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Conference abstract for CROI:
UNDERSTANDING THE IMPACT OF ART INTERRUPTION ON THYMIC OUTPUT AND TCR REPERTOIRE
Authors: Schou Sandgaard K, Attenborough T, Adams S, Gibbons D, Margets B, Holm M, Callard R, Gkazi Soragia A and Klein N
Background: ART interruptions in adults lead to decreases in CD4+ T cells and an increase in mortality and morbidity. ART interruptions in children also causes a rapid reduction in CD4+ T cells but with less clinical impact and with good CD4 restoration following ART reintroduction. In contrast to adults, who predominantly reconstitute their T cells from the peripheral cell population, children have a great capacity for immune reconstitution mainly from the thymus. In this study, we have investigated ART interruption in children with HIV to determine the impact on thymic output, peripheral T cell proliferation, TCR diversity and clonality.
Methods: TCR repertoire and TCR clonotypes was estimated by Next Generation Sequencing techniques in purified naive CD4+ T cells and memory CD8+ T cells. Thymic output was measured using a mathematical model, combining naive CD4+ T-cells proliferation rates with DNA PCR quantification of TCR excision circles, and IL-8, a chemokine released from naive T cells. Samples from 8 HIV-infected children were available for this study from a randomized controlled trial where one cohort remained on ART and the other had treatment withdrawn for 48 weeks.
Results: Thymic output was found to increase rapidly when ART was stopped. The increase in thymic output was associated with increased peripheral T cell proliferation, both returning to pre-interruption levels when the children re-started ART. TCR repertoire diversity and clonotype profiles appeared to be similar before treatment interruption and 3 years after ART re-introduction in both naive CD4+ T cells and memory CD8+ T cells. Specific clonotypes were seen to expand and being highly shared in the naïve CD4+ T cell population in response to ART interruption. There was no difference observed in these immune parameters in the HIV children receiving continuous treatment between baseline and end of study.
Conclusions: Importantly we found that thymic output, peripheral cell expansion, TCR repertoire and clonotypic profiles return to pre-interruption levels. This indicates that the high levels of thymic output in children may be sufficient to reverse the impact of ART cessation.
UNDERSTANDING THE IMPACT OF ART INTERRUPTION ON THYMIC OUTPUT AND TCR REPERTOIRE
Authors: Schou Sandgaard K, Attenborough T, Adams S, Gibbons D, Margets B, Holm M, Callard R, Gkazi Soragia A and Klein N
Background: ART interruptions in adults lead to decreases in CD4+ T cells and an increase in mortality and morbidity. ART interruptions in children also causes a rapid reduction in CD4+ T cells but with less clinical impact and with good CD4 restoration following ART reintroduction. In contrast to adults, who predominantly reconstitute their T cells from the peripheral cell population, children have a great capacity for immune reconstitution mainly from the thymus. In this study, we have investigated ART interruption in children with HIV to determine the impact on thymic output, peripheral T cell proliferation, TCR diversity and clonality.
Methods: TCR repertoire and TCR clonotypes was estimated by Next Generation Sequencing techniques in purified naive CD4+ T cells and memory CD8+ T cells. Thymic output was measured using a mathematical model, combining naive CD4+ T-cells proliferation rates with DNA PCR quantification of TCR excision circles, and IL-8, a chemokine released from naive T cells. Samples from 8 HIV-infected children were available for this study from a randomized controlled trial where one cohort remained on ART and the other had treatment withdrawn for 48 weeks.
Results: Thymic output was found to increase rapidly when ART was stopped. The increase in thymic output was associated with increased peripheral T cell proliferation, both returning to pre-interruption levels when the children re-started ART. TCR repertoire diversity and clonotype profiles appeared to be similar before treatment interruption and 3 years after ART re-introduction in both naive CD4+ T cells and memory CD8+ T cells. Specific clonotypes were seen to expand and being highly shared in the naïve CD4+ T cell population in response to ART interruption. There was no difference observed in these immune parameters in the HIV children receiving continuous treatment between baseline and end of study.
Conclusions: Importantly we found that thymic output, peripheral cell expansion, TCR repertoire and clonotypic profiles return to pre-interruption levels. This indicates that the high levels of thymic output in children may be sufficient to reverse the impact of ART cessation.
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