Functional and phenotypic characterization of CD57+CD4+ T cells and their association with HIV-1-induced T cell dysfunction

HIV-1 replication is associated with reduced or absent HIV-1-specific CD4(+) T cell proliferation and skewing of HIV-1-specific CD4(+) T cells toward an IFN-gamma-producing, CCR7(-) phenotype. The CCR7- T cell population is heterogeneous and can be subdivided based on the expression of CD57. Although CD57 expression on CD8(+) T cells is associated with proliferation incompetence and replicative senescence, less is known about the function of CD57(-)expressing CD4(+) T cells. In this study, the frequency, phenotype, and function of CD57(+)CD4(+) T cells were evaluated in 25 HIV-1-infected subjects and 10 seronegative controls. CD57(+)CD4(+) T cells were found to be proliferation incompetent, even after strong mitogen stimulation. Percentages of CD4(+) T cells that expressed CD57 were significantly higher in untreated HIV-1-infected subjects than in HIV-1-seronegative donors, and CD57 expression did not normalize in subjects receiving at least 6 mo of effective antiretroviral therapy. CD57 was predominately expressed on the CCR7(-) fraction of the CD4(+) T cell compartment and accounted for the majority of cells in the CCR7(-)CD45RA(+) population from untreated HIV-1-infected subjects. HIV-1-specific CD4(+) T cells producing only IFN-gamma had the highest expression of CD57, whereas few cells producing IL-2 alone expressed CD57. These findings further define a novel population of proliferation-incompetent CD4(+) T cells that are generated in the presence of chronic Ag exposure. A better understanding of the generation and persistence of CD57(+) T cells in HIV-1 infection could provide important insights into the immunopathogenesis of this disease.