title: T cells detect intracellular DNA but fail to induce type I IFN responses: implications for restriction of HIV replication.
abstract: HIV infects key cell types of the immune system, most notably macrophages and CD4+ T cells. Whereas macrophages represent an important viral reservoir, activated CD4+ T cells are the most permissive cell types supporting high levels of viral replication. In recent years, it has been appreciated that the innate immune system plays an important role in controlling HIV replication, e.g. via interferon (IFN)-inducible restriction factors. Moreover, innate immune responses are involved in driving chronic immune activation and the pathogenesis of progressive immunodeficiency. Several pattern recognition receptors detecting HIV have been reported, including Toll-like receptor 7 and Retinoic-inducible gene-I, which detects viral RNA. Here we report that human primary T cells fail to induce strong IFN responses, despite the fact that this cell type does express key molecules involved in DNA signaling pathways. We demonstrate that the DNA sensor IFI16 migrates to sites of foreign DNA localization in the cytoplasm and recruits the signaling molecules stimulator of IFN genes and Tank-binding kinase, but this does not result in expression of IFN and IFN-stimulated genes. Importantly, we show that cytosolic DNA fails to affect HIV replication. However, exogenous treatment of activated T cells with type I IFN has the capacity to induce expression of IFN-stimulated genes and suppress HIV replication. Our data suggest the existence of an impaired DNA signaling machinery in T cells, which may prevent this cell type from activating cell-autonomous anti-HIV responses. This phenomenon could contribute to the high permissiveness of CD4+ T cells for HIV-1.
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: Randi K
authors.initials: RK
authors.lastname: Berg
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark ; Aarhus Research Center for Innate Immunology, Aarhus, Denmark.
authors.forename: Stine H
authors.initials: SH
authors.lastname: Rahbek
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark ; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Emil
authors.initials: E
authors.lastname: Kofod-Olsen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark ; Aarhus Research Center for Innate Immunology, Aarhus, Denmark.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Holm
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Melchjorsen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: David G
authors.initials: DG
authors.lastname: Jensen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Anne Louise
authors.initials: AL
authors.lastname: Hansen
authors.affiliation: Department of Virology, The State Serum Institute, Copenhagen, Denmark.
authors.forename: Louise B
authors.initials: LB
authors.lastname: Jørgensen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Ostergaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: Carsten S
authors.initials: CS
authors.lastname: Larsen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark ; Aarhus Research Center for Innate Immunology, Aarhus, Denmark.
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark ; Aarhus Research Center for Innate Immunology, Aarhus, Denmark.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jakobsen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark ; Aarhus Research Center for Innate Immunology, Aarhus, Denmark.
authors.forename: Trine H
authors.initials: TH
authors.lastname: Mogensen
mesh_terms: D017209:Apoptosis; D001692:Biological Transport; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D014162:Transfection; D014779:Virus Replication / Q000276:immunology; D000099197:STING Protein
chemical_list: D016207:Cytokines; D004247:DNA; D018836:Inflammation Mediators; D007370:Interferon Type I; D007376:Interleukin-2; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C532857:STING1 protein, human; D000099197:STING Protein; C403191:TBK1 protein, human