Stimulation of the Human RAD51 Nucleofilament Restricts HIV-1 Integration In Vitro and in Infected Cells

Author:

Cosnefroy O.1,Tocco A.1,Lesbats P.1,Thierry S.2,Calmels C.1,Wiktorowicz T.3,Reigadas S.1,Kwon Y.4,De Cian A.5,Desfarges S.1,Bonot P.1,San Filippo J.6,Litvak S.1,Le Cam E.5,Rethwilm A.3,Fleury H.1,Connell P. P.7,Sung P.4,Delelis O.2,Andréola M. L.1,Parissi V.1

Affiliation:

1. Laboratoire MFP, UMR 5234, CNRS-Université Victor Segalen Bordeaux 2, IFR 66 Pathologies Infectieuses et Cancers, Bordeaux, France

2. LBPA, CNRS UMR8113, Ecole Normale Supérieure, Cachan, France

3. Institut für Virologie und Immunbiologie. Universität Würzburg, Würzburg, Germany

4. Yale University School of Medicine, Department of Molecular Biophysics and Biochemistry, New Haven, Connecticut, USA

5. Laboratoire de Microscopie Cellulaire et Moléculaire, UMR 8126, Univ. Paris Sud—CNRS, Institut Gustave Roussy, Villejuif, France

6. Roche Molecular Systems, Inc., Alameda, California, USA

7. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois, USA

Abstract

ABSTRACT Stable HIV-1 replication requires the DNA repair of the integration locus catalyzed by cellular factors. The human RAD51 (hRAD51) protein plays a major role in homologous recombination (HR) DNA repair and was previously shown to interact with HIV-1 integrase (IN) and inhibit its activity. Here we determined the molecular mechanism of inhibition of IN. Our standard in vitro integration assays performed under various conditions promoting or inhibiting hRAD51 activity demonstrated that the formation of an active hRAD51 nucleofilament is required for optimal inhibition involving an IN-DNA complex dissociation mechanism. Furthermore we show that this inhibition mechanism can be promoted in HIV-1-infected cells by chemical stimulation of the endogenous hRAD51 protein. This hRAD51 stimulation induced both an enhancement of the endogenous DNA repair process and the inhibition of the integration step. Elucidation of this molecular mechanism leading to the restriction of viral proliferation paves the way to a new concept of antiretroviral therapy based on the enhancement of endogenous hRAD51 recombination activity and highlights the functional interaction between HIV-1 IN and hRAD51.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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