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J. Biol. Chem., Vol. 280, Issue 27, 25517-25523, July 8, 2005

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Integrase Mutants Defective for Interaction with LEDGF/p75 Are Impaired in Chromosome Tethering and HIV-1 Replication^*

From the ^aInstitut Cochin, U567 INSERM, UPR8104 CNRS, Université Paris VI et VII, Tour 43, 2e étage, couloir 43–44, 2 place Jussieu, F-75251 Paris cedex 05, France, Department of Infectious Diseases, 27 rue du Faubourg Saint Jacques, Batiment Gustave Roussy, 75014 Paris, France, the ^cInstitut Jacques Monod, UMR7592 CNRS, Paris, France, the ^fLaboratory for Molecular Virology and Gene Therapy, KULAK and KULeuven, Flanders, Kapucijnenvoer 33 B-3000, Belgium, and theⁱ Hybrigenics S.A. 3–5 impasse Reille, 75014 Paris, France

The insertion of a DNA copy of its RNA genome into a chromosome of the host cell is mediated by the viral integrase with the help of mostly uncharacterized cellular cofactors. We have recently described that the transcriptional co-activator LEDGF/p75 strongly interacts with HIV-1 integrase. Here we show that interaction of HIV-1 integrase with LEDGF/p75 is important for viral replication. Using multiple approaches including two-hybrid interaction studies, random and directed mutagenesis, we could demonstrate that HIV-1 virus harboring a single mutation that disrupts integrase-LEDGF/p75 interaction, resulted in defective HIV-1 replication. Furthermore, we found that LEDGF/p75 tethers HIV-1 integrase to chromosomes and that this interaction may be important for the integration process and the replication of HIV-1.

Received for publication, February 7, 2005 , and in revised form, April 22, 2005.

^* This work was supported in part by grants from the Agence Nationale de Recherche sur le SIDA (ANRS) and Sidaction (to S. E., C. D., and R. B.), from Foundation pour la Recherche Médicale (FRM) (to S. E.), from la Ligue contre le Cancer and Agence de Recherche contre le Cancer (ARC) (to R. B.), from the SBO program of the Flemish Institute supporting Scientific-Technological Research in Industry (IWT) (to M. W. and Z. D.). Work at the Rega Institute and Institut Cochin was partially funded by the European Community Project TRIoH (LSHB-CT-2003-503480). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure and supplemental methods.

^d Both authors contributed equally to this work.

^e Supported by a fellowship from FRM.

^g Supported by a doctoral fellowship from ANRS.

^h Supported by grants from the IWT.

^j Supported by a fellowship from Sidaction.

^b To whom correspondence may be addressed. Tel.: 33-1-40-51-65-70; Fax: 33-1-40-51-65-71; E-mail: emiliani{at}cochin.inserm.fr. k To whom correspondence may be addressed. Tel.: 32-16-33-21-83; Fax: 3-2-16-33-21-31; E-mail: zeger.debyser{at}med.kuleuven.ac.be. l To whom correspondence may be addressed. Tel.: 33-1-40-51-65-70; Fax: 33-1-40-51-65-71; benarous{at}cochin.inserm.fr.

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