title: Dendritic cell-lymphocyte cross talk downregulates host restriction factor SAMHD1 and stimulates HIV-1 replication in dendritic cells.
abstract: Human immunodeficiency virus type 1 (HIV-1) replication in dendritic cells (DCs) is restricted by SAMHD1. This factor is counteracted by the viral protein Vpx; Vpx is found in HIV-2 and simian immunodeficiency virus (SIV) from sooty mangabeys (SIVsm) or from macaques (SIVmac) but is absent from HIV-1. We previously observed that HIV-1 replication in immature DCs is stimulated by cocultivation with primary T and B lymphocytes, suggesting that HIV-1 restriction in DCs may be overcome under coculture conditions. Here, we aimed to decipher the mechanism of SAMHD1-mediated restriction in DC-lymphocyte coculture. We found that coculture with lymphocytes downregulated SAMHD1 expression and was associated with increased HIV-1 replication in DCs. Moreover, in infected DC-T lymphocyte cocultures, DCs acquired maturation status and secreted type 1 interferon (alpha interferon [IFN-α]). The blockade of DC-lymphocyte cross talk by anti-ICAM-1 antibody markedly inhibited the stimulation of HIV-1 replication and prevented the downregulation of SAMHD1 expression in cocultured DCs. These results demonstrate that, in contrast to purified DCs, cross talk with lymphocytes downregulates SAMHD1 expression in DCs, triggering HIV-1 replication and an antiviral immune response. Therefore, HIV-1 replication and immune sensing by DCs should be investigated in more physiologically relevant models of DC/lymphocyte coculture.
  
  
  OBJECTIVE
  SAMHD1 restricts HIV-1 replication in dendritic cells (DCs). Here, we demonstrate that, in a coculture model of DCs and lymphocytes mimicking early mucosal HIV-1 infection, stimulation of HIV-1 replication in DCs is associated with downregulation of SAMHD1 expression and activation of innate immune sensing by DCs. We propose that DC-lymphocyte cross talk occurring in vivo modulates host restriction factor SAMHD1, promoting HIV-1 replication in cellular reservoirs and stimulating immune sensing.
authors.affiliation: INSERM U1110, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
authors.forename: Bin
authors.initials: B
authors.lastname: Su
authors.forename: Marina Elizabeth
authors.initials: ME
authors.lastname: Biedma
authors.forename: Alexandre
authors.initials: A
authors.lastname: Lederle
authors.forename: Maryse
authors.initials: M
authors.lastname: Peressin
authors.forename: Mélanie
authors.initials: M
authors.lastname: Lambotin
authors.forename: Alizé
authors.initials: A
authors.lastname: Proust
authors.forename: Thomas
authors.initials: T
authors.lastname: Decoville
authors.forename: Sylvie
authors.initials: S
authors.lastname: Schmidt
authors.forename: Géraldine
authors.initials: G
authors.lastname: Laumond
authors.forename: Christiane
authors.initials: C
authors.lastname: Moog
mesh_terms: D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D015536:Down-Regulation; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000276:immunology*; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis*; D000076106:SAM Domain and HD Domain-Containing Protein 1; D014776:Virus Cultivation; D014779:Virus Replication
chemical_list: D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins