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Here, we report on the expression of programmed death (PD)-1 on human virus-specific CD8⁺ T cells and the effect of manipulating signaling through PD-1 on the survival, proliferation, and cytokine function of these cells. PD-1 expression was found to be low on naive CD8⁺ T cells and increased on memory CD8⁺ T cells according to antigen specificity. Memory CD8⁺ T cells specific for poorly controlled chronic persistent virus (HIV) more frequently expressed PD-1 than memory CD8⁺ T cells specific for well-controlled persistent virus (cytomegalovirus) or acute (vaccinia) viruses. PD-1 expression was independent of maturational markers on memory CD8⁺ T cells and was not directly associated with an inability to produce cytokines. Importantly, the level of PD-1 surface expression was the primary determinant of apoptosis sensitivity of virus-specific CD8⁺ T cells. Manipulation of PD-1 led to changes in the ability of …