TY - JOUR
T1 - IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation
AU - Hotter, Dominik
AU - Bosso, Matteo
AU - Jønsson, Kasper L.
AU - Krapp, Christian
AU - Stürzel, Christina M.
AU - Das, Atze
AU - Littwitz-Salomon, Elisabeth
AU - Berkhout, Ben
AU - Russ, Alina
AU - Wittmann, Sabine
AU - Gramberg, Thomas
AU - Zheng, Yue
AU - Martins, Laura J.
AU - Planelles, Vicente
AU - Jakobsen, Martin R.
AU - Hahn, Beatrice H.
AU - Dittmer, Ulf
AU - Sauter, Daniel
AU - Kirchhoff, Frank
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85066855858&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31175045
U2 - https://doi.org/10.1016/j.chom.2019.05.002
DO - https://doi.org/10.1016/j.chom.2019.05.002
M3 - Article
C2 - 31175045
SN - 1931-3128
VL - 25
SP - 858-872.e13
JO - CELL Host & Microbe
JF - CELL Host & Microbe
IS - 6
ER -