HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-α

Abstract

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

Plasmacytoid dendritic cells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patients

“…14,15,18 This phenomenon is also seen after stimulation of pDCs with ligands for other intracellular TLRs, but not after incubation with agonists for TLR1-6 (Madeleine Kalb, G. Stary, F.K., and G. Stingl, manuscript in preparation: "The molecular players of TLR7/8-triggered dendritic cell cytotoxicity"). 15 Keeping in mind that HIV motifs can serve as natural TLR7 agonists, 16,17 we screened PBMCs of HIV-infected persons for TRAIL expression and, indeed, found such an occurrence on different leukocyte subsets.…”

“…Because TRAIL expression on pDCs is influenced by IFN-␣, 18 we performed inhibition experiments by adding neutralizing antibodies against either (1) TRAIL, (2) IFN-␣, (3) TRAIL plus IFN-␣, or, for control purposes, (4) Fas ligand. As shown in Figure 4C, preincubation of pDCs from a HIV-1 viremic patient with inhibitory anti-TRAIL plus anti-IFN-␣ antibodies essentially abolished pDC cytotoxicity against CD4 ϩ T cells from a HIV-1 viremic patient, whereas anti-Fas ligand antibodies had no effect.…”

“…16,17 TLR7 ligands are potent inducers of IFN-␣, and autologous IFN-␣ production can lead to surface expression of TRAIL on pDCs, endowing them to induce apoptosis in a TRAIL-sensitive tumor cell line. 15,18 Here, we sought to explore the in vivo relevance of this in vitro phenomenon by searching for and by phenotypically and functionally characterizing TRAIL-expressing cells in persons infected with HIV-1.…”

The TRAIL of Helpless CD8+T Cells in HIV Infection

“…28 In HIV infection, increased plasma levels of TRAIL have been reported affecting monocytes 25 and contributing to the characteristic depletion of CD4 ϩ T cells seen in this disease. [29][30][31] At the same time, TRAIL has not been studied yet in the conceptual framework of helpless CD8 ϩ T cells in humans. Because CD4 ϩ T cells are infected and depleted in the course of HIV infection, it seems conceivable that the resulting lack of CD4 ϩ T cell help will impair specific CD8 ϩ T cell immunity to HIV contributing to the inability to control the infection.…”

HIV Type 1 Infection of Plasmacytoid and Myeloid Dendritic Cells Is Restricted by High Levels of SAMHD1 and Cannot be Counteracted by Vpx

“…pDCs likely play a role in the early stages of infection by recruiting CCR5 + CD4 + T cells to mucosal sites of transmission 11 and by inducing the activation and apoptosis of CD4 + T cells through the production of type-I IFN. 12 While mDCs and pDCs express CD4 and CCR5 and can bind and internalize HIV-1, they are resistant to infection in vitro.…”