Session 44Poster Presentations Lymphocyte Dynamics Session Day and Time: Wednesday 1:30 - 3:30 pm Room: Hall D
337 T-cell Dynamics in HIV-1 Infected Children: A Longitudinal Study on TRECs, T-cell Numbers and Peripheral T-cell Division before and during Antiretroviral Therapy M. Hazenberg*1, J. Borghans1, S.Otto1, A. van Rossum2, H. Scherpbier3, R. de Groot2, T. Kuijpers3, J. lange3, D. Hamann1, R. de Boer4, F. Miedema1 1Sanquin Res at CLB and Academic Med Ctr, Amsterdam, The Netherlands; 2Sophia's Children Hosp, Rotterdam, The Netherlands; 3Academic Med Ctr, Amsterdam, The Netherlands; and 4Theoretical Biology, Utrecht Univ, The Netherlands
Background: Interference of HIV-1 with thymic function may be more easily demonstrable in pediatric HIV-1, because thymic output is higher in infants compared to adults. Measurement of T-cell receptor excision circles (TRECs) has been thought to allow quantitative analysis of thymic function. However, apart from thymic output, TREC dynamics are strongly influenced by other factors such as T-cell division and longevity of T-cells. It is not known to what extent pediatric T-cell division rates change with age and are affected by HIV-1 infection.
Methods: We combined longitudinal analyses of (CD45RA+CD27+) naive and (CD45RA- CD27+ or CD27-) memory CD4+ T-cell numbers and TREC dynamics with T-cell division rates (using Ki67 expression) in healthy (n = 29) and HIV-1 infected children (n = 16) of different ages before and during antiretroviral therapy. As CD4+ T-cell dynamics in children are affected by body growth, TREC dynamics were analyzed using a mathematical model accounting for body size.
Results: In healthy and HIV-1 infected children, T-cell division was strongly dependent on age, such that the youngest children had the highest proportions of Ki67+ naive and memory CD4+ T-cells. HIV-1 infection led to a significant increase in the fraction of Ki67+ T-cells in all subsets; Ki67 expression in HIV-1 infected children was several-fold higher than in adults. CD4 T-cell TREC contents in HIV-1 infected children were reduced, mainly in children under 6 yrs of age, suggesting thymic dysfunction. However, these children also showed the highest increase in T-cell division rates. Antiretroviral therapy led to an improvement of all parameters, comparable to immune restoration observed in adults. However, when related to age-matched reference values, naive CD4+ T-cell numbers failed to normalize in children older than 2 yrs.
Conclusions: Analyses of TRECs and naive T-cell numbers suggested early interference of HIV-1 with the establishment of the T-cell pool, but did not provide evidence for, nor excluded, ongoing thymic dysfunction. Immune activation by HIV-1 could explain the increased dilution of TRECs in HIV-1 infected children, as in adults. The fact that naive CD4+ T-cell numbers failed to normalize during antiretroviral therapy suggested that even in children recuperating from T-cell depletion, thymic output remains rather constant, albeit at higher levels compared to adults.
