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  • Basic Science Article
  • Published:

Effective early antiretroviral therapy in perinatal-HIV infection reduces subsequent plasma inflammatory profile

Pediatric Research volume 94, pages 1667–1674 (2023)Cite this article

Abstract

Background

The long-term immunologic effects of antiretroviral therapy (ART) in children with perinatally-acquired HIV (PHIV) have not been fully elucidated. Here, we investigated how the timing of ART initiation affects the long-term immune profile of children living with PHIV by measuring immunomodulatory plasma cytokines, chemokines, and adenosine deaminases (ADAs).

Methods

40 PHIV participants initiated ART during infancy. 39 participant samples were available; 30 initiated ART ≤6 months (early-ART treatment); 9 initiated ART >6 months and <2 years (late-ART treatment). We compared plasma cytokine and chemokine concentrations and ADA enzymatic activities between early-ART and late-ART treatment 12.5 years later and measured correlation with clinical covariates.

Results

Plasma concentrations of 10 cytokines and chemokines (IFNγ, IL-12p70, IL-13, IL-17A, IL-IRA, IL-5, IL-6, and IL-9 as well as CCL7, CXCL10), ADA1, and ADA total were significantly higher in late-ART compared to early-ART treatment. Furthermore, ADA1 was significantly positively correlated with IFNγ, IL-17A, and IL-12p70. Meanwhile, total ADA was positively correlated with IFNγ, IL-13, IL-17A, IL-1RA, IL-6, and IL-12p70 as well as CCL7.

Conclusions

Elevation of several pro-inflammatory plasma analytes in late-ART despite 12.5 years of virologic suppression compared to early-ART treatment suggests that early treatment dampens the long-term plasma inflammatory profile in PHIV participants.

Impact

  • This study examines differences in the plasma cytokine, chemokine, and ADA profiles 12.5 years after treatment between early (≤6months) and late (>6 months and <2 years) antiretroviral therapy (ART) treatment initiation in a cohort of European and UK study participants living with PHIV.

  • Several cytokines and chemokines (e.g., IFNγ, IL-12p70, IL-6, and CXCL10) as well as ADA-1 are elevated in late-ART treatment in comparison to early-ART treatment.

  • Our results suggest that effective ART treatment initiated within 6 months of life in PHIV participants dampens a long-term inflammatory plasma profile as compared to late-ART treatment.

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Fig. 1: Association of ART initiation on plasma cytokine and chemokine concentrations.
Fig. 2: Association of ART initiation and clinical variables on plasma ADA activity.
Fig. 3: Correlations of plasma ADA activity with plasma cytokine and chemokine concentrations between early- and late-treated children with PHIV.

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Data availability

The datasets generated during the current study are available from the corresponding authors on reasonable request.

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Acknowledgements

We thank our study participants, their families, our colleagues at the study sites and data collector teams. We thank the leadership of Boston Children’s Hospital, including Drs. Gary Fleisher and Kevin Churchwell as well as Mr. August Cervini, for their support of the Precision Vaccines Program. Mirabel C. Nguyen provided critical review of the manuscript. We also thank Andrea Oletto for PENTA Foundation data management as well as Ilaria Pepponi and Chiara Medri for sample management at Bambino Gesù Childrens’ Hospital.

Funding

Supported by EPIICAL (Early-treated Perinatally HIV-infected Individuals: Improving Children’s Actual Life with Novel Immunotherapeutic Strategies) project, funded through an independent grant by ViiV Healthcare United Kingdom. This work is part of the EPIICAL project (http://www.epiical.org/), supported by PENTA-ID foundation (http://penta-id.org/), funded through an independent grant by ViiV Healthcare United Kingdom

Author information

Author notes

  1. These authors contributed equally: Athena N. Nguyen, Alec L. Plotkin.

  2. These authors jointly supervised this work: Paolo Palma, Kinga K. Smolen.

Authors and Affiliations

  1. Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA

    Athena N. Nguyen, Alec L. Plotkin, Oludare A. Odumade, Caitlin Syphurs, Joann Diray-Arce, Al Ozonoff, Ofer Levy & Kinga K. Smolen

  2. Harvard Medical School, Boston, MA, USA

    Oludare A. Odumade, Caitlin Syphurs, Joann Diray-Arce, Al Ozonoff, Ofer Levy & Kinga K. Smolen

  3. Division of Medicine Critical Care, Boston Children’s Hospital, Boston, MA, USA

    Oludare A. Odumade

  4. Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA

    Lesley De Armas & Savita Pahwa

  5. Clinical Immunology and Vaccinology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Elena Morrocchi, Nicola Cotugno & Paolo Palma

  6. Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy

    Nicola Cotugno, Paolo Rossi & Paolo Palma

  7. Academic Department of Pediatrics (DPUO), Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Paolo Rossi

  8. Department of Paediatric Infectious Diseases, Imperial College Healthcare NHS Trust, London, UK

    Caroline Foster

  9. Fundación de Investigación Biomédica Hospital 12 de Octubre. Instituto de Investigación 12 de Octubre (imas12), Madrid, Spain

    Sara Domínguez-Rodríguez & Alfredo Tagarro

  10. Department of Pediatrics, Hospital Universitario Infanta Sofía. Fundación para la Investigación Biomédica e Innovación del Hospital Infanta Sofía y del Henares (FIIB HUIS HHEN). Universidad Europea de Madrid, Madrid, Spain

    Alfredo Tagarro

  11. Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Benoit Fatou

  12. Broad Institute of MIT & Harvard, Cambridge, MA, USA

    Al Ozonoff & Ofer Levy

  13. Fondazione PENTA (PENTA), Padova, Italy

    Carlo Giaquinto, Silvia Faggion, Daniel Gomez Pena, Inger Lindfors Rossi, William James, Alessandra Nardone & Federica D’Ambrosio

  14. Ospedale Pediatrico Bambino Gesù (OPBG), Rome, Italy

    Paola Zangari & Carla Paganin

  15. University College London (UCL), London, UK

    Eleni Nastouli & Moira Spyer

  16. Association de Recherche en Virologie et Dermatologie (ARVD), Paris, France

    Anne-Genevieve Marcelin & Vincent Calvez

  17. Servizio Madrileno de Salud (SERMAS-H12OCT), Madrid, Spain

    Pablo Rojo

  18. Servizio Madrileno de Salud SERMAS Hospital Gregorio Marañón (SERMAS-HGUGM), Madrid, Spain

    Maria Angeles Munoz

  19. Università degli Studi di Padova (UNIPD), Padova, Italy

    Anita De Rossi

  20. Stellenbosch University-Faculty of Medicine and Health Sciences (SU) Stellenbosch, Stellenbosch, South Africa

    Mark Cotton

  21. Africa Health Research Institute (AHRI) Durban, Durban, South Africa

    Nigel Klein

  22. Johns Hopkins University (JHU), Baltimore, MD, USA

    Deborah Persaud

  23. University of Utrecht (UU), Utrecht, Netherlands

    Rob J. De Boer & Juliane Schroeter

  24. Fondazione per la ricerca farmacologica Gianni Benzi (FGB), Bari, Italy

    Adriana Ceci & Viviana Giannuzzi

  25. University of Massachusetts Medical School Worcester (UMMS), Worcester, MA, USA

    Kathrine Luzuriaga

  26. Columbia University New York, New York, NY, USA

    Louise Kuhn & Andrew Yates

  27. University of the Witwatersrand, Johannesburg—Perinatal HIV Research Unit (PHRU), Johannesburg, South Africa

    Avy Violari & Kennedy Otwombe

  28. Fundação Ariel Glaser contra o SIDA Pediátrico (ARIEL), Maputo, Mozambique

    Paula Vaz & Maria Grazia Lain

  29. Fundação Manhiça (FM) Manhica, Manhica, Mozambique

    Elisa López-Varela & Tacilta Nhamposssa

  30. Barcelona Institute for Global Health Foundation (ISGlobal), Barcelona, Spain

    Elisa Lopez & Denise Naniche

  31. Umkhuseli Innovation and Research Management RF NPC (UIRM) KwaZulu Natal, Pietermaritzburg, South Africa

    Philip Goulder

  32. Brigham & Women’s Hospital (BWH), Boston, MA, USA

    Mathias Lichterfeld

  33. Research Triangle Institute dba RTI International (RTI), Durham, NC, USA

    Holly Peay

  34. Centre Hospitalier Universitaire Gabriel Touré Bamako, Bamako, Mali

    Pr Mariam Sylla & Almoustapha Maiga

  35. Chulangkorn University Bangkok, Bangkok, Thailand

    Thanyawee Puthanakit

  36. Joint Clinical Research Center Kampala, Kampala, Uganda

    Cissy Kityo

Authors
  1. Athena N. Nguyen
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  2. Alec L. Plotkin
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  3. Oludare A. Odumade
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  4. Lesley De Armas
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  5. Savita Pahwa
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  6. Elena Morrocchi
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  7. Nicola Cotugno
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  8. Paolo Rossi
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  9. Caroline Foster
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  10. Sara Domínguez-Rodríguez
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  11. Alfredo Tagarro
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  12. Caitlin Syphurs
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  13. Joann Diray-Arce
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  14. Benoit Fatou
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  15. Al Ozonoff
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  16. Ofer Levy
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  17. Paolo Palma
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  18. Kinga K. Smolen
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Consortia

on the behalf of the EPIICAL Consortium

  • Paolo Rossi
  • , Carlo Giaquinto
  • , Silvia Faggion
  • , Daniel Gomez Pena
  • , Inger Lindfors Rossi
  • , William James
  • , Alessandra Nardone
  • , Federica D’Ambrosio
  • , Paolo Palma
  • , Paola Zangari
  • , Carla Paganin
  • , Eleni Nastouli
  • , Moira Spyer
  • , Anne-Genevieve Marcelin
  • , Vincent Calvez
  • , Pablo Rojo
  • , Alfredo Tagarro
  • , Sara Domínguez-Rodríguez
  • , Maria Angeles Munoz
  • , Caroline Foster
  • , Savita Pahwa
  • , Anita De Rossi
  • , Mark Cotton
  • , Nigel Klein
  • , Deborah Persaud
  • , Rob J. De Boer
  • , Juliane Schroeter
  • , Adriana Ceci
  • , Viviana Giannuzzi
  • , Kathrine Luzuriaga
  • , Nicola Cotugno
  • , Louise Kuhn
  • , Andrew Yates
  • , Avy Violari
  • , Kennedy Otwombe
  • , Paula Vaz
  • , Maria Grazia Lain
  • , Elisa López-Varela
  • , Tacilta Nhamposssa
  • , Elisa Lopez
  • , Denise Naniche
  • , Ofer Levy
  • , Kinga K. Smolen
  • , Philip Goulder
  • , Mathias Lichterfeld
  • , Holly Peay
  • , Pr Mariam Sylla
  • , Almoustapha Maiga
  • , Thanyawee Puthanakit
  •  & Cissy Kityo

Contributions

A.N.N., A.L.P., K.K.S. conceived the paper design and analyzed data; A.N.N., A.L.P., K.K.S. wrote the manuscript; P.P., N.C., C.F., A.T., P.R., A.R., A.N., S.D. designed the study, enrolled participants, collected and managed clinical data; A.O., C.S., J.D.A. performed statistical analysis; A.N.N., A.L.P., O.A.O., L.D.A., A.R., N.C., E.M., B.F. performed experiments; P.S., O.L., P.P., K.K.S. supervised the work. All authors read, revised, and approved the manuscript.

Corresponding authors

Correspondence to Paolo Palma or Kinga K. Smolen.

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Competing interests

O.L. is a named inventor on patents relating to vaccine adjuvants and human in vitro systems to model vaccine action. O.L. reports a sponsored research agreement from GlaxoSmithKline (GSK) to evaluate vaccine adjuvants in vitro.

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Nguyen, A.N., Plotkin, A.L., Odumade, O.A. et al. Effective early antiretroviral therapy in perinatal-HIV infection reduces subsequent plasma inflammatory profile. Pediatr Res 94, 1667–1674 (2023). https://doi.org/10.1038/s41390-023-02669-0

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