학술논문
Determinants of B-Cell Compartment Hyperactivation in European Adolescents Living With Perinatally Acquired HIV-1 After Over 10 Years of Suppressive Therapy
Document Type
article
Author
Alessandra Ruggiero; Giuseppe Rubens Pascucci; Nicola Cotugno; Sara Domínguez-Rodríguez; Stefano Rinaldi; Alfredo Tagarro; Pablo Rojo; Caroline Foster; Alasdair Bamford; Anita De Rossi; Eleni Nastouli; Nigel Klein; Elena Morrocchi; Benoit Fatou; Kinga K. Smolen; Al Ozonoff; Michela Di Pastena; Katherine Luzuriaga; Hanno Steen; Carlo Giaquinto; Philip Goulder; Paolo Rossi; Ofer Levy; Savita Pahwa; Paolo Palma; the EPIICAL Consortium; Mark Cotton; Shaun Barnabas; Thanyawee Puthanakit; Louise Kuhn; Andrew Yates; Avy Violari; Kennedy Otwombe; Paula Vaz; Maria Grazia Lain; Tacilta Nampossa; Denise Naniche; Sheila Fernandez-Luis; Elisa Lopez; Holly Peay; Moira Spyer; Vincent Calvez; Anne-Genevieve Marcelin; Maria Angeles Munoz; Annalisa Dalzini; Raffaella Petrara; Kathleen Gartner; Lesley De Armas; Pahwa Rajendra; Suresh Pallikkuth; Deborah Persaud; Nicolas Chomont; Mathias Lichterfeld; Silvia Faggion; Daniel Gomez Pena; Andrea Oletto; Alessandra Nardone; Paola Zangari; Silvia Di Cesare; Chiara Medri; Olga Kolesova; Carla Paganin; William James; Inger Lindfors - Rossi; Shrabon Samiur Hassan; Francesca Mazzetto; Hellen Akisinku; Musakanya Chingandu; Francesca Rocchi; Ilaria Pepponi; Rob J. De Boer; Juliane Schroter; Viviana Giannuzzi; Sinead Morris
Source
Frontiers in Immunology, Vol 13 (2022)
Subject
Language
English
ISSN
1664-3224
Abstract
BackgroundDespite 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.MethodsWe studied 40 PHIV who started treatment by the 2nd 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.ResultsPhenotypic 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).ConclusionWe 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.