{"doi":"10.3389/fimmu.2021.785905","title":"Attenuated Negative Feedback in Monocyte-Derived Macrophages From Persons Living With HIV: A Role for IKAROS","abstract":"Persons living with HIV (PLWH) are at higher risk of developing secondary illnesses than their uninfected counterparts, suggestive of a dysfunctional immune system in these individuals. Upon exposure to pathogens, monocytes undergo epigenetic remodeling that results in either a trained or a tolerant phenotype, characterized by hyper-responsiveness or hypo-responsiveness to secondary stimuli, respectively. We utilized CD14 + monocytes from virally suppressed PLWH and healthy controls for in vitro analysis following polarization of these cells toward a pro-inflammatory monocyte-derived macrophage (MDM) phenotype. We found that in PLWH-derived MDMs, pro-inflammatory signals ( TNFA , IL6 , IL1B , miR-155-5p, and IDO1 ) dominate over negative feedback signals ( NCOR2 , GSN , MSC , BIN1 , and miR-146a-5p), favoring an abnormally trained phenotype. The mechanism of this reduction in negative feedback involves the attenuated expression of IKZF1, a transcription factor required for de novo synthesis of RELA during LPS-induced inflammatory responses. Furthermore, restoring IKZF1 expression in PLWH-MDMs partially reinstated expression of negative regulators of inflammation and lowered the expression of pro-inflammatory cytokines. Overall, this mechanism may provide a link between dysfunctional immune responses and susceptibility to co-morbidities in PLWH with low or undetectable viral load.","journal":"Frontiers in Immunology","year":2021,"id":203984,"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":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":680336,"name":"Karlie Plaisance‐Bonstaff","orcid":"0000-0002-4623-4596","position":1,"is_corresponding":false},{"id":786286,"name":"Cecilia Vittori","orcid":null,"position":2,"is_corresponding":false},{"id":640734,"name":"Dorota Wyczechowska","orcid":"0000-0002-8940-6861","position":3,"is_corresponding":false},{"id":786287,"name":"Adam Lassak","orcid":null,"position":4,"is_corresponding":false},{"id":786288,"name":"Mary Meyaski‐Schluter","orcid":null,"position":5,"is_corresponding":false},{"id":509673,"name":"Krzysztof Reiss","orcid":"0000-0002-2342-2973","position":6,"is_corresponding":false},{"id":785760,"name":"Francesca Peruzzi","orcid":"0000-0002-9441-2174","position":7,"is_corresponding":false},{"id":786285,"name":"Celeste Faia","orcid":null,"position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-18T23:51:22.166488Z","pmid":"34917094","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":[]}