title: Bacterial lipopolysaccharide activates HIV long terminal repeat through Toll-like receptor 4.
abstract: In HIV-infected patients, concurrent infections with bacteria and viruses are known to induce HIV replication as assessed by increases in plasma HIV RNA levels. In the present study, we determined the cell surface receptor and molecular mechanisms of enterobacterial LPS-induced HIV transcription. Human dermal microvessel endothelial cells (HMEC) were transfected with an HIV-long terminal repeat (LTR)-luciferase construct and subsequently stimulated with purified bacterial LPS. Our studies demonstrate that human Toll-like receptor 4 (TLR4) mediates LPS-induced NF-kappaB and HIV-LTR activation in HMEC through IL-1 signaling molecules, namely myeloid differentiation protein, IL-1R-associated kinase, TNFR-associated factor, and NF-kappaB-inducing kinase. Cotransfection of HMEC with HIV-LTR-luciferase and TLR4 cDNA from LPS-hyporesponsive C3H/HeJ mice abrogates LPS-induced HIV transcription as does the use of dominant-negative mutants of the IL-1 signaling molecules. Transfection of HMEC with an HIV-LTR-mutant that lacks the NF-kappaB binding site or pretreatment of cells with chemical inhibitors of the NF-kappaB pathway also blocked LPS-induced HIV-LTR transactivation. These data support the conclusion that TLR4 mediates enterobacterial LPS-induced HIV transcription via IL-1 signaling molecules and NF-kappaB activation plays an important role in HIV-LTR transactivation.
authors.affiliation: Division of Pediatric Infectious Diseases, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, CA 90048, USA. ozlem.equils@cshs.org
authors.forename: O
authors.initials: O
authors.lastname: Equils
authors.forename: E
authors.initials: E
authors.lastname: Faure
authors.forename: L
authors.initials: L
authors.lastname: Thomas
authors.forename: Y
authors.initials: Y
authors.lastname: Bulut
authors.forename: S
authors.initials: S
authors.lastname: Trushin
authors.forename: M
authors.initials: M
authors.lastname: Arditi
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D002867:Chromones / Q000494:pharmacology; D029721:Drosophila Proteins; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016325:HIV Long Terminal Repeat / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002867:Chromones; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008156:Luciferases; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015230:Prostaglandin D2; D011725:Pyridines; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases; C097240:15-deoxy-delta(12,14)-prostaglandin J2; C495345:TLR4 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093642:SB 203580