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. doi: 10.1016/j.chom.2019.05.002. Epub 2019 Jun 4.

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.

Keywords: HIV-1; PYHIN proteins; Sp1 transcription factor; interferon γ-inducible PYHIN protein 16; restriction factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Genotype
  • HIV-1 / classification
  • HIV-1 / genetics
  • HIV-1 / growth & development
  • HIV-1 / immunology*
  • Immunologic Factors / metabolism*
  • Mice
  • Nuclear Proteins / metabolism*
  • Phosphoproteins / metabolism*
  • Sp1 Transcription Factor / antagonists & inhibitors*
  • Transcription, Genetic*
  • Virus Activation*
  • Virus Latency*

Substances

  • Ifi16 protein, mouse
  • Immunologic Factors
  • Nuclear Proteins
  • Phosphoproteins
  • Sp1 Transcription Factor
  • SP1 protein, human