HIV inhibits CD4T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells

Infection with the human immunodefi- ciency virus type-1 (HIV) results in acute and progressive numeric loss of CD4 T-helper cells and functional impairment of T-cell responses. The mechanistic ba- sis of the functional impairment of the surviving cells is not clear. Indoleamine 2,3-dioxygenase (IDO) is an immunosup- pressive enzyme that inhibits T-cell prolif- eration by catabolizing the essential amino acid tryptophan (Trp) into the kynurenine (kyn) pathway. Here, we show that IDO mRNA expression is elevated in peripheral blood mononuclear cells (PB- MCs) from HIV patients compared with uninfected healthy controls (HCs), and that in vitro inhibition of IDO with the competitive blocker 1-methyl tryptophan (1-mT) results in increased CD4 T-cell proliferative response in PBMCs from HIV- infected patients. We developed an in vitro model in which exposure of PBMCs from HCs to either infectious or noninfec- tious, R5- or X4-tropic HIV induced IDO in plasmacytoid dendritic cells (pDCs). HIV- induced IDO was not inhibited by block- ing antibodies against interferon type I or type II, which, however, induced IDO in pDCs when added to PBMC cultures. Blockade of gp120/CD4 interactions with anti-CD4 Ab inhibited HIV-mediated IDO induction. Thus, induction of IDO in pDCs by HIV may contribute to the T-cell functional impairment observed in HIV/ AIDS by a non-interferon-dependent mechanism. (Blood. 2007;109:3351-3359)