title: Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration.
abstract: The cellular DNA repair hRAD51 protein has been shown to restrict HIV-1 integration both in vitro and in vivo. To investigate its regulatory functions, we performed a pharmacological analysis of the retroviral integration modulation by hRAD51. We found that, in vitro, chemical activation of hRAD51 stimulates its integration inhibitory properties, whereas inhibition of hRAD51 decreases the integration restriction, indicating that the modulation of HIV-1 integration depends on the hRAD51 recombinase activity. Cellular analyses demonstrated that cells exhibiting high hRAD51 levels prior to de novo infection are more resistant to integration. On the other hand, when hRAD51 was activated during integration, cells were more permissive. Altogether, these data establish the functional link between hRAD51 activity and HIV-1 integration. Our results highlight the multiple and opposite effects of the recombinase during integration and provide new insights into the cellular regulation of HIV-1 replication.
authors.affiliation: LBPA, UMR8113, CNRS, ENS-Cachan, 94235 Cachan, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Thierry
authors.affiliation: MFP, UMR5234, CNRS-Université de Bordeaux, SFR Transbiomed, 33076 Bordeaux, France.
authors.forename: Mohamed Salah
authors.initials: MS
authors.lastname: Benleulmi
authors.affiliation: MFP, UMR5234, CNRS-Université de Bordeaux, SFR Transbiomed, 33076 Bordeaux, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Sinzelle
authors.affiliation: LBPA, UMR8113, CNRS, ENS-Cachan, 94235 Cachan, France.
authors.forename: Eloise
authors.initials: E
authors.lastname: Thierry
authors.affiliation: MFP, UMR5234, CNRS-Université de Bordeaux, SFR Transbiomed, 33076 Bordeaux, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Calmels
authors.affiliation: Université de Bordeaux, UMR CNRS 5248 CBMN, 33076 Bordeaux, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Chaignepain
authors.affiliation: GESVAB, EA 3675 - UFR Pharmacie, Université de Bordeaux, ISVV, 33076 Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Waffo-Teguo
authors.affiliation: GESVAB, EA 3675 - UFR Pharmacie, Université de Bordeaux, ISVV, 33076 Bordeaux, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Merillon
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Budke
authors.affiliation: Laboratoire Biothérapies des Maladies Génétiques et Cancers, INSERM U1035, Université de Bordeaux, 33076 Bordeaux, France.
authors.forename: Jean-Max
authors.initials: JM
authors.lastname: Pasquet
authors.affiliation: MFP, UMR5234, CNRS-Université de Bordeaux, SFR Transbiomed, 33076 Bordeaux, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Litvak
authors.affiliation: Institute of Microbiology (IMUL), Lausanne University Hospital, 1011 Lausanne, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Ciuffi
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, CT 06320-8024, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sung
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Connell
authors.affiliation: HPI, Leibniz Institute for Experimental Virology, German Center for Infection Research (DZIF), 20251 Hamburg, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Hauber
authors.affiliation: HPI, Leibniz Institute for Experimental Virology, German Center for Infection Research (DZIF), 20251 Hamburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Hauber
authors.affiliation: MFP, UMR5234, CNRS-Université de Bordeaux, SFR Transbiomed, 33076 Bordeaux, France.
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Andreola
authors.affiliation: LBPA, UMR8113, CNRS, ENS-Cachan, 94235 Cachan, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delelis
authors.affiliation: MFP, UMR5234, CNRS-Université de Bordeaux, SFR Transbiomed, 33076 Bordeaux, France. Electronic address: vincent.parissi@reger.u-bordeaux2.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Parissi
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000378:metabolism; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004260:DNA Repair; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: C000605335:3-((benzylamino)sulfonyl)-4-bromo-N-(4-bromophenyl)benzamide; C576134:3-chloro-1-(3,4-dichlorophenyl)-4-(4-morpholinyl)-1H-pyrrole-2,5-dione; D052157:Aptamers, Nucleotide; D001549:Benzamides; D009025:Morpholines; D011758:Pyrroles; D013267:Stilbenes; D013449:Sulfonamides; C107773:pterostilbene; D004247:DNA; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid