Decreased CD4+ T cell counts are the best marker of disease progression during HIV infection. However, CD4+ T cells are heterogeneous in phenotype and function, and it is unknown how preferential depletion of specific CD4+ T cell subsets influences disease severity. CD4 + T cells can be classified into three subsets by the expression of receptors for two T cell-tropic cytokines, IL-2 (CD25) and IL-7 (CD127). The CD127+CD25low/- subset includes IL-2-producing naive and central memory T cells; the CD127-CD25- subset includes mainly effector T cells expressing perform and IFN-γ; and the CD127 lowCD25high subset includes FoxP3-expressing regulatory T cells. Herein we investigated how the proportions of these T cell subsets are changed during HIV infection. When compared with healthy controls, HIV-infected patients show a relative increase in CD4+CD127-CD25 - T cells that is related to an absolute decline of CD4 +CD127+CD25low/- T cells. Interestingly, this expansion of CD4+CD127- T cells was not observed in naturally SIV-infected sooty mangabeys. The relative expansion of CD4 +CD127-CD25- T cells correlated directly with the levels of total CD4+ T cell depletion and immune activation. CD4+CD127-CD25- T cells were not selectively resistant to HIV infection as levels of cell-associated virus were similar in all non-naive CD4+ T cell subsets. These data indicate that, during HIV infection, specific changes in the fraction of CD4+ T cells expressing CD25 and/or CD127 are associated with disease progression. Further studies will determine whether monitoring the three subsets of CD4+ T cells defined based on the expression of CD25 and CD127 should be used in the clinical management of HIV-infected individuals. The Journal of Immunology, 2008, 180:.