IntroductionThe immunologic hallmark of the acquired immunodeficiency syndrome (AIDS), resulting from infection with the human immunodeficiency virus type-1 (HIV), is the depletion of CD4 ϩ T cells. 1 However, qualitative alterations of the function of circulating T cells are observed that do not appear to be related to the decline of CD4 ϩ T-cell number. [2][3][4][5] In vitro T-cell responses are impaired in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients. Thus, proliferative responses to HIV epitopes are lost early during infection, 6-8 followed by sequential impairment of T-helper cell responses to recall antigens and mitogens. 9 This progressive loss of T-cell function during the course of HIV disease is predictive for the time of onset of AIDS and death. 10 Tryptophan (Trp) catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory mechanism that limits T-cell proliferation by depletion of the essential amino acid Trp and/or accumulation of catabolites with immune-suppressive activity (kynurenines, kyn). 11 Alterations of this mechanism have been suggested to be involved in (1) development of autoimmune conditions, such as multiple sclerosis and autoimmune diabetes 12,13 ; (2) failure of immune surveillance of tumor cells 14 ; and (3) rejection of semiallogenic fetuses. 15,16 The molecular basis for T-cell hyporesponsiveness in IDO-mediated Trp depletion has been recently clarified. The consequence of reduction in available Trp in the extracellular microenvironment is the accumulation of uncharged Trp-specific transfer RNA (free-tRNA trp ) in the cytoplasm. 17 Free-tRNA trp binds to the GCN2 kinase, a key enzyme of the cellular stress-response system. 17 Once activated by ligation to free-tRNA trp , the GCN2 kinase initiates a cascade of events leading to arrest of the cell cycle, which is, in turn, the ultimate effect of tryptophan starvation. 17 Increased IDO-mediated tryptophan catabolism during HIV infection has been reported. [18][19][20][21] IDO is induced in macrophages by HIV infection, and has been suggested to be involved in the induction of HIV encephalitis and AIDS-related dementia. 20,22,23 Inhibition of HIV-induced IDO in brain macrophages enhanced HIV-specific cytotoxic T-lymphocyte (CTL) response and elimination of infected macrophages in a murine model. 24 We recently reported that IDO mRNA expression is increased in the tonsils of HIV-infected patients in whom viral replication is not controlled by effective antiretroviral therapy (ART). 25 A similar increase of IDO was found in lymphoid tissues of macaques during acute simian immunodeficiency virus (SIV) and chronic SIV/HIV infection, and correlated with reduced immune responses. 26,27 However, the functional role of IDO in HIV-associated immunosuppression is unknown.In the present study, we tested the effect of 1-methyl-tryptophan (1-mT), a competitive inhibitor of IDO, on the stimulation of The online version of this article contains a data supplement.The publication costs of this article were ...

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Plasmacytoid dendritic cells (pDC) are key players in viral immunity and produce IFN-␣ after HIV-1 exposure, which in turn regulates TNF-related apoptosis-inducing ligand (TRAIL) expression by CD4 ؉ T cells. We show here that infectious and noninfectious HIV-1 virions induce activation of pDC into TRAIL-expressing IFN-producing killer pDC (IKpDC). IKpDC expressed high levels of activation markers (HLA-DR, CD80, CD83, and CD86) and the migration marker CCR7. Surprisingly, CXCR4 and CCR5 were down-regulated on IKpDC. We also show that HIV-1-induced IKpDC depended on Toll-like receptor 7 (TLR7) activation. HIV-1 or TLR7 agonistexposed IKpDC induced apoptosis of the CD4 ؉ T cell line SupT1 via the TRAIL pathway. Furthermore, IFN-␣ produced after HIV-induced TLR7 stimulation was responsible for TRAIL expression and the down-regulation of both CXCR4 and CCR5 by IKpDC. In contrast, activation and migration markers were not regulated by IFN-␣. Finally, IFN-␣ increased the survival of IKpDC. We characterized a subset of pDC with a killer activity that is activated by endosomal-associated viral RNA and not by infection.apoptosis ͉ endocytosis ͉ AT-2 HIV-1 ͉ CCR5 ͉ CXCR4