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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. Copyright © 2019 Elsevier Inc. All rights reserved.

Citation

Dominik Hotter, Matteo Bosso, Kasper L Jønsson, Christian Krapp, Christina M Stürzel, Atze Das, Elisabeth Littwitz-Salomon, Ben Berkhout, Alina Russ, Sabine Wittmann, Thomas Gramberg, Yue Zheng, Laura J Martins, Vicente Planelles, Martin R Jakobsen, Beatrice H Hahn, Ulf Dittmer, Daniel Sauter, Frank Kirchhoff. IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation. Cell host & microbe. 2019 Jun 12;25(6):858-872.e13

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PMID: 31175045

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