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To further understand differentiation and homeostasis of CD8 T cells specific for HIV, Epstein–Barr Virus (EBV) and cytomegalovirus (CMV) during HIV infection, we investigated interleukin-7 receptor α (IL-7Rα) expression on those virus-specific T cells.Microarrays and cytometry analyses were performed on peripheral blood mononuclear cells (PBMC), total and tetramer-binding virus-specific CD8 T cells from 66 HIV-infected patients.Microarray analysis revealed reduced levels of IL-7Rα and increased levels of perforin with disease progression in total PBMC. This loss of IL-7Rα expression was observed on CD8 T cells and was inversely related to perforin expression. The relative expression of both molecules defined three new subsets: IL-7RαposPerforinneg; IL-7RαlonegPerforinlo; and IL-7RαlonegPerforinhi corresponding to naive and effector-memory CD8 differentiation, as assessed by CD45RA/CD11a. The IL-7Rα expression decreased along the CD8 differentiation pathway defined by CD27 and CD28. In contrast, IL-7Rα expression was down-modulated on all the CD8 T cells specific for HIV, EBV and CMV that were almost exclusively IL-7Rαlo/negPerforinlo and was parallel with the CD27 expression. In addition, this low IL-7Rα expression on HIV-specific CD8 T cells was independent of virus load and T-cell activation and remained stable during the first 6 months of antiretroviral therapy despite successful control of HIV replication.The relative expression of IL-7Rα, perforin reveals new aspects of virus-specific CD8 T cell differentiation, independently of T-cell activation and virus load. This opens new perspectives for understanding homeostasis of those cells and immune-based therapeutic strategies.