title: HIV-1 Tat Protein Activates both the MyD88 and TRIF Pathways To Induce Tumor Necrosis Factor Alpha and Interleukin-10 in Human Monocytes.
abstract: In this study, we show that the HIV-1 Tat protein interacts with rapid kinetics to engage the Toll-like receptor 4 (TLR4) pathway, leading to the production of proinflammatory and anti-inflammatory cytokines. The pretreatment of human monocytes with Tat protein for 10 to 30 min suffices to irreversibly engage the activation of the TLR4 pathway, leading to the production of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10), two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection. Therefore, this study analyzed whether the HIV-1 Tat protein is able to activate these two pathways separately or simultaneously. Using three complementary approaches, including mice deficient in the MyD88, TIRAP/MAL, or TRIF adaptor, biochemical analysis, and the use of specific small interfering RNAs (siRNAs), we demonstrated (i) that Tat was able to activate both the MyD88 and TRIF pathways, (ii) the capacity of Tat to induce TIRAP/MAL degradation, (iii) the crucial role of the MyD88 pathway in the production of Tat-induced TNF-α and IL-10, (iv) a reduction but not abrogation of IL-10 and TNF-α by Tat-stimulated macrophages from mice deficient in TIRAP/MAL, and (v) the crucial role of the TRIF pathway in Tat-induced IL-10 production. Further, we showed that downstream of the MyD88 and TRIF pathways, the Tat protein activated the protein kinase C (PKC) βII isoform, the mitogen-activated protein (MAP) kinases p38 and extracellular signal-regulated kinase 1/2 (ERK1/2), and NF-κB in a TLR4-dependent manner. Collectively, our data show that by recruiting the TLR4 pathway with rapid kinetics, the HIV-1 Tat protein leads to the engagement of both the MyD88 and TRIF pathways and to the activation of PKC, MAP kinase, and NF-κB signaling to induce the production of TNF-α and IL-10.
  
  
  
  In this study, we demonstrate that by recruiting the TLR4 pathway with rapid kinetics, the HIV-1 Tat protein leads to the engagement of both the MyD88 and TRIF pathways and to the activation of PKC-βII, MAP kinase, and NF-κB signaling to induce the production of TNF-α and IL-10, two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection. Thus, it may be interesting to target Tat as a pathogenic factor early after HIV-1 infection. This could be achieved either by vaccination approaches including Tat as an immunogen in potential candidate vaccines or by developing molecules capable of neutralizing the effect of the Tat protein.
authors.affiliation: CPTP, U1043, INSERM/CNRS/UPS, Toulouse, France.|Université Paul Sabatier Toulouse 3, Toulouse, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Planès
authors.affiliation: CPTP, U1043, INSERM/CNRS/UPS, Toulouse, France.|Université Paul Sabatier Toulouse 3, Toulouse, France.
authors.forename: Nawal
authors.initials: N
authors.lastname: Ben Haij
authors.affiliation: CPTP, U1043, INSERM/CNRS/UPS, Toulouse, France.|Université Paul Sabatier Toulouse 3, Toulouse, France.
authors.forename: Kaoutar
authors.initials: K
authors.lastname: Leghmari
authors.affiliation: CPTP, U1043, INSERM/CNRS/UPS, Toulouse, France.|Université Paul Sabatier Toulouse 3, Toulouse, France.
authors.forename: Manutea
authors.initials: M
authors.lastname: Serrero
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.|Institute for Immunology, Irvine, California, USA.
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
authors.affiliation: CPTP, U1043, INSERM/CNRS/UPS, Toulouse, France bahraoui@cict.fr.|Université Paul Sabatier Toulouse 3, Toulouse, France.
authors.forename: Elmostafa
authors.initials: E
authors.lastname: Bahraoui
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000378:metabolism; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000502:physiology; D008562:Membrane Glycoproteins / Q000172:deficiency; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1 / Q000172:deficiency; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C508609:IL10 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1; C470409:TICAM1 protein, human; C499045:TIRAP protein, mouse; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; D016753:Interleukin-10; D011493:Protein Kinase C; D048052:Mitogen-Activated Protein Kinase 3