Immune reconstitution in human immunodeficiency virus type 1-infected children with different virological responses to anti-retroviral therapy

Abstract

Immune repopulation, despite virological failure, often occurs in children under highly active anti-retroviral therapy (HAART). The aim of this study was to analyse the characteristics of immune repopulation and activation in children with and without virological response to HAART. Fourteen human immunodeficiency virus type 1 (HIV-1)-infected children with suppression of HIV-1 plasma viraemia (virological responders, VR) and 16 virological non-responders (VNR) to therapy were studied at baseline and after approximately 2 years of HAART. During therapy, CD4+ T cells increased in both groups, but were higher in the VR than in the VNR group. All CD4+ T cell subsets (naive, central memory, effector/memory and CD38+) increased significantly in VR children, while there was a significant increase only in naive cells in VNR children. Naive CD8+ T cells and T cell receptor rearrangement excision circles (TREC), an indicator of thymic output, increased in both VR and VNR children. Activated CD8+ CD38+ T cells decreased in VR but remained high in VNR children. Levels of circulating lipopolysaccharide (LPS), an indicator of microbial translocation, further increased in VNR children. In conclusion, HAART induced an increase in naive cells in all children, regardless of their virological response. However, the persistence of viraemia resulted in an impaired expansion of memory CD4+ T cells susceptible to HIV-1 infection, and together with the microbial translocation sustained the persistence of a high level of immune activation.

Fig. 1

The phenotypic characteristics of CD4⁺ and CD8⁺ T subsets from 17 human immunodeficiency virus type 1 (HIV-1)-uninfected children and 30 HIV-1-infected children at highly active anti-retroviral therapy initiation are illustrated. CD27, CD45RA and CD38 expression in CD3⁺CD4⁺ T cells (a) and CD3⁺CD8⁺ T cells (b) were analysed by flow cytometry. Boxes and whiskers represent the 25th−75th and 10th−90th percentiles, respectively; the median is the central line in each box. P-values were determined by the Mann–Whitney U-test.

Fig. 3

T cell repopulation in virological responder (VR) and virological non-responder (VNR) children is illustrated. CD27, CD45RA and CD38 expression in CD3⁺CD4⁺ T cells (a and b) and CD3⁺CD8⁺ T cells (c and d) were analysed in 14 VR children (a and c) and in 16 VNR children (b and d) at baseline and after 2 years of highly active anti-retroviral therapy. Data were compared with those obtained from 17 uninfected children. Boxes and whiskers represent the 25th−75th and 10th−90th percentiles, respectively; the median is the central line in each box. P-values were determined by the Wilcoxon test.

Fig. 2

T cell subsets are illustrated in virological responder (VR) and virological non-responder (VNR) children at highly active anti-retroviral therapy initiation. CD27, CD45RA and CD38 expression in CD3⁺CD4⁺ T cells (a) and CD3⁺CD8⁺ T cells (b) were analysed in 14 VR and 16 VNR children by flow cytometry. Boxes and whiskers represent the 25th−75th and 10th−90th percentiles, respectively; the median is the central line in each box. P-values were determined by the Mann–Whitney U-test.

Fig. 4

The dynamics of thymic output and CD4⁺CD45RA⁺CD27⁺ T cells in six virological responder (VR) and eight virological non-responder (VNR) children is illustrated. T cell receptor rearrangement excision circles (TREC) (a) and CD4⁺CD45RA⁺CD27⁺ T cell levels (b) were analysed at baseline and after 2 years of highly active anti-retroviral therapy. Slopes of TREC (c) and CD4⁺CD45RA⁺CD27⁺ T cells (d) in VR and VNR children. Boxes and whiskers represent the 25th−75th and 10th−90th percentiles, respectively; the central line in each box indicates the median. P-values were determined by the Wilcoxon (a and b) and the Mann–Whitney U-tests (c and d).

Fig. 5

Microbial translocation in human immunodeficiency virus type 1 (HIV-1)-infected children is illustrated. Plasma lipopolysaccharide levels were determined in HIV-1-uninfected and HIV-1-infected children before highly active anti-retroviral therapy (HAART) initiation (a) and in virological responder (VR) and virological non-responder (VNR) children at baseline and after HAART (b). Boxes and whiskers represent the 25th−75th and 10th−90th percentiles, respectively; the central line in each box indicates the median. *P < 0·001 in comparison of the control group versus HIV-1-infected children.