title: The HIV-1 envelope transmembrane domain binds TLR2 through a distinct dimerization motif and inhibits TLR2-mediated responses.
abstract: HIV-1 uses a number of means to manipulate the immune system, to avoid recognition and to highjack signaling pathways. HIV-1 infected cells show limited Toll-Like Receptor (TLR) responsiveness via as yet unknown mechanisms. Using biochemical and biophysical approaches, we demonstrate that the trans-membrane domain (TMD) of the HIV-1 envelope (ENV) directly interacts with TLR2 TMD within the membrane milieu. This interaction attenuates TNFα, IL-6 and MCP-1 secretion in macrophages, induced by natural ligands of TLR2 both in in vitro and in vivo models. This was associated with decreased levels of ERK phosphorylation. Furthermore, mutagenesis demonstrated the importance of a conserved GxxxG motif in driving this interaction within the membrane milieu. The administration of the ENV TMD in vivo to lipotechoic acid (LTA)/Galactosamine-mediated septic mice resulted in a significant decrease in mortality and in tissue damage, due to the weakening of systemic macrophage activation. Our findings suggest that the TMD of ENV is involved in modulation of the innate immune response during HIV infection. Furthermore, due to the high functional homology of viral ENV proteins this function may be a general character of viral-induced immune modulation.
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Eliran Moshe
authors.initials: EM
authors.lastname: Reuven
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ali
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Etai
authors.initials: E
authors.lastname: Rotem
authors.forename: Roland
authors.initials: R
authors.lastname: Schwarzer
authors.affiliation: Institut für Biologie, AG Molekulare Biophysik, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schwarzter
authors.affiliation: Institut für Biologie, AG Molekulare Biophysik, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gramatica
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Shai
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D019281:Dimerization; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D057131:Immune Evasion / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000276:immunology* / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014759:Viral Envelope Proteins