Altered phenotype of regulatory T cells associated with lack of human immunodeficiency virus (HIV)-1-specific suppressive function

Mechanisms by which CD4 ⁺ regulatory T cells (T _regs) mediate suppression of virus-specific responses remain poorly defined. Adenosine, mediated via CD39 and CD73, has been shown to play a role in the action of murine T _regs. In this study we investigate the phenotype of T _regs in the context of human immunodeficiency virus (HIV)-1 infection, and the function of these cells in response to HIV-1-Gag and cytomegalovirus (CMV) peptides. Phenotypic data demonstrate a decrease in forkhead box transcription factor 3 (FoxP3 ⁺) T _reg numbers in the peripheral blood of HIV-1 ⁺ individuals compared to healthy controls, which is most pronounced in those with high HIV-1 RNA plasma load. Due to aberrant expression of CD27 and CD127 during HIV-1 disease, these markers are unreliable for T _reg identification. The CD3 ⁺CD4 ⁺CD25 ^hiCD45RO ⁺ phenotype correlated well with FoxP3 expression in both the HIV-1 ⁺ and seronegative control cohorts. We observed expression of CD39 but not CD73 on T _regs from HIV-1 ⁺ and healthy control cohorts. We demonstrate, through T _reg depletion, the suppressive potential of T _regs over anti-CMV responses in the context of HIV-1 infection; however, no recovery of the HIV-1-specific T cell response was observed indicating a preferential loss of HIV-1-specific T _reg function. We propose that before immunotherapeutic manipulation of T _regs is considered, the immunoregulatory profile and distribution kinetics of this population in chronic HIV-1 infection must be elucidated fully.