1. IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation
- Author
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Christian Krapp, Ben Berkhout, Matteo Bosso, Martin R. Jakobsen, Sabine Wittmann, Thomas Gramberg, Kasper L Jønsson, Daniel Sauter, Christina M. Stürzel, Dominik Hotter, Elisabeth Littwitz-Salomon, Yue Zheng, Alina Russ, Ulf Dittmer, Frank Kirchhoff, Vicente Planelles, Beatrice H. Hahn, Atze T. Das, Laura J. Martins, Medical Microbiology and Infection Prevention, and AII - Infectious diseases
- Subjects
CD4-Positive T-Lymphocytes ,Transcription, Genetic ,Medizin ,Pyrin domain ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Retrovirus ,Transcription (biology) ,Interferon ,Gene expression ,Cells, Cultured ,BIOLOGICAL PHENOTYPE ,0303 health sciences ,biology ,PYHIN proteins ,GENETIC IDENTITY ,Nuclear Proteins ,Cell biology ,Virus Latency ,interferon γ-inducible PYHIN protein 16 ,INNATE IMMUNE SENSOR ,medicine.drug ,TAT PROTEIN ,Genotype ,Sp1 Transcription Factor ,Microbiology ,Article ,03 medical and health sciences ,Virology ,medicine ,Animals ,Immunologic Factors ,030304 developmental biology ,RESTRICTION FACTORS ,Sp1 transcription factor ,IFI16 ,VIRAL MATRIX PROTEIN ,IN-VITRO ,AIM2 INFLAMMASOME ,biology.organism_classification ,Phosphoproteins ,GENOMIC SEQUENCE ,chemistry ,T-CELLS ,HIV-1 ,Parasitology ,Virus Activation ,030217 neurology & neurosurgery ,DNA - Abstract
The interferon γ-inducible protein 16 (IFI16) is known as immune sensor of retroviral DNA intermediates. We show that IFI16 restricts HIV-1 independently of immune sensing by binding and inhibiting the host transcription factor Sp1 that drives viral gene expression. This antiretroviral activity and ability to bind Sp1 require the N-terminal pyrin domain and nuclear localization of IFI16, but not the HIN domains involved in DNA binding. Highly prevalent clade C HIV-1 strains are more resistant to IFI16 and less dependent on Sp1 than other HIV-1 subtypes. Furthermore, inhibition of Sp1 by IFI16 or pharmacologically by Mithramycin A suppresses reactivation of latent HIV-1 in CD4+ T cells. Finally, IFI16 also inhibits retrotransposition of LINE-1, known to engage Sp1, and murine IFI16 homologs restrict Friend retrovirus replication in mice. Thus, IFI16 restricts retroviruses and retrotransposons by interfering with Sp1-dependent gene expression, and evasion from this restriction may facilitate spread of HIV-1 subtype C.
- Published
- 2018
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