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J. Biol. Chem., Vol. 281, Issue 32, 22736-22743, August 11, 2006

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Inhibition of Early Steps of HIV-1 Replication by SNF5/Ini1^*

Marlène Maroun^¶||1, Olivier Delelis^**2, Gaël Coadou^¶||, Thomas Bader^¶||, Emmanuel Ségéral^¶||, Gladys Mbemba^**, Caroline Petit^¶||, Pierre Sonigo^¶||, Jean-Christophe Rain, Jean-François Mouscadet^**, Richard Benarous^¶||, and Stéphane Emiliani^¶||3

From the Institut Cochin, Département Maladies Infectieuses, F-75014 Paris, Inserm, U567, F-75014 Paris, ^¶CNRS, Unité Mixte de Recherche 8104, F-75014 Paris, ^||Université Paris Descartes, Faculté deMédecine René Descartes, Unité Mixte de Recherche S 8104, F-75014 Paris, ^**Laboratoire de Biotechnologie et Genetique Appliquée, Ecole Normale Supérieure de Cachan, CNRS Unité Mixte de Recherche 8532, F-94235 Cachan, and Hybrigenics S.A., F-75014 Paris, France

To replicate, human immunodeficiency virus, type 1 (HIV-1) needs to integrate a cDNA copy of its RNA genome into a chromosome of the host cell, a step controlled by the viral integrase (IN) protein. Viral integration involves the participation of several cellular proteins. SNF5/Ini1, a subunit of the SWI/SNF chromatin remodeling complex, was the first cofactor identified to interact with IN. We report here that SNF5/Ini1 interferes with early steps of HIV-1 replication. Inhibition of SNF5/Ini1 expression by RNA interference increases HIV-1 replication. Using quantitative PCR, we show that both the 2-long terminal repeat circle and integrated DNA forms accumulate upon SNF5/Ini1 knock down. By yeast two-hybrid assay, we screened a library of HIV-1 IN random mutants obtained by PCR random mutagenesis using SNF5/Ini1 as prey. Two different mutants of interaction, IN E69G and IN K71R, were impaired for SNF5/Ini1 interaction. The E69G substitution completely abolished integrase catalytic activity, leading to a replication-defective virus. On the contrary, IN K71R retained in vitro integrase activity. K71R substitution stimulates viral replication and results in higher infectious titers. Taken together, these results suggest that, by interacting with IN, SNF5/Ini1 interferes with early steps of HIV-1 infection.

Received for publication, May 19, 2006

^* This work was supported in part by grants from the Agence Nationale de Recherche sur le SIDA (ANRS), Sidaction, Association Pour la Recherche sur le Cancer, and by EC project "Hidden HIV Challenge" (FP6-2003-LIFESCI-HEALTH-3/012182) (to S. E.). The Benarous and Mouscadet laboratories are supported by EC 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 supplemental Fig. S1.

¹ Supported by doctoral fellowships from ANRS and Fondation pour la Recherche Medicale.

² Supported by a postdoctoral fellowship from EC project TRIoH (LSHB-CT-2003-503480).

³ To whom correspondence should be addressed: Institut Cochin, Département Maladies Infectieuses, 27 Rue du Faubourg Saint Jacques, Batiment Gustave Roussy, 75014 Paris, France. Tel.: 33-1-40-51-65-76; Fax: 33-1-40-51-65-71; E-mail: emiliani{at}cochin.inserm.fr.

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