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IL-7 is essential for T-cell homeostasis. Elevated serum IL-7 levels in lymphopenic states, including HIV infection, are thought to be due to increased production by homeostatic feedback, decreased receptor-mediated clearance, or both. The goal of this study was to understand how immune reconstitution through antiretroviral therapy (ART) in HIV+ patients affects IL-7 serum levels, expression of the IL-7 receptor (CD127), and T-cell cycling. Immunophenotypic analysis of T cells from 29 HIV- controls and 43 untreated HIV+ patients (30 of whom were followed longitudinally for ≤ 24 months on ART) was performed. Restoration of both CD4+ and CD8+ T cells was driven by increases in CD127+ naive and central memory T cells. CD4+ T-cell subsets were not fully restored after 2 years of ART, whereas serum IL-7 levels normalized by 1 year of ART. Mathematical modeling indicated that changes in serum IL-7 levels could be accounted for by changes in the receptor concentration. These data suggest that T-cell restoration after ART in HIV infection is driven predominantly by CD127+ cells and that decreases of serum IL-7 can be largely explained by improved CD127-mediated clearance. [ABSTRACT FROM AUTHOR]