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Effects of highly active antiretroviral therapy on thymical reconstitution of CD4 T lymphocytes in vertically HIV-infected children

2002; Lippincott Williams & Wilkins; Volume: 16; Issue: 8 Linguagem: Inglês

10.1097/00002030-200205240-00013

1473-5571

Rafael Correa‐Rocha, María Ángeles Muñoz‐Fernández,

HIV-related health complications and treatments

CD4 T-cell percentages, viral load and thymic function measured as T-cell receptor rearrangement excision circle (TREC) levels were determined every 2–3 months in six treated HIV-infected children for 4 years. All children experienced a marked increase in CD4 cell count after therapy, accompanied by a concomitantly marked increase in TREC levels. In children, the decrease in viral load caused by antiviral therapy leads to an increase in CD4 T cells, mainly because of a recovery in the thymic production of new T cells. HIV infection leads to a marked decrease in CD4 T cells, both as a result of peripheral CD4 T-cell depletion caused by the virus and inadequate replacement of the destroyed T cells. The natural thymic involution with ageing results in a limited capacity to produce naive T cells in adults. By contrast, children maintain thymic function and thus the capacity for the renewal of T cells that enables the replacement of lost clones, making immune reconstitution possible. However, HIV can infect human thymocytes and lead to their destruction [1]. An earlier study by our group [2] showed that the decrease in CD4 T cells observed in infected children is mainly caused by the inhibitory effect of T-tropic viruses on thymic function. A suppression of viral replication that diminishes the inhibition of the thymus would thus be advisable for recovering thymic function. A widely reported fact is that highly active antiretroviral therapy (HAART) leads to a substantial increase in CD4 T cells, and within them in naive CD4 T cells [3–5], postulating a putative immune reconstitution. However, this fact could be explained by the recovery of thymic function, but also by the redistribution or peripheral expansion of pre-existent naive cells [4], or by reversion from memory to naive phenotype in peripheral T cells [6]. We have studied the effect of antiviral therapy on the production of naive T cells by the thymus, to assess the source of the increased CD4 T cells in infected children. Thymic function was determined by quantifying T-cell receptor rearrangement excision circles (TREC), a highly specific marker of recently produced T cells by the thymus [7]. We performed a longitudinal study in six vertically HIV-infected children treated with combination antiretroviral therapy (children 1, 2 and 3) consisting of two nucleoside analogues, or with HAART consisting of two nucleoside analogues plus a protease inhibitor (children 4, 5 and 6). Informed consent was obtained from all parents or legal guardians, and the Local Ethics Committee of the hospital also gave consent. Every 2–3 months, CD4 T-cell percentages, plasma viral loads and TREC were measured in all children. TREC values were determined in peripheral blood mononuclear cells by real-time quantitative polymerase chain reaction in a fluororimetric thermocycler (LightCycler; Roche Molecular Biochemicals, Idaho Falls, USA) using hybridization probes specific to the TREC sequence. All samples from each child were measured in the same assay to avoid inter-assay variations, and always included a β-globin control polymerase chain reaction to verify that all samples had the same DNA content. Correlation among variables was analysed by using Pearson's correlation coefficient. Our results showed that antiretroviral therapy induced a decrease in viral load in the three children on combination therapy, and a complete suppression to undetectable levels in the three children on HAART (Fig. 1), which may decrease the inhibitory effect of HIV in thymic function. A marked increase in CD4 T-cell percentages was observed in the six children, showing a significant inverse correlation with viral load (P < 0.05). Most interestingly, the increase in CD4 T cells after antiretroviral therapy was accompanied in all six children by a concomitantly marked increase in TREC levels, as early as 2 months in children 2, 4 and 5, disclosing a highly significant correlation between both variables (P < 0.001 in children 1, 2, 4, 5, and 6, and P < 0.05 in child 3). The other two pathways for CD4 T-cell recovery, i.e. a redistribution or increase in the division rates of peripheral T cells more prevalent in adults [4], seem to be much less important in children because they would have produced a dilution of naive T cells from the thymus, and therefore a decrease in TREC levels.Fig. 1.: Evolution of viral load, CD4 T-cell percentages and T-cell receptor rearrangement excision circles per 105 peripheral blood mononuclear cells in six HIV-1-infected children on antiretroviral therapy. Children 1, 2 and 3 were treated with combination antiretroviral therapy; and children 4, 5 and 6 were treated with highly active antiretroviral therapy. The 0 months value represents the beginning of the treatment. Antiretroviral therapy led to a marked increase in CD4 T cells, which correlated inversely with viral load, and was accompanied in all cases by a concomitantly marked increase in T-cell receptor rearrangement excision circle (TREC) levels. —○— T-cell receptor rearrangement excision circle levels; —▴— % CD4 cells; —▪— viral load.The results thus show that in all children included in the study, the source of the majority of restored CD4 T cells is the thymic production of new naive T cells. This is an important fact, because not only is a quantitative recovery of CD4 cells occurring, but also the generation of new T-cell clones, which could recover the repertoire of specificities capable of responding to different pathogenic agents. Rafael Correa Angeles Muñoz-Fernández Acknowledgements The authors are grateful to Daniel C. Douek for supplying the plasmid for the standard curve and the method of quantification of TREC, and M.D. Dolores Gurbindo for the clinical follow-up of the children.