Primate Immunodeficiency Virus Proteins Vpx and Vpr Counteract Transcriptional Repression of Proviruses by the HUSH Complex

Nat Microbiol. 2018 Dec;3(12):1354-1361. doi: 10.1038/s41564-018-0256-x. Epub 2018 Oct 8.

Abstract

Host factors that silence provirus transcription in CD4+ memory T cells help HIV-1 escape eradication by the host immune system and by antiviral drugs1. These same factors, however, must be overcome for HIV-1 to propagate. Here we show that Vpx and Vpr encoded by diverse primate immunodeficiency viruses activate provirus transcription. Vpx and Vpr are adaptor proteins for the DCAF1-CUL4A/B E3 ubiquitin ligase that degrade SAMHD1 and increase reverse transcription2-4. Nonetheless, Vpx and Vpr have effects on reporter gene expression that are not explained by SAMHD1 degradation5-8. A screen for factors that mimic these effects identified the human silencing hub (HUSH) complex, FAM208A (TASOR/RAP140), MPHOSPH8 (MPP8), PPHLN1 (PERIPHILIN) and MORC29-13. Vpx associated with the HUSH complex and decreased steady-state level of these proteins in a DCAF1/CUL4A/B/proteasome-dependent manner14,15. Replication kinetics of HIV-1 and SIVMAC was accelerated to a similar extent by vpx or FAM208A knockdown. Finally, vpx increased steady-state levels of LINE-1 ORF1p, as previously described for FAM208A disruption11. These results demonstrate that the HUSH complex represses primate immunodeficiency virus transcription, and that, to counteract this restriction, viral Vpx or Vpr proteins degrade the HUSH complex.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, Neoplasm
  • Carrier Proteins
  • Cullin Proteins
  • Gene Products, vpr / genetics
  • Gene Products, vpr / metabolism*
  • HEK293 Cells
  • HIV Infections / virology
  • HIV-1 / genetics
  • Humans
  • Lentiviruses, Primate / genetics
  • Lentiviruses, Primate / metabolism*
  • Nuclear Proteins
  • Phosphoproteins
  • Protein-Serine-Threonine Kinases
  • Proviruses / metabolism*
  • SAM Domain and HD Domain-Containing Protein 1 / metabolism
  • Transcription Factors / genetics
  • Ubiquitin-Protein Ligases
  • Viral Regulatory and Accessory Proteins / genetics
  • Viral Regulatory and Accessory Proteins / metabolism*
  • vpr Gene Products, Human Immunodeficiency Virus

Substances

  • Antigens, Neoplasm
  • CUL4A protein, human
  • CUL4B protein, human
  • Carrier Proteins
  • Cullin Proteins
  • Gene Products, vpr
  • MORC2 protein, human
  • MPHOSPH8 protein, human
  • Nuclear Proteins
  • PPHLN1 protein, human
  • Phosphoproteins
  • TASOR protein, human
  • Transcription Factors
  • Viral Regulatory and Accessory Proteins
  • vpr Gene Products, Human Immunodeficiency Virus
  • vpr protein, Human immunodeficiency virus 1
  • Ubiquitin-Protein Ligases
  • DCAF1 protein, human
  • Protein-Serine-Threonine Kinases
  • SAM Domain and HD Domain-Containing Protein 1