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

Anne M. Meehan, Dyana T. Saenz, James H. Morrison, Jose A. Garcia-Rivera, Mary Peretz, Manuel Llano, Eric M. Poeschla

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere1000522
JournalPLoS Pathogens
Volume5
Issue number7
DOIs
StatePublished - Jul 2009

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Chromatin
HIV-1
Integrases
Proteins
Ligands
lens epithelium-derived growth factor
Nucleosomes
Kaposi's Sarcoma
Retroviridae
Histones
Viruses
Peptides
DNA

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Meehan, A. M., Saenz, D. T., Morrison, J. H., Garcia-Rivera, J. A., Peretz, M., Llano, M., & Poeschla, E. M. (2009). LEDGF/p75 proteins with alternative chromatin tethers are functional HIV-1 cofactors. PLoS Pathogens, 5(7), [e1000522]. https://doi.org/10.1371/journal.ppat.1000522

LEDGF/p75 proteins with alternative chromatin tethers are functional HIV-1 cofactors. / Meehan, Anne M.; Saenz, Dyana T.; Morrison, James H.; Garcia-Rivera, Jose A.; Peretz, Mary; Llano, Manuel; Poeschla, Eric M.

In: PLoS Pathogens, Vol. 5, No. 7, e1000522, 07.2009.

Research output: Contribution to journalArticle

Meehan, AM, Saenz, DT, Morrison, JH, Garcia-Rivera, JA, Peretz, M, Llano, M & Poeschla, EM 2009, 'LEDGF/p75 proteins with alternative chromatin tethers are functional HIV-1 cofactors', PLoS Pathogens, vol. 5, no. 7, e1000522. https://doi.org/10.1371/journal.ppat.1000522
Meehan AM, Saenz DT, Morrison JH, Garcia-Rivera JA, Peretz M, Llano M et al. LEDGF/p75 proteins with alternative chromatin tethers are functional HIV-1 cofactors. PLoS Pathogens. 2009 Jul;5(7). e1000522. https://doi.org/10.1371/journal.ppat.1000522
Meehan, Anne M. ; Saenz, Dyana T. ; Morrison, James H. ; Garcia-Rivera, Jose A. ; Peretz, Mary ; Llano, Manuel ; Poeschla, Eric M. / LEDGF/p75 proteins with alternative chromatin tethers are functional HIV-1 cofactors. In: PLoS Pathogens. 2009 ; Vol. 5, No. 7.
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