP1 is sufficient to trigger inflammasome activation. Together, these findings reveal a pathway of NLRP1 inflammasome activation induced by de novo expressed HIV icRNA in HIV-infected myeloid cells.","journal":"PLoS Biology","year":2025,"id":524388,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"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":1397890,"name":"I A Hughes","orcid":"0000-0002-8769-4011","position":1,"is_corresponding":false},{"id":331884,"name":"Hisashi Akiyama","orcid":"0000-0001-9228-0465","position":2,"is_corresponding":false},{"id":1246732,"name":"Aldana D. Gojanovich","orcid":null,"position":3,"is_corresponding":false},{"id":1160189,"name":"Andrés A. Quiñones-Molina","orcid":"0009-0004-4534-0524","position":4,"is_corresponding":false},{"id":1129950,"name":"Mengwei Yang","orcid":"0000-0002-4775-5406","position":5,"is_corresponding":false},{"id":292062,"name":"Andrew J. Henderson","orcid":"0000-0002-9299-5302","position":6,"is_corresponding":false},{"id":253657,"name":"Gustavo Mostoslavsky","orcid":"0000-0002-0784-2169","position":7,"is_corresponding":false},{"id":69465,"name":"Suryaram Gummuluru","orcid":"0000-0002-8606-8481","position":8,"is_corresponding":false},{"id":808538,"name":"Sallieu Jalloh","orcid":null,"position":0,"is_corresponding":true}],"reference_count":127,"raw_metadata":null,"created_at":"2026-07-19T02:50:12.083054Z","pmid":"40920844","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":[]}