To identify factors related to progression to CMV end-organ disease, cytokine production, proliferative capacity and phenotype of CMV-specific CD4(+) T-cells were analysed longitudinally. Numbers of IFNgamma(+)CD4(+) and IFNgamma(+)IL-2(+)CD4(+) T-cells tended to decrease in individuals progressing to AIDS with CMV end-organ disease (AIDS-CMV), whereas they remained detectable in long-term asymptomatics (LTAs) and progressors to AIDS with opportunistic infections (AIDS-OI). In parallel, CMV-specific proliferative capacity was lost in AIDS-CMV. Initially, the majority of the CMV-specific IFNgamma(+)CD4(+) T-cells were of the CD45RO(+)CD27(-) subset, but during progression to AIDS-CMV a shift in phenotype to the CD45RO(-)CD27(-) subset was observed. Our data indicate that a decrease in CMV-specific cytokine production and proliferative capacity precedes progression to AIDS-CMV. Accumulation of CD4(+) T-cells with a CD45RO(-)CD27(-) phenotype suggests that persistent antigen exposure drives differentiation of CMV-specific CD4(+) T-cells towards a poorly proliferating, and highly differentiated "effector" subset, which eventually fails to produce IFNgamma in patients developing AIDS-CMV.