Shift of CMV-specific CD4+ T-cells to the highly differentiated CD45RO−CD27− phenotype parallels loss of proliferative capacity and precedes progression to HIV-related CMV end-organ disease

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 IFNγ+CD4+ and IFNγ+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 IFNγ+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 IFNγ in patients developing AIDS–CMV.