Immune activation during chronic HIV infection is a strong clinical predictor of 
death and may mediate CD4(+) T cell depletion. Regulatory T cells (Tregs) are 
CD4(+)CD25(bright)CD62L(high) cells that actively down-regulate immune 
responses. We asked whether loss of Tregs during HIV infection mediates immune 
activation in a cross-sectional study of 81 HIV-positive Ugandan volunteers. We 
found that Treg number is strongly correlated with both CD4(+) and CD8(+) T cell 
activation. In multivariate modeling, this relationship between Treg depletion 
and CD4(+) T cell activation was stronger than any other clinical factor 
examined, including viral load and absolute CD4 count. Tregs appear to decline 
at different rates compared with other CD4(+) T cells, resulting in an increased 
regulator to helper ratio in many patients with advanced disease. We hypothesize 
that this skewing may contribute to T cell effector dysfunction. Our findings 
suggest Tregs are a major contributor to the immune activation observed during 
chronic HIV infection.