{"doi":"10.3389/fimmu.2021.757843","title":"Dynamics of T-Lymphocyte Activation Related to Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in Persons With Advanced HIV","abstract":"Most persons living with HIV (PLWH) experience a significant restoration of their immunity associated with successful inhibition of viral replication after antiretroviral therapy (ART) initiation. Nevertheless, with the robust quantitative and qualitative restoration of CD4 + T-lymphocytes, a fraction of patients co-infected with tuberculosis develop immune reconstitution inflammatory syndrome (TB-IRIS), a dysregulated inflammatory response that can be associated with significant tissue damage. Several studies underscored the role of adaptive immune cells in IRIS pathogenesis, but to what degree T lymphocyte activation contributes to TB-IRIS development remains largely elusive. Here, we sought to dissect the phenotypic landscape of T lymphocyte activation in PLWH coinfected with TB inititating ART, focusing on characterization of the profiles linked to development of TB-IRIS. We confirmed previous observations demonstrating that TB-IRIS individuals display pronounced CD4 + lymphopenia prior to ART initiation. Additionally, we found an ART-induced increase in T lymphocyte activation, proliferation and cytotoxicity among TB-IRIS patients. Importantly, we demonstrate that TB-IRIS subjects display higher frequencies of cytotoxic CD8 + T lymphocytes which is not affected by ART. Moreover, These patients exhibit higher levels of activated (HLA-DR + ) and profilerative (Ki-67 + ) CD4 + T cells after ART commencenment than their Non-IRIS counterparts. Our network analysis reveal significant negative correlations between Total CD4 + T cells counts and the frequencies of Cytotoxic CD8 + T cells in our study population which could suggest the existance of compensatory mechanisms for Mtb-infected cells elimination in the face of severe CD4 + T cell lymphopenia. We also investigated the correlation between T lymphocyte activation profiles and the abundance of several inflammatory molecules in plasma. We applied unsupervised machine learning techniques to predict and diagnose TB-IRIS before and during ART. Our analyses suggest that CD4 + T cell activation markers are good TB-IRIS predictors, whereas the combination of CD4 + and CD8 + T cells markers are better at diagnosing TB-IRIS patients during IRIS events Overall, our findings contribute to a more refined understanding of immunological mechanisms in TB-IRIS pathogenesis that may assist in new diagnostic tools and more targeted patient management.","journal":"Frontiers in Immunology","year":2021,"id":189416,"datarank":0.6720504323811173,"base_score":2.772588722239781,"endowment":2.772588722239781,"self_citation_contribution":0.41588830833596724,"citation_network_contribution":0.25616212404515004,"self_endowment_contribution":0.41588830833596724,"citer_contribution":0.25616212404515004,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":12,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT00933790"]},"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":517545,"name":"Beatriz Barreto‐Duarte","orcid":"0000-0002-9901-8328","position":1,"is_corresponding":false},{"id":752747,"name":"Gopolan Naredren","orcid":null,"position":2,"is_corresponding":false},{"id":382615,"name":"Artur T. L. Queiroz","orcid":"0000-0003-4908-9993","position":3,"is_corresponding":false},{"id":752748,"name":"Anbalagan Selvaraj","orcid":null,"position":4,"is_corresponding":false},{"id":372003,"name":"Kaustuv Nayak","orcid":"0000-0002-7898-0294","position":5,"is_corresponding":false},{"id":752749,"name":"Narayanan Ravichandran","orcid":null,"position":6,"is_corresponding":false},{"id":752750,"name":"Rajasekaran Subramani","orcid":null,"position":7,"is_corresponding":false},{"id":672968,"name":"Lis Ribeiro do Valle Antonelli","orcid":"0000-0002-4969-8812","position":8,"is_corresponding":false},{"id":752751,"name":"Kumar Satagopan","orcid":null,"position":9,"is_corresponding":false},{"id":752752,"name":"Komathi Anbalagan","orcid":null,"position":10,"is_corresponding":false},{"id":752753,"name":"Brian Porter","orcid":null,"position":11,"is_corresponding":false},{"id":330710,"name":"Alan Sher","orcid":"0000-0001-7053-2895","position":12,"is_corresponding":false},{"id":22837,"name":"Soumya Swaminathan","orcid":"0009-0004-2233-7250","position":13,"is_corresponding":false},{"id":241760,"name":"Irini Sereti","orcid":"0000-0002-0076-0224","position":14,"is_corresponding":false},{"id":252301,"name":"Bruno B. Andrade","orcid":"0000-0001-6833-3811","position":15,"is_corresponding":false},{"id":335546,"name":"Rafael Tibúrcio","orcid":null,"position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-18T23:49:18.604374Z","pmid":"34691079","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":[]}