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Changes in T-cell function are a hallmark of human immunodeficiency virus type 1 (HIV-1) infection, but the pathogenic mechanisms leading to these changes are unclear. We examined the gene expression profiles in ex vivo human CD4! and CD8! T cells from untreated HIV-1-infected individuals at different clinical stages and rates of disease progression. Profiles of pure CD4! and CD8! T-cell subsets from HIV-1-infected nonprogressors with controlled viremia were indistinguishable from those of individuals not infected with HIV-1. Similarly, no gene clusters could distinguish T cells from individuals with early infection from those seen in chronic progressive HIV-1 infection, whereas differences were observed between uninfected individuals or nonprogressors versus early or chronic progressors. In early and chronic HIV-1 infection, three character-istic gene expression signatures were observed. (i) CD4! and CD8! T cells showed increased expression of interferon-stimulated genes (ISGs). However, some ISGs, including CXCL9, CXCL10, and CXCL11, and the interleukin-15 alpha receptor were not upregulated. (ii) CD4! and CD8! T cells showed a cluster similar to that observed in thymocytes. (iii) More genes were differentially regulated in CD8! T cells than in CD4! T cells, including a cluster of genes downregulated exclusively in CD8! T cells. In conclusion, HIV-1 infection induces a persistent T-cell transcriptional profile, early in infection, characterized by a dramatic but poten