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J. Biol. Chem., Vol. 280, Issue 18, 17841-17847, May 6, 2005

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The Interaction of LEDGF/p75 with Integrase Is Lentivirus-specific and Promotes DNA Binding^*

Katrien Busschots¶, Jo Vercammen||, Stéphane Emiliani**, Richard Benarous**, Yves Engelborghs||, Frauke Christ, and Zeger Debyser

From the Laboratory for Molecular Virology and Gene Therapy, Katholieke Universiteit Leuven and Interdisciplinary Research Center Katholieke Universiteit Leuven Campus Kortrijk, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium, ^||Laboratory of Biomolecular Dynamics, Katholieke Universiteit Leuven, Celestijnenlaan 200D, B-3001 Leuven, Flanders, Belgium, and ^**Institut Cochin, U567 INSERM, UMR8104 CNRS, Department of Infectious Diseases, 27 Rue du Faubourg St. Jacques, 75104 Paris, France

We have previously shown that the p75 isoform of the transcriptional co-activator lens epithelium-derived growth factor (LEDGF) interacts tightly with human immunodeficiency virus (HIV)-1 integrase (IN) and is essential for nuclear targeting of this protein in human cells (Cherepanov, P., Maertens, G., Proost, P., Devreese, B., Van Beeumen, J., Engelborghs, Y., De Clercq, E., and Debyser, Z. (2003) J. Biol. Chem. 278, 372–381; Maertens, G., Cherepanov, P., Pluymers, W., Busschots, K., De Clercq, E., Debyser, Z., and Engelborghs, Y. (2003) J. Biol. Chem. 278, 33528–33539). Here the interaction between recombinant LEDGF/p75 and HIV-1 IN was examined in a pull-down binding test. LEDGF/p75 was shown to increase the solubility of HIV-1 IN. Next, fluorescent correlation spectroscopy was used to measure the interaction of LEDGF/p75 or the complex of HIV-1 IN and LEDGF/p75 with a specific double-stranded DNA oligonucleotide. Whereas LEDGF/p75 displayed only a moderate affinity for DNA, it strongly promoted the binding of HIV-1 IN to DNA. This effect was specific for the p75 isoform of LEDGF and was not seen with p52. In the pull-down assay LEDGF/p75 interacted with HIV-1, HIV-2, and feline immunodeficiency virus IN, but not with the IN of human T-cell lymphotropic virus type 2, Moloney murine leukemia virus, or Rous sarcoma virus. These results strongly suggest that the interaction of LEDGF/p75 with IN is specific to lentiviridae. LEDGF/p75 stimulated the binding of HIV-1 and HIV-2 IN, but not Moloney murine leukemia virus or Rous sarcoma virus IN, to an aspecific DNA. These results provide supporting evidence for our hypothesis that LEDGF/p75 plays a role in the tethering of lentiviral IN to the chromosomal DNA.

Received for publication, October 14, 2004 , and in revised form, February 17, 2005.

^* This work was supported in part by European Commission Targeting Replication and Integration of HIV (TRIoH) Project LSHB-CT-2003-503480 and Grant 530-030239 from the Strategic Basic Research Program of the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^¶ Supported by a grant from the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT).

To whom correspondence should be addressed. Tel.: 32-16-332183; Fax: 32-16-332131; E-mail: zeger.debyser{at}med.kuleuven.ac.be.

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