IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation

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DOI

  • Dominik Hotter, Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstrasse 1, 89081, Ulm, Germany.
  • ,
  • Matteo Bosso, Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstrasse 1, 89081, Ulm, Germany.
  • ,
  • Kasper L Jønsson
  • Christian Krapp
  • Christina M Stürzel, Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstrasse 1, 89081, Ulm, Germany.
  • ,
  • Atze Das, Laboratory of Experimental Virology, Department of Medical Microbiology, Centre for Infection and Immunity Amsterdam (CINIMA), Academic Medical Centre, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands
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  • Elisabeth Littwitz-Salomon, Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
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  • Ben Berkhout, Laboratory of Experimental Virology, Department of Medical Microbiology, Centre for Infection and Immunity Amsterdam (CINIMA), Academic Medical Centre, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands
  • ,
  • Alina Russ, Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
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  • Sabine Wittmann, Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
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  • Thomas Gramberg, Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
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  • Yue Zheng, Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
  • ,
  • Laura J Martins, Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
  • ,
  • Vicente Planelles, Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
  • ,
  • Martin R Jakobsen
  • Beatrice H Hahn, Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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  • Ulf Dittmer, Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
  • ,
  • Daniel Sauter, Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstrasse 1, 89081, Ulm, Germany.
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  • Frank Kirchhoff, Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany. Electronic address: frank.kirchhoff@uni-ulm.de.

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.

OriginalsprogEngelsk
TidsskriftCell Host & Microbe
ISSN1931-3128
DOI
StatusE-pub ahead of print - 31 maj 2019

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