The pathogenesis of human and simian immunodeficiency viruses is characterized by CD4⁺ T cell depletion and chronic T cell activation, leading ultimately to AIDS. CD4⁺ T helper (T_H) cells provide protective immunity and immune regulation through different immune cell functional subsets, including T_H1, T_H2, T regulatory (T_reg), and interleukin-17 (IL-17)–secreting T_H17 cells. Because IL-17 can enhance host defenses against microbial agents, thus maintaining the integrity of the mucosal barrier, loss of T_H17 cells may foster microbial translocation and sustained inflammation. Here, we study HIV-seropositive subjects and find that progressive disease is associated with the loss of T_H17 cells and a reciprocal increase in the fraction of the immunosuppressive T_reg cells both in peripheral blood and in rectosigmoid biopsies. The loss of T_H17/T_reg balance is associated with induction of indoleamine 2,3-dioxygenase 1 (IDO1) by myeloid antigen-presenting dendritic cells and with increased plasma concentration of microbial products. In vitro, the loss of T_H17/T_reg balance is mediated directly by the proximal tryptophan catabolite from IDO metabolism, 3-hydroxyanthranilic acid. We postulate that induction of IDO may represent a critical initiating event that results in inversion of the T_H17/T_reg balance and in the consequent maintenance of a chronic inflammatory state in progressive HIV disease.