Mette Holm

Plasticity of the Immune System in Children Following Treatment Interruption in HIV-1 Infection

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Katrine Schou Sandgaard
  • Ben Margetts, UCL Great Ormond Street Institute of Child Health
  • ,
  • Teresa Attenborough, University College London
  • ,
  • Triantafylia Gkouleli, University College London
  • ,
  • Stuart Adams, UCL Great Ormond Street Institute of Child Health
  • ,
  • Mette Holm
  • Diana Gibb, Medical Research Council
  • ,
  • Deena Gibbons, King’s College London
  • ,
  • Carlo Giaquinto, University of Padova
  • ,
  • Anita De Rossi, University of Padova, IRCCS Istituto Oncologico Veneto - Padova
  • ,
  • Alasdair Bamford, University College London, UCL Great Ormond Street Institute of Child Health, Medical Research Council
  • ,
  • Paolo Palma, IRCCS Ospedale pediatrico Bambino Gesù - Roma
  • ,
  • Benny Chain, University College London
  • ,
  • Athina S. Gkazi, University College London
  • ,
  • Nigel Klein, University College London

It is intriguing that, unlike adults with HIV-1, children with HIV-1 reach a greater CD4+ T cell recovery following planned treatment cessation. The reasons for the better outcomes in children remain unknown but may be related to increased thymic output and diversity of T cell receptor repertoires. HIV-1 infected children from the PENTA 11 trial tolerated planned treatment interruption without adverse long-term clinical, virological, or immunological consequences, once antiretroviral therapy was re-introduced. This contrasts to treatment interruption trials of HIV-1 infected adults, who had rapid changes in T cells and slow recovery when antiretroviral therapy was restarted. How children can develop such effective immune responses to planned treatment interruption may be critical for future studies. PENTA 11 was a randomized, phase II trial of planned treatment interruptions in HIV-1-infected children (ISRCTN 36694210). In this sub-study, eight patients in long-term follow-up were chosen with CD4+ count>500/ml, viral load <50c/ml at baseline: four patients on treatment interruption and four on continuous treatment. Together with measurements of thymic output, we used high-throughput next generation sequencing and bioinformatics to systematically organize memory CD8+ and naïve CD4+ T cell receptors according to diversity, clonal expansions, sequence sharing, antigen specificity, and T cell receptor similarities following treatment interruption compared to continuous treatment. We observed an increase in thymic output following treatment interruption compared to continuous treatment. This was accompanied by an increase in T cell receptor clonal expansions, increased T cell receptor sharing, and higher sequence similarities between patients, suggesting a more focused T cell receptor repertoire. The low numbers of patients included is a limitation and the data should be interpreted with caution. Nonetheless, the high levels of thymic output and the high diversity of the T cell receptor repertoire in children may be sufficient to reconstitute the T cell immune repertoire and reverse the impact of interruption of antiretroviral therapy. Importantly, the effective T cell receptor repertoires following treatment interruption may inform novel therapeutic strategies in children infected with HIV-1.

Original languageEnglish
Article number643189
JournalFrontiers in Immunology
Volume12
ISSN1664-3224
DOIs
Publication statusPublished - Jul 2021

Bibliographical note

Publisher Copyright:
© Copyright © 2021 Sandgaard, Margetts, Attenborough, Gkouleli, Adams, Holm, Gibb, Gibbons, Giaquinto, De Rossi, Bamford, Palma, Chain, Gkazi and Klein.

    Research areas

  • antiretroviral treatment interruption, high throughout sequencing, HIV-1, immune repertoires, T cell receptor, T cells, thymic output, T cell receptor clonal expansions

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