DCIR-mediated enhancement of HIV-1 infection requires the ITIM-associated signal transduction pathway

• Published in: Blood 2011-06, Vol.117 (24), p.6589-6599
• Main Authors: Lambert, Alexandra A., Barabé, Frédéric, Gilbert, Caroline, Tremblay, Michel J.
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - physiology; Cells, Cultured; Disease Progression; HIV Infections - genetics; HIV Infections - metabolism; HIV Infections - pathology; HIV-1 - growth & development; HIV-1 - physiology; Humans; Lectins, C-Type - chemistry; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Lectins, C-Type - physiology; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Phosphorylation - genetics; Protein Binding - drug effects; Protein Binding - physiology; Protein Interaction Domains and Motifs - genetics; Protein Interaction Domains and Motifs - physiology; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Receptors, Immunologic - chemistry; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Receptors, Immunologic - physiology; Signal Transduction - genetics; Signal Transduction - physiology; Tyrosine - metabolism; Tyrosine - physiology; Up-Regulation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-01-331363

Dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor expressed at high levels on dendritic cells (DCs). This surface molecule acts as an attachment factor for HIV-1 on DCs and contributes to trans- and cis-infection pathways. Moreover, DICR is induced by HIV-1 in CD4+ T cells and promotes virus replication in this cell type. Nothing is known hitherto about the DCIR-dependent signaling, which is induced following HIV-1 ligation. First, specific pharmacologic inhibitors were tested on HIV-1 binding/entry and, second, specific antisense oligonucleotides targeted, more specifically kinases and phosphatases, were used. Our results show that SHP-1, SHP-2, Syk, and Src kinases (ie, Src, Fyn, and Hck) as well as PKC-α and MAP kinases (ie, Erk1/2 and p38) are all involved in the DCIR-mediated signal transduction pathway triggered by HIV-1. By mutagenesis and through the use of intracellular phosphorylated peptides, we show as well a pivotal role for the tyrosine and threonine residues of the DCIR immunoreceptor tyrosine-based inhibitory motif (ITIM). Our data suggest for the first time an involvement of ITIM domain in HIV-1–mediated signaling events and a relationship between phosphorylation events and DCIR function with respect to HIV-1 biology.