Continuous improvement in the immune system of HIV-infected children on prolonged antiretroviral therapy

Abstract

Background: The goal of HAART is to promote reconstitution of CD4+ T cells and other immune responses. We evaluated the extent and the kinetics of immune reconstitution in HIV-infected children over 144 weeks of successful HAART.

Methods: Thirty-seven children receiving their first HAART regimen had plasma HIV RNA; T cells and subpopulations; T-cell rearrangement excision circles (TREC) DNA; candida, HIVCD4 and HIVCD8 enzyme-linked immunospot measured at regular intervals.

Results: Plasma HIV RNA became undetectable in 81% of patients at 24 weeks and remained undetectable in 77% at 144 weeks. In contrast, CD4+% continuously increased. Distribution of T-cell subpopulations changed rapidly during the first 48 weeks of HAART and more slowly thereafter. At 144 weeks, total, naive and activated CD4+% and naive CD8+% of HIV-infected children were not significantly different from those of healthy age-matched controls, whereas total and activated CD8+% remained elevated. CD4 and CD8 TREC content increased only during the first 48 weeks of HAART. They positively correlated with each other and with total CD4+%, naive CD4+% and naive CD8+%. Candida and HIVCD4 enzyme-linked immunospot increased over time reaching peak values at 48 weeks and 144 weeks, respectively. HIVCD8 enzyme-linked immunospot decreased in magnitude over 144 weeks of HAART but retained its breadth. Baseline CD4+% positively correlated with CD4+% and with functional immune reconstitution at week 144, whereas baseline TREC correlated with TREC at week 144.

Conclusion: HIV-infected children acquired normal distribution of CD4 T cells and other subpopulations and recovered CD4-mediated HIV immunity after 144 weeks of HAART.

Figures

Fig. 1. Kinetics of plasma HIV RNA levels and CD4+% in HIV-infected children on their first HAART regimen

(a) HIV RNA and (b) CD4+%. Data represent medians, upper and lower quartiles at each time point by age group. The continuous line indicates data derived from 21 children aged 3-12 years and the interrupted line from 16 children aged 13-21 years. N1 indicates the number of patients in the younger group that contribute data at each time point and N2 in the older group.

Fig. 2. Kinetics of lymphocyte subpopulations in HIV-infected children receiving their first HAART regimen

Boxes represent upper and lower quartiles with the median as an internal line; whiskers show 95% upper and lower boundaries; and asterisks indicate outliers. N indicates the number of patients contributing data at each time point. (a) Naive CD4+CD45RA+CD62L+%; (b) activated CD4+CD38+HLADR+%; (c) naive CD8+CD45RA+CD62L+%; (d) activated CD8+CD38+HLADR %; (e) memory CD4+CD28+CD95+% over time of HAART.

Fig. 3. Kinetics of CD4+ and CD8+ T-cell rearrangement excision circle content in HIV-infected children on their first HAART regimen

(a) CD4+TREC; (b) CD8+TREC DNA contents per 106 CD4+ and CD8+ cells, respectively. The continuous line indicates data derived from 21 children aged 3-12 years and the interrupted line from 16 children aged 13-21 years. N1 indicates the number of patients in the younger group that contribute data at each time point and N2 in the older group. TREC, T-cell rearrangement excision circle.

Fig. 4. Functional immune reconstitution in HIV-infected children receiving their first HAART regimen

Boxes represent upper and lower quartiles with the median as an internal line; whiskers show 95% upper and lower boundaries; and asterisks indicate outliers. N indicates the number of patients contributing data at each time point. (a) The time course of candida-specific ELISPOT responses; (b) CD8-mediated HIV-specific ELISPOT responses after stimulation with peptide pools derived from Gag, Pol, Nef and Env; (c) the breadth of CD8-mediated HIV-specific ELISPOT responses expressed as a fraction of the number of peptide pools that elicited any response divided by the total number of pools tested; (d) CD4-mediated HIV-specific responses after stimulation with inactivated whole HIV virion. N indicates the number of patients contributing data at each time point. ELISPOT, enzyme-linked immunospot; PBMC, peripheral blood mononuclear cells; SFC, spot forming centers.