Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration. Issue 6 (18th June 2015)

• Record Type: Journal Article
• Authors: Thierry, Sylvain; Benleulmi, Mohamed Salah; Sinzelle, Ludivine; Thierry, Eloise; Calmels, Christina; Chaignepain, Stephane; Waffo-Teguo, Pierre; Merillon, Jean-Michel; Budke, Brian; Pasquet, Jean-Max; Litvak, Simon; Ciuffi, Angela; Sung, Patrick; Connell, Philip; Hauber, Ilona; Hauber, Joachim; Andreola, Marie-Line; Delelis, Olivier; Parissi, Vincent
• Is Part Of: Chemistry & biology. Volume 22:Issue 6(2015)
• Page Start: 712
• Page End: 723
• Publication Date: 2015-06-18
• Subjects: Biochemistry -- Periodicals; 540
• DOI: 10.1016/j.chembiol.2015.04.020
• Languages: English
• ISSNs: 1074-5521

Abstract

Summary: 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. Graphical Abstract: Highlights: Recombinase activity of hRAD51 correlates with its ability to inhibit HIV-1 IN Chemical modulations of hRAD51 can have opposite effects on HIV-1 integration Optimal intracellular activity of hRAD51 is required for efficient HIV-1 replication Efficient HIV-1 integration depends on the cellular hRAD51 level Abstract : HIV-1 replication depends on the integration of the viral genome into the infected cell DNA. This step can be modulated by the hRAD51 DNA repair protein. Pharmacological strategies, employed by Thierry et al., establish a direct correlation between the stimulation of hRAD51 and the inhibition of HIV-1 integration, highlighting the multiple and opposite regulatory functions of the recombinase on this important replication step.