An in vitro proliferative defect has been observed in HIV-1-specific CD4+ T cells from infected subjects with high-level plasma HIV-1 viremia. To determine the mechanism of this defect, HIV-1 Gag-specific CD4+ T cells from treated and untreated HIV-1-infected subjects were analyzed for cytokine profile, proliferative capacity, and maturation state. Unexpectedly high frequencies of HIV-1-specific, IL-2-producing CD4+ T cells were measured in subjects with low or undetectable plasma HIV-1 loads, regardless of treatment status, and IL-2 frequencies correlated inversely with viral loads. IL-2-producing CD4+ T cells also primarily displayed a central memory (T Cm; CCR7+ CD45RA−) maturation phenotype, whereas IFN-γ-producing cells were mostly effector memory (T Em, CCR7− CD45RA−). Among Gag-specific, IFN-γ-producing CD4+ T cells, higher T Em frequencies and lower T Cm frequencies were observed in untreated, high viral load subjects than in subjects with low viral loads. The percentage of HIV-1 Gag-specific CD4+ T Cm correlated inversely with HIV-1 viral load and directly with Gag-specific CD4+ T cell proliferation, whereas the opposite relationships were observed for HIV-1-specific CD4+ T Em. These results suggest that HIV-1 viremia skews Gag-specific CD4+ T cells away from an IL-2-producing T Cm phenotype and toward a poorly proliferating T Em phenotype, which may limit the effectiveness of the HIV-1-specific immune response.