title: Tetherin does not significantly restrict dendritic cell-mediated HIV-1 transmission and its expression is upregulated by newly synthesized HIV-1 Nef.
abstract: BACKGROUND
  Dendritic cells (DCs) are among the first cells to encounter HIV-1 and play important roles in viral transmission and pathogenesis. Immature DCs allow productive HIV-1 replication and long-term viral dissemination. The pro-inflammatory factor lipopolysaccharide (LPS) induces DC maturation and enhances the efficiency of DC-mediated HIV-1 transmission. Type I interferon (IFN) partially inhibits HIV-1 replication and cell-cell transmission in CD4+ T cells and macrophages. Tetherin is a type I IFN-inducible restriction factor that blocks HIV-1 release and modulates CD4+ T cell-mediated cell-to-cell transmission of HIV-1. However, the role of type I IFN and tetherin in HIV-1 infection of DCs and DC-mediated viral transmission remains unknown.
  
  
  RESULTS
  We demonstrated that IFN-alpha (IFNα)-induced mature DCs restricted HIV-1 replication and trans-infection of CD4+ T cells. Tetherin expression in monocyte-derived immature DCs was undetectable or very low. High levels of tetherin were transiently expressed in LPS- and IFNα-induced mature DCs, while HIV-1 localized into distinct patches in these DCs. Knockdown of induced tetherin in LPS- or IFNα-matured DCs modestly enhanced HIV-1 transmission to CD4+ T cells, but had no significant effect on wild-type HIV-1 replication in mature DCs. Intriguingly, we found that HIV-1 replication in immature DCs induced significant tetherin expression in a Nef-dependent manner.
  
  
  CONCLUSIONS
  The restriction of HIV-1 replication and transmission in IFNα-induced mature DCs indicates a potent anti-HIV-1 response; however, high levels of tetherin induced in mature DCs cannot significantly restrict wild-type HIV-1 release and DC-mediated HIV-1 transmission. Nef-dependent tetherin induction in HIV-1-infected immature DCs suggests an innate immune response of DCs to HIV-1 infection.
authors.affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Coleman
authors.forename: Paul
authors.initials: P
authors.lastname: Spearman
authors.forename: Li
authors.initials: L
authors.lastname: Wu
mesh_terms: D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000254:growth & development* / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology / Q000378:metabolism; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D054311:nef Gene Products, Human Immunodeficiency Virus; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514837:nef protein, Human immunodeficiency virus 1