The importance of functional CD4+ T cells and antigen control in the maintenance of CD127 expression on antigen-specific CD8+ T cells is poorly understood in humans. We compared CD127 expression on antigen-specific CD8+ T cells in 4 groups of human immunodeficiency virus (HIV)-infected patients. This analysis demonstrated that HIV-specific CD8+CD127hi T cells are maintained as long-lived memory cells only in HIV-infected individuals treated early with antiretroviral therapy (ART). This population of CD127hi T cells fluctuates with viral load (VL) such that the antigen-specific T cell pool oscillates from a CD127 hi memory to a CD127lo effector phenotype depending on the levels of plasma VL. In individuals with chronic infection, the CD127 hi pool diminishes or is lost with time despite virologic control while receiving ART. These studies show that functionally competent subsets of antigen-specific memory CD8+ T cells in HIV-infected individuals are maintained but only if control of viremia is attained early during the course of infection. © 2006 by the Infectious Diseases Society of America. All rights reserved.