LEDGF/p75 proteins with alternative chromatin tethers are functional HIV-1 cofactors

PLoS Pathog. 2009 Jul;5(7):e1000522. doi: 10.1371/journal.ppat.1000522. Epub 2009 Jul 17.


LEDGF/p75 can tether over-expressed lentiviral integrase proteins to chromatin but how this underlies its integration cofactor role for these retroviruses is unclear. While a single integrase binding domain (IBD) binds integrase, a complex N-terminal domain ensemble (NDE) interacts with unknown chromatin ligands. Whether integration requires chromatin tethering per se, specific NDE-chromatin ligand interactions or other emergent properties of LEDGF/p75 has been elusive. Here we replaced the NDE with strongly divergent chromatin-binding modules. The chimeras rescued integrase tethering and HIV-1 integration in LEDGF/p75-deficient cells. Furthermore, chromatin ligands could reside inside or outside the nucleosome core, and could be protein or DNA. Remarkably, a short Kaposi's sarcoma virus peptide that binds the histone 2A/B dimer converted GFP-IBD from an integration blocker to an integration cofactor that rescues over two logs of infectivity. NDE mutants were corroborative. Chromatin tethering per se is a basic HIV-1 requirement and this rather than engagement of particular chromatin ligands is important for the LEDGF/p75 cofactor mechanism.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antigens, Viral / metabolism
  • Antiviral Agents / metabolism
  • Base Sequence
  • Cell Line
  • Cells, Cultured
  • Chromatin / metabolism*
  • DNA-Binding Proteins / metabolism
  • Green Fluorescent Proteins
  • HIV Infections / virology*
  • HIV Integrase / metabolism
  • HIV-1 / metabolism*
  • HIV-1 / physiology
  • Histones / metabolism
  • Humans
  • Mice
  • Molecular Sequence Data
  • Nuclear Proteins / metabolism
  • Peptide Fragments / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA Interference
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Virus Replication


  • Adaptor Proteins, Signal Transducing
  • Antigens, Viral
  • Antiviral Agents
  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • Nuclear Proteins
  • PSIP1 protein, human
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • Transcription Factors
  • latency-associated nuclear antigen
  • Green Fluorescent Proteins
  • HIV Integrase
  • Proteasome Endopeptidase Complex