TY - JOUR
T1 - Plasticity of the Immune System in Children Following Treatment Interruption in HIV-1 Infection
AU - Schou Sandgaard, Katrine
AU - Margetts, Ben
AU - Attenborough, Teresa
AU - Gkouleli, Triantafylia
AU - Adams, Stuart
AU - Holm, Mette
AU - Gibb, Diane
AU - Gibbons, Deena
AU - Giaquinto, Carlo
AU - De Rossi, Anita
AU - Bamford, Alisdair
AU - Palma, Paolo
AU - Chain, Benny
AU - Gkazi, Athina
AU - Klein, Nigel
N1 - Funding Information:
KS performed the Flow cytometry and NGS experiments, applied the mathematical and bioinformatic analysis to the data, created the data presentation/visualization, and wrote the original draft. NK designed the study aims and acquired the financial support of the study. NK and AG oversaw and had leadership responsibility for the research planning and execution and contributed to drafting the manuscript. AG designed and supervised the NGS methodology. BC developed the NGS methodology. BC, BM, and TA supervised the bioinformatics. TG contributed to performing NGS experiments. SA designed and performed the TRECs analysis. DeG designed and supervised the CXCL8 methodology. BC, BM, TA, DG, and TG contributed to drafting the manuscript. MH, CG, AR, AB, and PP contributed to the conception and design of the study and writing the manuscript draft. All authors contributed to the article and approved the submitted version.
Publisher Copyright:
© Copyright © 2021 Sandgaard, Margetts, Attenborough, Gkouleli, Adams, Holm, Gibb, Gibbons, Giaquinto, De Rossi, Bamford, Palma, Chain, Gkazi and Klein.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7/29
Y1 - 2021/7/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85114020333&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.643189
DO - 10.3389/fimmu.2021.643189
M3 - Article
SN - 1664-3224
VL - 12
SP - 3098
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 643189
ER -