title: IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication.
abstract: Replication of lentiviruses generates different DNA forms, including RNA:DNA hybrids, ssDNA, and dsDNA. Nucleic acids stimulate innate immune responses, and pattern recognition receptors detecting dsDNA have been identified. However, sensors for ssDNA have not been reported, and the ability of RNA:DNA hybrids to stimulate innate immune responses is controversial. Using ssDNAs derived from HIV-1 proviral DNA, we report that this DNA form potently induces the expression of IFNs in primary human macrophages. This response was stimulated by stem regions in the DNA structure and was dependent on IFN-inducible protein 16 (IFI16), which bound immunostimulatory DNA directly and activated the stimulator of IFN genes -TANK-binding kinase 1 - IFN regulatory factors 3/7 (STING-TBK1-IRF3/7) pathway. Importantly, IFI16 colocalized and associated with lentiviral DNA in the cytoplasm in macrophages, and IFI16 knockdown in this cell type augmented lentiviral transduction and also HIV-1 replication. Thus, IFI16 is a sensor for DNA forms produced during the lentiviral replication cycle and regulates HIV-1 replication in macrophages.
authors.affiliation: Department of Biomedicine and Aarhus Research Center for Innate Immunology, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jakobsen
authors.forename: Rasmus O
authors.initials: RO
authors.lastname: Bak
authors.forename: Annika
authors.initials: A
authors.lastname: Andersen
authors.forename: Randi K
authors.initials: RK
authors.lastname: Berg
authors.forename: Søren B
authors.initials: SB
authors.lastname: Jensen
authors.forename: Jin
authors.initials: J
authors.lastname: Tengchuan
authors.forename: Tengchuan
authors.initials: T
authors.lastname: Jin
authors.forename: Anders
authors.initials: A
authors.lastname: Laustsen
authors.forename: Kathrine
authors.initials: K
authors.lastname: Hansen
authors.forename: Lars
authors.initials: L
authors.lastname: Ostergaard
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: T Sam
authors.initials: TS
authors.lastname: Xiao
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Mikkelsen
authors.forename: Trine H
authors.initials: TH
authors.lastname: Mogensen
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
mesh_terms: D004279:DNA, Viral / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D017404:In Situ Hybridization, Fluorescence; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D014779:Virus Replication / Q000502:physiology*; D000099197:STING Protein
chemical_list: D004279:DNA, Viral; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C532857:STING1 protein, human; D000099197:STING Protein; C076700:IFI16 protein, human
keywords: DNA sensing; antiviral defense; innate immunity