Elevated effector cell sensitivity to Treg-cell suppression that is not associated with reduced Th17-cell expression distinguishes HIV ⁺ asymptomatic subjects from progressors

Suppression mediated by Treg cells is a balance between Treg-cell suppressive potency versus sensitivity of effector cells to Treg-cell suppression. We assessed if this balance, along with Treg-cell number relative to the Treg-cell counter-regulatory cytokine IL-17, differs between asymptomatic HIV ⁺ subjects versus those who progress onto disease. Cross-over studies comparing Treg-cell potency, measured by effector cell proliferation or IFN-γ expression, from HIV-infected versus control subjects to suppress the proliferation of allogeneic control effector cells demonstrated increased sensitivity of CD4 ⁺CD25 ^- effector cells from asymptomatic HIV ⁺ subjects to suppression, rather than an increase in the suppressive potential of their CD4 ⁺CD25 ⁺ Treg cells. In contrast, HIV ⁺ progressors did not differ from controls in Treg-cell potency or effector cell sensitivity to Treg-cell suppression. Both CD4 ⁺CD25 ⁺Foxp3 ⁺ Treg and effector IL-17 absolute cell numbers were significantly lower in all HIV ⁺ subjects tested and not restored by antiviral therapy. Thus, these novel data suggest that elevated Treg-cell-mediated suppression due to increased sensitivity of effectors to Treg cells may be a natural host response in chronic asymptomatic HIV infection, which is lost as disease progresses and that this feature of CD25 ^- effector cells is not inextricably linked to reduced production of the Treg-cell counter-regulatory cytokine IL-17.