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

Katrine Schou Sandgaard; Ben Margetts; Teresa Attenborough; Triantafylia Gkouleli; Stuart Adams; Mette Holm; Diana Gibb; Deena Gibbons; Carlo Giaquinto; Anita De Rossi; Alasdair Bamford; Paolo Palma; Benny Chain; Athina S. Gkazi; Nigel Klein

doi:10.3389/fimmu.2021.643189

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

Katrine Schou Sandgaard^*, Ben Margetts, Teresa Attenborough, Triantafylia Gkouleli, Stuart Adams, Mette Holm, Diana Gibb, Deena Gibbons, Carlo Giaquinto, Anita De Rossi, Alasdair Bamford, Paolo Palma, Benny Chain, Athina S. Gkazi, Nigel Klein

^*Corresponding author for this work

Department of Clinical Medicine - Department of Paediatrics

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

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 language	English
Article number	643189
Journal	Frontiers in Immunology
Volume	12
ISSN	1664-3224
DOIs	https://doi.org/10.3389/fimmu.2021.643189
Publication status	Published - Jul 2021

Keywords

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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10.3389/fimmu.2021.643189Licence: CC BY

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Sandgaard, K. S., Margetts, B., Attenborough, T., Gkouleli, T., Adams, S., Holm, M., Gibb, D., Gibbons, D., Giaquinto, C., De Rossi, A., Bamford, A., Palma, P., Chain, B., Gkazi, A. S., & Klein, N. (2021). Plasticity of the Immune System in Children Following Treatment Interruption in HIV-1 Infection. Frontiers in Immunology, 12, Article 643189. https://doi.org/10.3389/fimmu.2021.643189

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abstract = "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 na{\"i}ve 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.",

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

author = "Sandgaard, {Katrine Schou} and Ben Margetts and Teresa Attenborough and Triantafylia Gkouleli and Stuart Adams and Mette Holm and Diana Gibb and Deena Gibbons and Carlo Giaquinto and {De Rossi}, Anita and Alasdair Bamford and Paolo Palma and Benny Chain and Gkazi, {Athina S.} and Nigel Klein",

note = "Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2021 Sandgaard, Margetts, Attenborough, Gkouleli, Adams, Holm, Gibb, Gibbons, Giaquinto, De Rossi, Bamford, Palma, Chain, Gkazi and Klein.",

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Plasticity of the Immune System in Children Following Treatment Interruption in HIV-1 Infection. / Sandgaard, Katrine Schou; Margetts, Ben; Attenborough, Teresa et al.
In: Frontiers in Immunology, Vol. 12, 643189, 07.2021.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - Plasticity of the Immune System in Children Following Treatment Interruption in HIV-1 Infection

AU - Sandgaard, Katrine Schou

AU - Margetts, Ben

AU - Attenborough, Teresa

AU - Gkouleli, Triantafylia

AU - Adams, Stuart

AU - Holm, Mette

AU - Gibb, Diana

AU - Gibbons, Deena

AU - Giaquinto, Carlo

AU - De Rossi, Anita

AU - Bamford, Alasdair

AU - Palma, Paolo

AU - Chain, Benny

AU - Gkazi, Athina S.

AU - Klein, Nigel

PY - 2021/7

Y1 - 2021/7

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.

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KW - high throughout sequencing

KW - HIV-1

KW - immune repertoires

KW - T cell receptor

KW - T cells

KW - thymic output

KW - T cell receptor clonal expansions

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DO - 10.3389/fimmu.2021.643189

M3 - Journal article

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AN - SCOPUS:85114020333

SN - 1664-3224

VL - 12

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 643189

ER -

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

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Keywords

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