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

31 Pages Posted: 19 Nov 2021

See all articles by Alessandra Ruggiero

Alessandra Ruggiero

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO); University of Verona - Department of Neurosciences, Biomedicine and Movement Sciences

Giuseppe Rubens Pascucci

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO)

Nicola Cotugno

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO)

Sara Domínguez-Rodríguez

Instituto de Investigación 12 de Octubre (imas12) - Pediatric Infectious Diseases Unit

Stefano Rinaldi

University of Miami - Department of Microbiology and Immunology

Alfredo Tagarro

Universidad Europea de Madrid - Paediatrics Research Group; Instituto de Investigación 12 de Octubre (imas12) - Pediatric Infectious Diseases Unit

Pablo Rojo Conejo

Instituto de Investigación 12 de Octubre (imas12) - Pediatric Infectious Diseases Unit

Caroline Foster

Imperial College London - Department of Paedaitric Infectious Diseases

Alasdair Bamford

University College London - MRC Clinical Trials Unit

Anita De Rossi

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO); University of Padova

Eleni Nastouli

University College London Hospitals NHS Foundation Trust - Advanced Pathogen Diagnostics Unit; Great Ormond Street Hospital for Children

Nigel Klein

University College London - Department of Infection, Inflammation and Immunity

Elena Morrocchi

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO)

Benoit Fatou

Boston Children's Hospital - Precision Vaccines Program

Smolen K. Kinga

Boston Children's Hospital - Precision Vaccines Program

Al Ozonoff

Boston Children's Hospital - Precision Vaccines Program

Luzuriaga Katherine

University of Massachusetts Worcester - Program in Molecular Medicine

Hanno Steen

Boston Children's Hospital - Precision Vaccines Program

Carlo Giaquinto

University of Padua - Department of Women’s and Children’s Health

Philip Goulder

University of Oxford - Department of Paediatrics

Paolo Rossi

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO)

Levy Ofer

Boston Children's Hospital - Precision Vaccines Program

Savita Pahwa

University of Miami - Department of Microbiology and Immunology

Paolo Palma

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO)

on behalf of the EPIICAL consortium

affiliation not provided to SSRN

More...

Abstract

Background: Despite a successful antiretroviral therapy (ART), adolescence living with perinatally acquired HIV (PHIV) experience B-cells dysfunction, 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: Here, we studied 40 PHIV who started treatment by 2nd year of life and maintain 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-omics 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.

Findings: Elevated levels of aging B-cells (T-bet+CD11c+) were associated with later start of treatment, detectable cell-associated HIV-1 RNA, Spikes, higher frequency of exhausted T-cells (PD-1+, LAG3+, TIGIT+). The proteomic analysis revealed that subjects with expansion of aging B-cells and exhausted T-cells had enrichment of proteins involved in immune inflammation and complement activation pathways. Signs of precocious aging were associated with a reduced capacity to maintain virological memory against measles vaccination.

Interpretation: To our knowledge, this is the first study focusing on precocious B-cell aging and dysfunctionality in PHIV with long-term virological suppression. We identified clinical, viral, cellular and plasma soluble markers associated with B-cells aging. Our results pave the way to further define risk of disease progression or lymphoproliferative disorders in PHIV.

Funding Information: PENTA-ID Foundation (http://penta-id.org/); NIH; CFAR.

Declaration of Interests: The authors have declared that no conflict of interest exists.

Ethics Approval Statement: This is a multi-center study which include the following institutions: Bambino Gesù Children’s Hospital (OPBG, Rome, Italy), University of Padua (Padova, Italy), University Hospital 12 de Octubre (Madrid, Spain), Hospital Gregorio Marañón (Madrid, Spain), Imperial College Healthcare NHS Trust (London, UK), Great Ormond Street Hospital (London, UK), Brighton and Sussex University Hospitals (Brighton, UK). Each recruiting sites received approval by local ethic committees (Foster, Dominguez-Rodriguez et al. 2020). Study participants or their legal guardians gave written informed consent in accordance with the Declaration of Helsinki.

Keywords: Perinatal HIV/AIDS, immune activation, late ART, aging B-cells, exhausted T-cells, T-bet, CD11c, proteomic profiling, caHIV-1 RNA

Suggested Citation

Ruggiero, Alessandra and Pascucci, Giuseppe Rubens and Cotugno, Nicola and Domínguez-Rodríguez, Sara and Rinaldi, Stefano and Tagarro, Alfredo and Rojo Conejo, Pablo and Foster, Caroline and Bamford, Alasdair and De Rossi, Anita and Nastouli, Eleni and Klein, Nigel and Morrocchi, Elena and Fatou, Benoit and Kinga, Smolen K. and Ozonoff, Al and Katherine, Luzuriaga and Steen, Hanno and Giaquinto, Carlo and Goulder, Philip and Rossi, Paolo and Ofer, Levy and Pahwa, Savita and Palma, Paolo and EPIICAL consortium, on behalf of the, Determinants of Precocious B-Cell Aging in European Adolescents Living With Perinatally Acquired HIV-1 After Over 10 Years of Suppressive Therapy. Available at SSRN: https://ssrn.com/abstract=3967067 or http://dx.doi.org/10.2139/ssrn.3967067

Alessandra Ruggiero

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO) ( email )

Rome
Italy

University of Verona - Department of Neurosciences, Biomedicine and Movement Sciences ( email )

Verona
Italy

Giuseppe Rubens Pascucci

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO) ( email )

Rome
Italy

Nicola Cotugno

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO) ( email )

Rome
Italy

Sara Domínguez-Rodríguez

Instituto de Investigación 12 de Octubre (imas12) - Pediatric Infectious Diseases Unit ( email )

Madrid
Spain

Stefano Rinaldi

University of Miami - Department of Microbiology and Immunology ( email )

Miami, FL
United States

Alfredo Tagarro

Universidad Europea de Madrid - Paediatrics Research Group ( email )

Madrid
Spain

Instituto de Investigación 12 de Octubre (imas12) - Pediatric Infectious Diseases Unit ( email )

Madrid
Spain

Pablo Rojo Conejo

Instituto de Investigación 12 de Octubre (imas12) - Pediatric Infectious Diseases Unit ( email )

Madrid
Spain

Caroline Foster

Imperial College London - Department of Paedaitric Infectious Diseases ( email )

London
United Kingdom

Alasdair Bamford

University College London - MRC Clinical Trials Unit ( email )

London
United States

Anita De Rossi

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO) ( email )

Italy

University of Padova ( email )

Italy

Eleni Nastouli

University College London Hospitals NHS Foundation Trust - Advanced Pathogen Diagnostics Unit ( email )

United Kingdom

Great Ormond Street Hospital for Children ( email )

London
United Kingdom

Nigel Klein

University College London - Department of Infection, Inflammation and Immunity ( email )

30 Guilford Street
London
United Kingdom

Elena Morrocchi

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO) ( email )

Rome
Italy

Benoit Fatou

Boston Children's Hospital - Precision Vaccines Program ( email )

MA
United States

Smolen K. Kinga

Boston Children's Hospital - Precision Vaccines Program ( email )

MA
United States

Al Ozonoff

Boston Children's Hospital - Precision Vaccines Program ( email )

MA
United States

Luzuriaga Katherine

University of Massachusetts Worcester - Program in Molecular Medicine ( email )

Program in Molecular Medicine
Worcester, MA 01605
United States

Hanno Steen

Boston Children's Hospital - Precision Vaccines Program ( email )

MA
United States

Carlo Giaquinto

University of Padua - Department of Women’s and Children’s Health ( email )

Via Giustiniani
Padova, 3-35128
Italy

Philip Goulder

University of Oxford - Department of Paediatrics ( email )

Oxford
United Kingdom

Paolo Rossi

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO) ( email )

Rome
Italy

Levy Ofer

Boston Children's Hospital - Precision Vaccines Program ( email )

MA
United States

Savita Pahwa

University of Miami - Department of Microbiology and Immunology ( email )

Miami, FL
United States

Paolo Palma (Contact Author)

Bambino Gesù Children's Hospital - Academic Department of Pediatrics (DPUO) ( email )

Italy

On behalf of the EPIICAL consortium

affiliation not provided to SSRN

No Address Available

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