The mechanism of CD4⁺ T-cell depletion during chronic human immunodeficiency virus type 1 (HIV-1) infection remains unknown. Many studies suggest a significant role for chronic CD4⁺ T-cell activation. We assumed that the pathogenic process of excessive CD4⁺ T-cell activation would be reflected in the transcriptional profiles of activated CD4⁺ T cells. Here we demonstrate that the transcriptional programs of in vivo-activated CD4⁺ T cells from untreated HIV-positive (HIV⁺) individuals are clearly different from those of activated CD4⁺ T cells from HIV-negative (HIV⁻) individuals. We observed a dramatic up-regulation of cell cycle-associated and interferon-stimulated transcripts in activated CD4⁺ T cells of untreated HIV⁺ individuals. Furthermore, we find an enrichment of proliferative and type I interferon-responsive transcription factor binding sites in the promoters of genes that are differentially expressed in activated CD4⁺ T cells of untreated HIV⁺ individuals compared to those of HIV⁻ individuals. We confirm these findings by examination of in vivo-activated CD4⁺ T cells. Taken together, these results suggest that activated CD4⁺ T cells from untreated HIV⁺ individuals are in a hyperproliferative state that is modulated by type I interferons. From these results, we propose a new model for CD4⁺ T-cell depletion during chronic HIV-1 infection.