{"doi":"10.3389/fimmu.2021.601298","title":"Long Non-coding RNA GAS5 Regulates T Cell Functions via miR21-Mediated Signaling in People Living With HIV","abstract":"T cells are critical for the control of viral infections and T cell responses are regulated by a dynamic network of non-coding RNAs, including microRNAs (miR) and long non-coding RNAs (lncRNA). Here we show that an activation-induced decline of lncRNA growth arrest-specific transcript 5 (GAS5) activates DNA damage response (DDR), and regulates cellular functions and apoptosis in CD4 T cells derived from people living with HIV (PLHIV) via upregulation of miR-21. Notably, GAS5-miR21-mediated DDR and T cell dysfunction are observed in PLHIV on antiretroviral therapy (ART), who often exhibit immune activation due to low-grade inflammation despite robust virologic control. We found that GAS5 negatively regulates miR-21 expression, which in turn controls critical signaling pathways involved in DNA damage and cellular response. The sustained stimulation of T cells decreased GAS5, increased miR-21 and, as a result, caused dysfunction and apoptosis in CD4 T cells. Importantly, this inflammation-driven T cell over-activation and aberrant apoptosis in ART-controlled PLHIV and healthy subjects (HS) could be reversed by antagonizing the GAS5-miR-21 axis. Also, mutation of the miR-21 binding site on exon 4 of GAS5 gene to generate a GAS5 mutant abolished its ability to regulate miR-21 expression as well as T cell activation and apoptosis markers compared to the wild-type GAS5 transcript. Our data suggest that GAS5 regulates TCR-mediated activation and apoptosis in CD4 T cells during HIV infection through miR-21-mediated signaling. However, GAS5 effects on T cell exhaustion during HIV infection may be mediated by a mechanism beyond the GAS5-miR-21-mediated signaling. These results indicate that targeting the GAS5-miR-21 axis may improve activity and longevity of CD4 T cells in ART-treated PLHIV. This approach may also be useful for targeting other infectious or inflammatory diseases associated with T cell over-activation, exhaustion, and premature immune aging.","journal":"Frontiers in Immunology","year":2021,"id":163283,"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":42,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"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":336316,"name":"Lam Nhat Nguyen","orcid":"0000-0002-8419-8354","position":1,"is_corresponding":false},{"id":336312,"name":"Juan Zhao","orcid":"0000-0002-1809-3124","position":2,"is_corresponding":false},{"id":336311,"name":"Madison Schank","orcid":"0000-0001-9017-3180","position":3,"is_corresponding":false},{"id":338131,"name":"Xindi Dang","orcid":null,"position":4,"is_corresponding":false},{"id":336315,"name":"Dechao Cao","orcid":"0000-0001-5038-1807","position":5,"is_corresponding":false},{"id":336317,"name":"Sushant Khanal","orcid":"0000-0001-8028-6034","position":6,"is_corresponding":false},{"id":336318,"name":"Bal Krishna Chand Thakuri","orcid":"0000-0003-3768-279X","position":7,"is_corresponding":false},{"id":336320,"name":"Zeyuan Lu","orcid":"0000-0003-4572-6289","position":8,"is_corresponding":false},{"id":350576,"name":"Jinyu Zhang","orcid":"0009-0005-8571-9368","position":9,"is_corresponding":false},{"id":336314,"name":"Zhengke Li","orcid":"0000-0001-5560-343X","position":10,"is_corresponding":false},{"id":338134,"name":"Zheng D. Morrison","orcid":null,"position":11,"is_corresponding":false},{"id":338133,"name":"Xiao Y. Wu","orcid":null,"position":12,"is_corresponding":false},{"id":338135,"name":"Mohamed El Gazzar","orcid":null,"position":13,"is_corresponding":false},{"id":336322,"name":"Shunbin Ning","orcid":"0000-0001-5484-5779","position":14,"is_corresponding":false},{"id":336313,"name":"Ling Wang","orcid":"0000-0001-7861-2769","position":15,"is_corresponding":false},{"id":336323,"name":"Jonathan P. Moorman","orcid":"0000-0002-6102-6541","position":16,"is_corresponding":false},{"id":336324,"name":"Zhi Q. 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