CD4 T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester–based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4 T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4 T cells were identified in aviremic patients, CD45RA CCR7 central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA CCR7 effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-. Longitudinal analysis of HIV epitope–specific CD4 T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-–producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4 T cell memory depends on IL-2–producing CD4 T cells and that IFN-only–producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-only–producing cells that lack self-renewal capacity.