{"doi":"10.3389/fimmu.2022.860418","title":"Determinants of B-Cell Compartment Hyperactivation in European Adolescents Living With Perinatally Acquired HIV-1 After Over 10 Years of Suppressive Therapy","abstract":"Background: Despite a successful antiretroviral therapy (ART), adolescents living with perinatally acquired HIV (PHIV) experience signs of B-cell hyperactivation with expansion of 'namely' atypical B-cell phenotypes, including double negative (CD27-IgD-) and termed age associated (ABCs) B-cells (T-bet+CD11c+), which may result in reduced cell functionality, including loss of vaccine-induced immunological memory and higher risk of developing B-cells associated tumors. In this context, perinatally HIV infected children (PHIV) deserve particular attention, given their life-long exposure to chronic immune activation. Methods: year of life and maintained virological suppression for 13.5 years, with 5/40 patients experiencing transient elevation of the HIV-1 load in the plasma (Spike). We applied a multi-disciplinary approach including immunological B and T cell phenotype, plasma proteomics analysis, and serum level of anti-measles antibodies as functional correlates of vaccine-induced immunity. Results: Phenotypic signs of B cell hyperactivation were elevated in subjects starting ART later (%DN T-bet+CD11c+ p=0.03; %AM T-bet+CD11c+ p=0.02) and were associated with detectable cell-associated HIV-1 RNA (%AM T-bet+CD11c+ p=0.0003) and transient elevation of the plasma viral load (spike). Furthermore, B-cell hyperactivation appeared to be present in individuals with higher frequency of exhausted T-cells, in particular: %CD4 TIGIT+ were associated with %DN (p=0.008), %DN T-bet+CD11c+ (p=0.0002) and %AM T-bet+CD11c+ (p=0.002) and %CD4 PD-1 were associated with %DN (p=0.048), %DN T-bet+CD11c+ (p=0.039) and %AM T-bet+CD11c+ (p=0.006). The proteomic analysis revealed that subjects with expansion of these atypical B-cells and exhausted T-cells had enrichment of proteins involved in immune inflammation and complement activation pathways. Furthermore, we observed that higher levels of ABCs were associated a reduced capacity to maintain vaccine-induced antibody immunity against measles (%B-cells CD19+CD10- T-bet+, p=0.035). Conclusion: We identified that the levels of hyperactivated B cell subsets were strongly affected by time of ART start and associated with clinical, viral, cellular and plasma soluble markers. Furthermore, the expansion of ABCs also had a direct impact on the capacity to develop antibodies response following routine vaccination.","journal":"Frontiers in Immunology","year":2022,"id":271709,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":380955,"name":"Giuseppe Rubens Pascucci","orcid":"0000-0002-5978-1193","position":1,"is_corresponding":false},{"id":380953,"name":"Nicola Cotugno","orcid":"0000-0002-7748-1581","position":2,"is_corresponding":false},{"id":724406,"name":"Sara Domínguez‐Rodríguez","orcid":"0000-0003-3747-9265","position":3,"is_corresponding":false},{"id":522232,"name":"Stefano Rinaldi","orcid":"0000-0002-1499-4435","position":4,"is_corresponding":false},{"id":724407,"name":"Alfredo Tagarro","orcid":"0000-0003-2860-3455","position":5,"is_corresponding":false},{"id":724408,"name":"Pablo Rojo","orcid":"0000-0002-0197-5462","position":6,"is_corresponding":false},{"id":438212,"name":"Caroline Foster","orcid":"0000-0001-8278-8564","position":7,"is_corresponding":false},{"id":82211,"name":"Alasdair Bamford","orcid":"0000-0003-4764-229X","position":8,"is_corresponding":false},{"id":724410,"name":"Anita De Rossi","orcid":"0000-0001-6435-7509","position":9,"is_corresponding":false},{"id":576181,"name":"Eleni Nastouli","orcid":"0000-0002-1684-2013","position":10,"is_corresponding":false},{"id":80427,"name":"Nigel Klein","orcid":null,"position":11,"is_corresponding":false},{"id":522230,"name":"Francesca Rocchi","orcid":"0000-0002-4255-0823","position":12,"is_corresponding":false},{"id":109108,"name":"Benoit Fatou","orcid":"0000-0003-0317-0243","position":13,"is_corresponding":false},{"id":266216,"name":"Kinga K. 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