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

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, Andrew Yates, Sinead Morris

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. We 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. 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). 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.