Journal of Clinical Immunology, Vol. 23, No. 5, September 2003 ( C  2003) Increased Interleukin-7 Plasma Levels Are Associated with Recovery of CD4 + T Cells in HIV-Infected Children RAFAEL CORREA, 1 SALVADOR RESINO, 1 and M. ANGELES MU ˜ NOZ-FERN ´ ANDEZ 1,2 Accepted: April 5, 2003 To asses the role of interleukin 7 (IL-7) in the thymic recon- stitution of CD4 T cells observed in children after successful antiretroviral therapy, a longitudinal study in five vertically HIV-1-infected children was carried out. Thymic function, IL-7 plasma levels, viral load, and T-lymphocytes subsets were determined every 2 or 3 months for about 90 months. In all the children, the drop in CD4+ T cells below 5–10% was asso- ciated with a marked increase in IL-7 plasma levels. The drastic decrease in viral load after treatment, led in all the cases to a re- cover of CD4 to levels higher than 30%, which was associated to an increase in thymic production of T cells and followed by a de- crease in IL-7 to the normal levels. We conclude that the drop in CD4 in HIV children would induce an increase of IL-7 as part of a homeostatic mechanism. IL-7 would induce the thymus to pro- duce new T cells to recover the normal levels of CD4 when the viral load was low and so the thymic function was not inhibited. The increase in the thymic production of new T cells recovers the CD4 population, and leads to a normalization of IL-7 levels. KEY WORDS: IL-7; CD4; TRECs; HIV; children; immune reconstitution. INTRODUCTION HIV infection results in a severe immunodeficiency char- acterized by a marked decrease in the CD4 + T cells. This decrease could be the consequence of two facts; a pe- ripheral CD4 + T-cell depletion by the virus and an in- sufficient replacement of the destroyed T cells. Current treatments with HAART have been successful in substan- tially reducing viral load in these patients, but a complete 1 Department of Immunology, Hospital General Universitario “Gregorio Mara˜ n´ on,” Madrid, Spain. 2 To whom correspondence should be addressed at Servicio de In- munolog´ ıa, HGU Gregorio Mara˜ n´ on, C/Dr. Esquerdo, 46 28007 Madrid, Spain; e-mail: mmunoz@cbm.uam.es. immunologic recovery is not usually achieved, and thus, discontinuation of antiretroviral treatment results in even- tual rebound in the viral load. Therefore, one of the current challenges in the treatment of HIV lies in achieving a com- plete restoration of the immune responses to the virus. After antiretroviral therapy, a substantial increase in na¨ ıve CD4 + T cells has been reported (1–3). This fact could be explained by the redistribution or peripheral ex- pansion of preexistent na¨ ıve cells (2); by the recovery of thymic production of new T cells (4) ; or by reversion from memory to na¨ ıve phenotype in peripheral T cells (5). Thus, the identification of the source of na¨ ıve cells is an im- portant issue in immune recovery since a redistribution of proliferation of the preexistent cells only increases the number of cells from the clones that have survived the infection. In contrast, the thymic production of new T cells can lead to the recovery of the entire repertoire of specificities, some of them lost with the infection, includ- ing the specific HIV clones, that have been shown to be preferentially depleted by the virus (6). Along these lines, the thymus has demonstrated to play a key role in the reconstitution of the immune system in HIV-infected patients, mainly in children (4, 7). Thus, treatments that enhance this thymic function, could lead to the recuperation of the immune responses against HIV and other opportunistic pathogens. The observation that, after suppression of viral load, there is a marked increase in the thymic production of new T cells to recover the depleted CD4 + population (4) supports the hypothesis that a compensatory feedback loop might exist, which would lead to an increase in T-cell production. This homeostatic mechanism might be regulated by produc- tion of factors that stimulates the differentiation, survival and/or, expansion of T cells, as it has been described for other hematopoietic lineages (8, 9). A similar feedback loop might connect the peripheral lymphoid compartment with bone marrow or thymus, regulating the homeostasis in the lymphoid lineage (10). 401 0271-9142/03/0900-0401/0 C  2003 Plenum Publishing Corporation