title: TLR-4 engagement of dendritic cells confers a BST-2/tetherin-mediated restriction of HIV-1 infection to CD4+ T cells across the virological synapse.
abstract: BACKGROUND
  Dendritic cells and their subsets, located at mucosal surfaces, are among the first immune cells to encounter disseminating pathogens. The cellular restriction factor BST-2/tetherin (also known as CD317 or HM1.24) potently restricts HIV-1 release by retaining viral particles at the cell surface in many cell types, including primary cells such as macrophages. However, BST-2/tetherin does not efficiently restrict HIV-1 infection in immature dendritic cells.
  
  
  RESULTS
  We now report that BST-2/tetherin expression in myeloid (myDC) and monocyte-derived dendritic cells (DC) can be significantly up-regulated by IFN-α treatment and TLR-4 engagement with LPS. In contrast to HeLa or 293T cells, infectious HIV-1 release in immature DC and IFN-α-matured DC was only modestly affected in the absence of Vpu compared to wild-type viruses. Strikingly, immunofluorescence analysis revealed that BST-2/tetherin was excluded from HIV containing tetraspanin-enriched microdomains (TEMs) in both immature DC and IFN-α-matured DC. In contrast, in LPS-mediated mature DC, BST-2/tetherin exerted a significant restriction in transfer of HIV-1 infection to CD4+ T cells. Additionally, LPS, but not IFN-α stimulation of immature DC, leads to a dramatic redistribution of cellular restriction factors to the TEM as well as at the virological synapse between DC and CD4+ T cells.
  
  
  CONCLUSIONS
  In conclusion, we demonstrate that TLR-4 engagement in immature DC significantly up-regulates the intrinsic antiviral activity of BST-2/tetherin, during cis-infection of CD4+ T cells across the DC/T cell virological synapse. Manipulating the function and potency of cellular restriction factors such as BST-2/tetherin to HIV-1 infection, has implications in the design of antiviral therapeutic strategies.
authors: Department of Dermatology and Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, 3rd Floor, Glamorgan house, Heath Park, Wales, Cardiff, CF14 4XN, United Kingdom.
authors: Fabien P
authors: FP
authors: Blanchet
authors: Romaine
authors: R
authors: Stalder
authors: Magdalena
authors: M
authors: Czubala
authors: Martin
authors: M
authors: Lehmann
authors: Laura
authors: L
authors: Rio
authors: Bastien
authors: B
authors: Mangeat
authors: Vincent
authors: V
authors: Piguet
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D054992:Immunological Synapses / Q000187:drug effects / Q000821:virology*; D016898:Interferon-alpha / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000821:virology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D061251:Primary Cell Culture; D015398:Signal Transduction; D059470:Tetraspanins / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014771:Virion / Q000187:drug effects / Q000276:immunology*; D057074:Virus Release / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D059470:Tetraspanins; D051197:Toll-Like Receptor 4; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C495345:TLR4 protein, human