On the tail of a new step in HIV-1 replication
Retroviral infection requires the insertion of the viral genome into the chromosomes of the infected cell. The association between the integration complexes (intasomes) and chromatin is a crucial step in this process.
The work of our team was focused these last years in the characterization of the final association between retroviral intasomes and nucleosomes, components of the chromatin and substrates for integration. We have previously shown that this association is regulated by both chromatin dynamics and intasome structure (Lesbats et al., PLoS Pathogens 2011, Benleulmi et al., Retrovirology 2015, Matysiak et al., Retrovirology 2017). More recently, we have reported that the functional association between the incoming HIV-1 intasome and the nucleosome involves direct interactions between the viral integrase and the N-terminal histone 4 tail (Benleulmi et al., Retrovirology 2017). This work led our team to unveil a new host-pathogen interaction as well as a new “chromatin-reading” function in the C-terminal domain of retroviral integrases.
Our last project aimed to understand further the role of the integrase/histone tail interaction in the integration process. Biochemical and structural approaches developed in collaboration with M. Ruff (IGBMC), P. Gouet (IBCP) and S. Bouaziz (U. Paris Descartes) led us to demonstrate that the binding of HIV-1 intasome to human H4 tail induces structural changes in the integration complex leading to its activation for efficient insertion of the viral DNA into the nucleosome (Mauro et al., NAR 2019).
These results highlight a new undiscovered step in the integration process resulting in the activation of the intasome at the contact of the host chromatin. Further works aiming to select drugs that modulate the integrase/histone tails association are under way in order to use this interaction as a new therapeutic target.
This work was supported by the French ANRS agency and Sidaction.
Human H4 tail stimulates HIV-1 integration through structural changes in the carboxyterminal domain of integrase. Mauro E.1¶& , Lesbats, P.1¶& , Lapaillerie D.1¶& , Chaignepain S.2& , Maillot B. 3 , Oladosu D.3 , Robert X.4& , Fiorini F.4& , Kieffer B.3 , Bouaziz S.5& , Gouet P.4& , Ruff M.3& , Parissi V.1¶& . Nucleic Acids Res. 2019.
1Fundamental Microbiology and Pathogenicity Laboratory, UMR 5234 CNRS-University of Bordeaux, SFR TransBioMed. Bordeaux, France. 2Université de Bordeaux, UMR CNRS 5248 CBMN (Chimie Biologie des Membranes et Nanoobjets), 33076, Bordeaux, France. 3IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Département de Biologie Structurale Intégrative, UDS, U596 INSERM, UMR7104 CNRS, Strasbourg, France. 4MMSB-Institute of the Biology and Chemistry of Proteins, UMR 5086 CNRS-Lyon 1 University, Lyon, France. 5Sorbonne Paris Cité, Laboratoire de Cristallographie et RMN Biologiques, Université Paris Descartes, UMR 8015 CNRS, Paris, France. ¶International Associated Laboratory (LIA) of Microbiology and Immunology, CNRS/University de Bordeaux/Heinrich Pette Institute-Leibniz Institute for Experimental Virology. &Viral DNA Integration and Chromatin Dynamics Network (DyNAVir).