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

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.

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

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.