Consequences of Treg expansion in HIV-infected patients. HIV infection leads to increased Treg frequencies directly through gp120/CD4 interaction and, indirectly, via alteration of DCs or as a consequence of generalized immune activation. Tregs can inhibit HIV-specific T-cell responses directly via a cell-cell contact dependent mechanism or through induction of IL-10 production by monocytes. However, HIV-specific CD8 T cells restricted by protective HLA alleles (in HIV controllers) are resistant to Treg-mediated suppression. Tregs may dampen low level of residual immune activation in ART-treated patients but are not efficient in primary and chronic untreated HIV-infected patients exhibiting high levels of immune activation. CD39 expression on Tregs increases during HIV infection and is associated with disease progression. Indeed, CD39 activity leads to elevated adenosine levels which activates the A2aR pathway involved in T-cell anergy and unresponsiveness. On the other hand, CD39⁺ Tregs might decrease viral replication in activated CD4 T cells through a cAMP-dependent mechanism.