Virus-specific CD8⁺ T cells emerge after infection with herpesviruses and maintain latency to these persistent pathogens. It has been demonstrated that murine memory CD8⁺ T-cell precursors specific for acute lymphocytic choriomeningitis virus express interleukin-7 receptor α (IL-7Rα), and IL-7 is involved in maintaining memory populations after the clearance of antigen. To investigate whether human CD8⁺ T cells reactive toward persistent viruses are maintained similarly, we analyzed IL-7Rα expression and function on these virus-specific cells. During primary infection, all cytomegalovirus (CMV)-specific CD8⁺ T cells and most Epstein-Barr virus (EBV)-specific CD8⁺ T cells lacked IL-7Rα expression. Only some virus-specific T cells expressed IL-7Rα late after viral replication became undetectable. CD8⁺ T cells specific for cleared viruses, influenza (FLU), and respiratory syncytial virus (RSV) all expressed IL-7Rα. Remarkably, the percentage of IL-7Rα^- CMV-specific T cells correlated with the height of viral replication in the acute phase. Virus-specific IL-7Rα⁺ cells proliferated vigorously in response to IL-7, IL-15, or peptide, whereas IL-7Rα^- cells required both peptide and helper-cell activation or IL-2 or IL-15 for optimal expansion. Our data suggest that although IL-7 is essential for the maintenance of memory cells in the absence of antigen, CD8⁺ T cells specific for latent viruses need T-cell receptor activation plus helper factors to persist. (Blood. 2005;106:2091-2098)