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CD4+ T-cell depletion is central to HIV pathogenesis. However, the relative impact of HIV on Th17 and regulatory T cell (Treg) subsets remains unclear. CD161+ CD4 cells are a recently identified, gut-homing Th17 precursor population. The balance between pro-inflammatory Th17 and immunoregulatory Tregs may be critical in HIV pathogenesis. This study addressed changes in CD161+, Th17 and Treg subsets during untreated HIV infection.Peripheral blood mononuclear cells were isolated from HIV-infected and HIV-uninfected individuals and stained to characterize CD161+ CD4 cells, Th17 cells [by elaboration of interleukin (IL)-17A], Tregs (CD3+CD4+CD25hiFoxP3+ cells) and CD8 activation (CD38+/HLA-DR+ cells). In-vitro infectability of CD161+ and Th17 cells by HIV was assessed in healthy donor CD4 cells by intracellular p24 expression.Peripheral blood Th17 cells were depleted 10-fold in HIV-infected, compared to HIV-uninfected individuals (P < 0.0001) across a range of disease stages, accompanied by a significant reduction of CD161+ T cells (P = 0.024). Both Th17 cells and CD161+ CD4+ T cells were permissive to HIV replication in vitro. Profound loss of Th17 cells before the onset of advanced disease contrasted with a gradual decline in absolute Tregs during HIV disease progression in untreated individuals followed longitudinally (R = 0.71, P = 0.003). Loss of Tregs was associated with increased immune activation (R = −0.33, P = 0.03).HIV-infected individuals showed profound loss of Th17 cells, which may impair mucosal immunity, and reduced CD161+ CD4 cells, which may limit Th17 reconstitution. A gradual decline in Tregs during disease progression was associated with increased immune activation.