Frontiers in Immunology (Mar 2022)

Determinants of B-Cell Compartment Hyperactivation in European Adolescents Living With Perinatally Acquired HIV-1 After Over 10 Years of Suppressive Therapy

  • Alessandra Ruggiero,
  • Alessandra Ruggiero,
  • Giuseppe Rubens Pascucci,
  • Giuseppe Rubens Pascucci,
  • Nicola Cotugno,
  • Nicola Cotugno,
  • Sara Domínguez-Rodríguez,
  • Sara Domínguez-Rodríguez,
  • Stefano Rinaldi,
  • Alfredo Tagarro,
  • Alfredo Tagarro,
  • Alfredo Tagarro,
  • Alfredo Tagarro,
  • Pablo Rojo,
  • Pablo Rojo,
  • Caroline Foster,
  • Alasdair Bamford,
  • Alasdair Bamford,
  • Alasdair Bamford,
  • Anita De Rossi,
  • Anita De Rossi,
  • Eleni Nastouli,
  • Nigel Klein,
  • Elena Morrocchi,
  • Benoit Fatou,
  • Benoit Fatou,
  • Benoit Fatou,
  • Kinga K. Smolen,
  • Kinga K. Smolen,
  • Al Ozonoff,
  • Al Ozonoff,
  • Michela Di Pastena,
  • Michela Di Pastena,
  • Katherine Luzuriaga,
  • Hanno Steen,
  • Hanno Steen,
  • Hanno Steen,
  • Carlo Giaquinto,
  • Philip Goulder,
  • Paolo Rossi,
  • Paolo Rossi,
  • Ofer Levy,
  • Ofer Levy,
  • Savita Pahwa,
  • Paolo Palma,
  • 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,
  • Andrew Yates,
  • Sinead Morris

DOI
https://doi.org/10.3389/fimmu.2022.860418
Journal volume & issue
Vol. 13

Abstract

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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.

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