HIV-1 Tat Protein Induces the Production of IDO in Human Monocyte Derived-Dendritic Cells through a Direct Mechanism: Effect on T Cells Proliferation

Abstract

During HIV-1 infection, an increase of indoleamine 2,3 dioxygenase (IDO) expression, and dendritic cells (DC) dysfunction were often associated with AIDS disease progression. In this work, we investigated the effect of HIV-1 Tat protein on the expression of IDO, in MoDCs. We show that Tat induces IDO protein expression and activity in a dose dependent manner by acting at the cell membrane. Using Tat-mutants, we show that the N-Terminal domain, Tat 1–45, but not the central region, Tat 30–72, is sufficient to induce the expression of active IDO. Tat protein is also able to induce several cytokines in MoDCs, including IFN-γ, a strong inducer of IDO. In order to understand whether IDO is induced directly by Tat protein or indirectly following IFN-γ production, complementary experiments were performed and showed that: i) at the kinetic level, Tat induced IDO expression before the production of IFN-γ ii) treatment of MoDCs with Tat-conditioned medium was unable to stimulate IDO expression, iii) coculture of MoDCs in a transwell cell system did not allow IDO expression in MoDCs not previously treated by Tat, iv) direct contact between Tat-treated and untreated MoDCs was not sufficient to induce IDO expression in a Tat-independent manner, and v) treatment of MoDCs in the presence of IFN-γ pathway inhibitors, Jak I and Ly294002, inhibited IFN-γ-induced IDO but had no effect on Tat-induced IDO. At the functional level, our data showed that treatment of MoDCs with Tat led to the inhibition of their capacity to stimulate T cell proliferation. This impairement was totally abolished when the stimulation was performed in the presence of 1MT, an inhibitor of IDO activity, arguing for the implication of the kynurenine pathway. By inducing IDO, Tat protein may be considered, as a viral pathogenic factor, in the dysregulation of the DC functions during HIV-1 infection.