title: Frontline Science: HIV infection of Kupffer cells results in an amplified proinflammatory response to LPS.
abstract: End-stage liver disease is a common cause of non-AIDS-related mortality in HIV+patients, despite effective anti-retroviral therapies (ARTs). HIV-1 infection causes gut CD4 depletion and is thought to contribute to increased gut permeability, bacterial translocation, and immune activation. Microbial products drain from the gut into the liver via the portal vein where Kupffer cells (KCs), the resident liver macrophage, clear translocated microbial products. As bacterial translocation is implicated in fibrogenesis in HIV patients through unclear mechanisms, we tested the hypothesis that HIV infection of KCs alters their response to LPS in a TLR4-dependent manner. We showed that HIV-1 productively infected KCs, enhanced cell-surface TLR4 and CD14 expression, and increased IL-6 and TNF-α expression, which was blocked by a small molecule TLR4 inhibitor. Our study demonstrated that HIV infection sensitizes KCs to the proinflammatory effects of LPS in a TLR4-dependent manner. These findings suggest that HIV-1-infected KCs and their dysregulated innate immune response to LPS may play a role in hepatic inflammation and fibrosis and represent a novel target for therapy.
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Arevik
authors.initials: A
authors.lastname: Mosoian
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Lumin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.affiliation: University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
authors.forename: Francesc
authors.initials: F
authors.lastname: Cunyat
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Adeeb
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Riti
authors.initials: R
authors.lastname: Bhalla
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ankur
authors.initials: A
authors.lastname: Panchal
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Yedidya
authors.initials: Y
authors.lastname: Saiman
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Fiel
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Sander
authors.initials: S
authors.lastname: Florman
authors.affiliation: Recanati Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; and.
authors.forename: Sasan
authors.initials: S
authors.lastname: Roayaie
authors.affiliation: Recanati Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; and.
authors.forename: Myron
authors.initials: M
authors.lastname: Schwartz
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Branch
authors.affiliation: University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Stevenson
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; meena.bansal@mssm.edu.
authors.forename: Meena B
authors.initials: MB
authors.lastname: Bansal
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D058625:End Stage Liver Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology*; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000821:virology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D061251:Primary Cell Culture; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D013449:Sulfonamides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
keywords: HIV-induced hepatic inflammation; liver fibrosis; microbial translocation