title: HIV-1 Tat Protein Induces Production of Proinflammatory Cytokines by Human Dendritic Cells and Monocytes/Macrophages through Engagement of TLR4-MD2-CD14 Complex and Activation of NF-κB Pathway.
abstract: We recently reported that the human immunodeficiency virus type-1 (HIV-1) Tat protein induced the expression of programmed death ligand-1 (PD-L1) on dendritic cells (DCs) through a TLR4 pathway. However, the underlying mechanisms by which HIV-1 Tat protein induces the abnormal hyper-activation of the immune system seen in HIV-1 infected patients remain to be fully elucidated. In the present study, we report that HIV-1 Tat protein induced the production of significant amounts of the pro-inflammatory IL-6 and IL-8 cytokines by DCs and monocytes from both healthy and HIV-1 infected patients. Such production was abrogated in the presence of anti-TLR4 blocking antibodies or soluble recombinant TLR4-MD2 as a decoy receptor, suggesting TLR4 was recruited by Tat protein. Tat-induced murine IL-6 and CXCL1/KC a functional homologue of human IL-8 was abolished in peritoneal macrophages derived from TLR4 KO but not from Wt mice, confirming the involvement of the TLR4 pathway. Furthermore, the recruitment of TLR4-MD2-CD14 complex by Tat protein was demonstrated by the activation of TLR4 downstream pathways including NF-κB and SOCS-1 and by down-modulation of cell surface TLR4 by endocytosis in dynamin and lipid-raft-dependent manners. Collectively, these findings demonstrate, for the first time, that HIV-1 Tat interacts with TLR4-MD2-CD14 complex and activates the NF-κB pathway, leading to overproduction of IL-6 and IL-8 pro-inflammatory cytokines by myeloid cells from both healthy and HIV-1 infected patients. This study reveals a novel mechanism by which HIV-1, via its early expressed Tat protein, hijacks the TLR4 pathway, hence establishing abnormal hyper-activation of the immune system.
authors.affiliation: INSERM, U1043, Toulouse, France, CNRS, U5282, Toulouse, France; Université Paul Sabatier Toulouse, Toulouse, France; Department of Infectious Diseases, Toulouse University Hospital, Toulouse, France.
authors.forename: Nawal
authors.initials: N
authors.lastname: Ben Haij
authors.affiliation: INSERM, U1043, Toulouse, France, CNRS, U5282, Toulouse, France; Université Paul Sabatier Toulouse, Toulouse, France; Department of Infectious Diseases, Toulouse University Hospital, Toulouse, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Planès
authors.affiliation: INSERM, U1043, Toulouse, France, CNRS, U5282, Toulouse, France; Université Paul Sabatier Toulouse, Toulouse, France; Department of Infectious Diseases, Toulouse University Hospital, Toulouse, France.
authors.forename: Kaoutar
authors.initials: K
authors.lastname: Leghmari
authors.affiliation: INSERM, U1043, Toulouse, France, CNRS, U5282, Toulouse, France; Université Paul Sabatier Toulouse, Toulouse, France; Department of Infectious Diseases, Toulouse University Hospital, Toulouse, France.
authors.forename: Manutea
authors.initials: M
authors.lastname: Serrero
authors.affiliation: INSERM, U1043, Toulouse, France, CNRS, U5282, Toulouse, France; Université Paul Sabatier Toulouse, Toulouse, France; Department of Infectious Diseases, Toulouse University Hospital, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Delobel
authors.affiliation: INSERM, U1043, Toulouse, France, CNRS, U5282, Toulouse, France; Université Paul Sabatier Toulouse, Toulouse, France; Department of Infectious Diseases, Toulouse University Hospital, Toulouse, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Izopet
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA, 92697, United States of America; Institute for Immunology, Irvine, CA, 92697, United States of America; Department of Molecular Biology & Biochemistry, University of California Irvine, School of Medicine, Irvine, CA, 92697, United States of America.
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
authors.affiliation: INSERM, U1043, Toulouse, France, CNRS, U5282, Toulouse, France; Université Paul Sabatier Toulouse, Toulouse, France; Department of Infectious Diseases, Toulouse University Hospital, Toulouse, France.
authors.forename: Elmostafa
authors.initials: E
authors.lastname: Bahraoui
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D046912:Multiprotein Complexes; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D051218:Lymphocyte Antigen 96; D046912:Multiprotein Complexes; D016328:NF-kappa B; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051197:Toll-Like Receptor 4; D054322:tat Gene Products, Human Immunodeficiency Virus; D034281:Dynamins