The importance of taking ART appropriately in children and adolescents with HIV-1 to reach the highest capacity of immune function later in life

Katrine Schou Sandgaard; Triantafylia Gkouleli; Teresa Attenborough; Stuart Adams; Deena Gibbons; Mette Holm; Sarah Eisen; Helen Baxendale; Anita De Rossi; Savita Pahwa; Benny Chain; Athina S Gkazi; Nigel Klein

doi:10.3389/fimmu.2022.860316

The importance of taking ART appropriately in children and adolescents with HIV-1 to reach the highest capacity of immune function later in life

Katrine Schou Sandgaard^*, Triantafylia Gkouleli, Teresa Attenborough, Stuart Adams, Deena Gibbons, Mette Holm, Sarah Eisen, Helen Baxendale, Anita De Rossi, Savita Pahwa, 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

Current antiretroviral therapy (ART) guidelines recommend treating all children with HIV-1 infection. This has changed from the broader use of ART to treat children to improve morbidity and minimise mortality. However, prior to current recommendations, not everyone with HIV-1 received timely treatment. What happens to the paediatric immune system when HIV-1 replication is not appropriately supressed remains unclear. 11 samples from adolescents with HIV-1 on ART and uninfected controls in the UK, aged 12-25 years, were examined; overall, adolescents with CD4+ counts > 500/μl and a viral load < 50 copies/ml were compared with adolescents with CD4+ counts < 500/μl and a viral load > 50 copies/ml at time of sampling. Measurements of thymic output were combined with high throughput next generation sequencing and bioinformatics to systematically organize CD4+ and CD8+ T cell receptor (TCR) repertoires. TCR repertoire diversity, clonal expansions, TCR sequence sharing, and formation of TCR clusters in HIV-1 infected adolescents with successful HIV-1 suppression were compared to adolescents with ineffective HIV-1 suppression. Thymic output and CD4+ T cell numbers were decreased in HIV-1 infected adolescents with poor HIV-1 suppression. A strong homeostatic TCR response, driven by the decreased CD4+ T cell compartment and reduced thymic output was observed in the virally uncontrolled HIV-1-infected adolescents. Formation of abundant robust TCR clusters and structurally related TCRs were found in the adolescents with effective HIV-1 suppression. Numerous CD4+ T cell numbers in the virally controlled adolescents emphasize the importance of high thymic output and formation of robust TCR clusters in the maintenance of HIV-1 suppression. While the profound capacity for immune recovery in children may allow better opportunity to deal with immunological stress, when ART is taken appropriately, this study demonstrates new insights into the unique paediatric immune system and the immunological changes when HIV-1 replication is ongoing.

Original language	English
Article number	860316
Journal	Frontiers in Immunology
Volume	13
Number of pages	14
ISSN	1664-3224
DOIs	https://doi.org/10.3389/fimmu.2022.860316
Publication status	Published - Jul 2022

Keywords

Adolescent
Anti-Retroviral Agents/therapeutic use
Child
HIV Infections
HIV Seropositivity/drug therapy
HIV-1
Humans
Immunity
Receptors, Antigen, T-Cell

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10.3389/fimmu.2022.860316Licence: CC BY

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Sandgaard, K. S., Gkouleli, T., Attenborough, T., Adams, S., Gibbons, D., Holm, M., Eisen, S., Baxendale, H., De Rossi, A., Pahwa, S., Chain, B., Gkazi, A. S., & Klein, N. (2022). The importance of taking ART appropriately in children and adolescents with HIV-1 to reach the highest capacity of immune function later in life. Frontiers in Immunology, 13, Article 860316. https://doi.org/10.3389/fimmu.2022.860316

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title = "The importance of taking ART appropriately in children and adolescents with HIV-1 to reach the highest capacity of immune function later in life",

abstract = "Current antiretroviral therapy (ART) guidelines recommend treating all children with HIV-1 infection. This has changed from the broader use of ART to treat children to improve morbidity and minimise mortality. However, prior to current recommendations, not everyone with HIV-1 received timely treatment. What happens to the paediatric immune system when HIV-1 replication is not appropriately supressed remains unclear. 11 samples from adolescents with HIV-1 on ART and uninfected controls in the UK, aged 12-25 years, were examined; overall, adolescents with CD4+ counts > 500/μl and a viral load < 50 copies/ml were compared with adolescents with CD4+ counts < 500/μl and a viral load > 50 copies/ml at time of sampling. Measurements of thymic output were combined with high throughput next generation sequencing and bioinformatics to systematically organize CD4+ and CD8+ T cell receptor (TCR) repertoires. TCR repertoire diversity, clonal expansions, TCR sequence sharing, and formation of TCR clusters in HIV-1 infected adolescents with successful HIV-1 suppression were compared to adolescents with ineffective HIV-1 suppression. Thymic output and CD4+ T cell numbers were decreased in HIV-1 infected adolescents with poor HIV-1 suppression. A strong homeostatic TCR response, driven by the decreased CD4+ T cell compartment and reduced thymic output was observed in the virally uncontrolled HIV-1-infected adolescents. Formation of abundant robust TCR clusters and structurally related TCRs were found in the adolescents with effective HIV-1 suppression. Numerous CD4+ T cell numbers in the virally controlled adolescents emphasize the importance of high thymic output and formation of robust TCR clusters in the maintenance of HIV-1 suppression. While the profound capacity for immune recovery in children may allow better opportunity to deal with immunological stress, when ART is taken appropriately, this study demonstrates new insights into the unique paediatric immune system and the immunological changes when HIV-1 replication is ongoing.",

keywords = "Adolescent, Anti-Retroviral Agents/therapeutic use, Child, HIV Infections, HIV Seropositivity/drug therapy, HIV-1, Humans, Immunity, Receptors, Antigen, T-Cell",

author = "Sandgaard, {Katrine Schou} and Triantafylia Gkouleli and Teresa Attenborough and Stuart Adams and Deena Gibbons and Mette Holm and Sarah Eisen and Helen Baxendale and {De Rossi}, Anita and Savita Pahwa and Benny Chain and Gkazi, {Athina S} and Nigel Klein",

note = "Copyright {\textcopyright} 2022 Sandgaard, Gkouleli, Attenborough, Adams, Gibbons, Holm, Eisen, Baxendale, De Rossi, Pahwa, Chain, Gkazi and Klein.",

year = "2022",

month = jul,

doi = "10.3389/fimmu.2022.860316",

language = "English",

volume = "13",

journal = "Frontiers in Immunology",

issn = "1664-3224",

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Sandgaard, KS, Gkouleli, T, Attenborough, T, Adams, S, Gibbons, D, Holm, M, Eisen, S, Baxendale, H, De Rossi, A, Pahwa, S, Chain, B, Gkazi, AS & Klein, N 2022, 'The importance of taking ART appropriately in children and adolescents with HIV-1 to reach the highest capacity of immune function later in life', Frontiers in Immunology, vol. 13, 860316. https://doi.org/10.3389/fimmu.2022.860316

The importance of taking ART appropriately in children and adolescents with HIV-1 to reach the highest capacity of immune function later in life. / Sandgaard, Katrine Schou; Gkouleli, Triantafylia; Attenborough, Teresa et al.
In: Frontiers in Immunology, Vol. 13, 860316, 07.2022.

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

TY - JOUR

T1 - The importance of taking ART appropriately in children and adolescents with HIV-1 to reach the highest capacity of immune function later in life

AU - Sandgaard, Katrine Schou

AU - Gkouleli, Triantafylia

AU - Attenborough, Teresa

AU - Adams, Stuart

AU - Gibbons, Deena

AU - Holm, Mette

AU - Eisen, Sarah

AU - Baxendale, Helen

AU - De Rossi, Anita

AU - Pahwa, Savita

AU - Chain, Benny

AU - Gkazi, Athina S

AU - Klein, Nigel

PY - 2022/7

Y1 - 2022/7

N2 - Current antiretroviral therapy (ART) guidelines recommend treating all children with HIV-1 infection. This has changed from the broader use of ART to treat children to improve morbidity and minimise mortality. However, prior to current recommendations, not everyone with HIV-1 received timely treatment. What happens to the paediatric immune system when HIV-1 replication is not appropriately supressed remains unclear. 11 samples from adolescents with HIV-1 on ART and uninfected controls in the UK, aged 12-25 years, were examined; overall, adolescents with CD4+ counts > 500/μl and a viral load < 50 copies/ml were compared with adolescents with CD4+ counts < 500/μl and a viral load > 50 copies/ml at time of sampling. Measurements of thymic output were combined with high throughput next generation sequencing and bioinformatics to systematically organize CD4+ and CD8+ T cell receptor (TCR) repertoires. TCR repertoire diversity, clonal expansions, TCR sequence sharing, and formation of TCR clusters in HIV-1 infected adolescents with successful HIV-1 suppression were compared to adolescents with ineffective HIV-1 suppression. Thymic output and CD4+ T cell numbers were decreased in HIV-1 infected adolescents with poor HIV-1 suppression. A strong homeostatic TCR response, driven by the decreased CD4+ T cell compartment and reduced thymic output was observed in the virally uncontrolled HIV-1-infected adolescents. Formation of abundant robust TCR clusters and structurally related TCRs were found in the adolescents with effective HIV-1 suppression. Numerous CD4+ T cell numbers in the virally controlled adolescents emphasize the importance of high thymic output and formation of robust TCR clusters in the maintenance of HIV-1 suppression. While the profound capacity for immune recovery in children may allow better opportunity to deal with immunological stress, when ART is taken appropriately, this study demonstrates new insights into the unique paediatric immune system and the immunological changes when HIV-1 replication is ongoing.

AB - Current antiretroviral therapy (ART) guidelines recommend treating all children with HIV-1 infection. This has changed from the broader use of ART to treat children to improve morbidity and minimise mortality. However, prior to current recommendations, not everyone with HIV-1 received timely treatment. What happens to the paediatric immune system when HIV-1 replication is not appropriately supressed remains unclear. 11 samples from adolescents with HIV-1 on ART and uninfected controls in the UK, aged 12-25 years, were examined; overall, adolescents with CD4+ counts > 500/μl and a viral load < 50 copies/ml were compared with adolescents with CD4+ counts < 500/μl and a viral load > 50 copies/ml at time of sampling. Measurements of thymic output were combined with high throughput next generation sequencing and bioinformatics to systematically organize CD4+ and CD8+ T cell receptor (TCR) repertoires. TCR repertoire diversity, clonal expansions, TCR sequence sharing, and formation of TCR clusters in HIV-1 infected adolescents with successful HIV-1 suppression were compared to adolescents with ineffective HIV-1 suppression. Thymic output and CD4+ T cell numbers were decreased in HIV-1 infected adolescents with poor HIV-1 suppression. A strong homeostatic TCR response, driven by the decreased CD4+ T cell compartment and reduced thymic output was observed in the virally uncontrolled HIV-1-infected adolescents. Formation of abundant robust TCR clusters and structurally related TCRs were found in the adolescents with effective HIV-1 suppression. Numerous CD4+ T cell numbers in the virally controlled adolescents emphasize the importance of high thymic output and formation of robust TCR clusters in the maintenance of HIV-1 suppression. While the profound capacity for immune recovery in children may allow better opportunity to deal with immunological stress, when ART is taken appropriately, this study demonstrates new insights into the unique paediatric immune system and the immunological changes when HIV-1 replication is ongoing.

KW - Adolescent

KW - Anti-Retroviral Agents/therapeutic use

KW - Child

KW - HIV Infections

KW - HIV Seropositivity/drug therapy

KW - HIV-1

KW - Humans

KW - Immunity

KW - Receptors, Antigen, T-Cell

U2 - 10.3389/fimmu.2022.860316

DO - 10.3389/fimmu.2022.860316

M3 - Journal article

C2 - 35967315

SN - 1664-3224

VL - 13

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 860316

ER -

The importance of taking ART appropriately in children and adolescents with HIV-1 to reach the highest capacity of immune function later in life

Abstract

Keywords

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