Alterations in CD4⁺ and CD8⁺ T-cells induced by HIV-1 infection will have a significant impact on immune function, and subsequently on HIV-1 disease progression. The objectives of our study are: (1) to determine if untreated HIV-1 infection and progression is associated with a premature aging in memory T-cells and naïve CD4⁺ T-cells; (2) to investigate the correlation between Regulatory T-cells (Tregs) and T-cell activation during untreated HIV-1 infection, as well as their association with disease progression. We conducted a nested case-control study within the Multicenter AIDS Cohort Study (MACS). Twenty HIV-1 infected fast progressors and 40 slow progressors were included in our study using risk-set sampling, as well as 9 age matched HIV uninfected men. Cryopreserved peripheral blood mononuclear cells (PMBC) were tested using flow cytometry analyses. Our data indicate that HIV-1 disease progression was associated with premature aging of memory T-cells as indicated by the accelerated loss of CD28 molecules in CD4⁺ and CD8⁺ T-cells and an enrichment of intermediate- and late- differentiated CD8⁺ T-cells. HIV-1 infection induced premature aging in the naïve CD4 ⁺ T-cell compartment as indicated by decreased CD31 expression on naïve CD4⁺ T cells of recent thymic origin, and induced a selective depiction of peripherally proliferated naïve CD4⁺ T-cells. Thus, the overall change during HIV-1 infection and progression is the shift of T-cell population towards an aged conformation, which may further be compromised by the impaired renewal of the younger CD4⁺ T-cell population. We further demonstrated that there was an increase of Tregs relative to other CD4⁺ T-cell subsets during HIV-1 infection, which was associated with disease progression. The increased Tell activation during HIV-1 infection correlated with HIV-1 disease progression. Counter to the assumed role of Tregs as the activation suppressor, the expansion of Tregs was positively correlated with CD4⁺ T-cell activation among HIV-1 infected fast progressors. The high level of Tregs associated with rapid HIV progression may suggest a detrimental role of these cells in the immune control of HIV-1 infection.