Modulation of the functional association between the HIV-1 intasome and the nucleosome by histone amino-terminal tails.

Oyindamola Oladosu, Vincent Parissi, Patrice Gouet, Marc Ruff, Zoltán Ivics, Olivier Delelis, Marie-Line Andreola, Marc Lavigne, Oscar Leon, Eloïse Thierry, Mohamed S Benleulmi, Christina Calmels, Daniel R Henriquez, Stéphane Chaignepain, Paul Lesbats, Delphine Lapaillerie, Eric Mauro, Csaba Miskey, Xavier Robert, Julien Matysiak

Journal: Retrovirology 2018;14(1):54

PMID: 29179726

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Abstract

BACKGROUND

Stable insertion of the retroviral DNA genome into host chromatin requires the functional association between the intasome (integrase·viral DNA complex) and the nucleosome. The data from the literature suggest that direct protein-protein contacts between integrase and histones may be involved in anchoring the intasome to the nucleosome. Since histone tails are candidates for interactions with the incoming intasomes we have investigated whether they could participate in modulating the nucleosomal integration process.

RESULTS

We show here that histone tails are required for an optimal association between HIV-1 integrase (IN) and the nucleosome for efficient integration. We also demonstrate direct interactions between IN and the amino-terminal tail of human histone H4 in vitro. Structure/function studies enabled us to identify amino acids in the carboxy-terminal domain of IN that are important for this interaction. Analysis of the nucleosome-binding properties of catalytically active mutated INs confirmed that their ability to engage the nucleosome for integration in vitro was affected. Pseudovirus particles bearing mutations that affect the IN/H4 association also showed impaired replication capacity due to altered integration and re-targeting of their insertion sites toward dynamic regions of the chromatin with lower nucleosome occupancy.

CONCLUSIONS

Collectively, our data support a functional association between HIV-1 IN and histone tails that promotes anchoring of the intasome to nucleosomes and optimal integration into chromatin.

Address: Fundamental Microbiology and Pathogenicity Laboratory, UMR 5234 CNRS-University of Bordeaux, SFR TransBioMed, 146 rue Léo Saignat, Bordeaux Cedex, France.; International Associated Laboratory (LIA) of Microbiology and Immunology, CNRS, University de Bordeaux/Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Bordeaux, France.; MMSB-Institute of the Biology and Chemistry of Proteins, UMR 5086 CNRS-Lyon 1 University, Lyon, France.; Division of Medical Biotechnology, Paul Ehrlich Institute, Langen, Germany.; Viral DNA Integration and Chromatin Dynamics Network (DyNAVir), Bordeaux, France.; UMR CNRS 5248 CBMN (Chimie Biologie des Membranes et Nanoobjets), Université de Bordeaux, 33076, Bordeaux, France.; Virology Program, ICBM, Faculty of Medicine, University of Chile, Santiago of Chile, Chile.; Département de Biologie Structurale Intégrative, UDS, U596 INSERM, UMR7104 CNRS, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France.; LBPA, UMR8113, CNRS, ENS-Cachan, 94235, Cachan, France.; Dpt de Virologie, UMR 3569, CNRS, Institut Pasteur, Paris, France.; Institut Cochin-Inserm U1016-CNRS UMR8104-Université Paris Descartes, Paris, France.; Fundamental Microbiology and Pathogenicity Laboratory, UMR 5234 CNRS-University of Bordeaux, SFR TransBioMed, 146 rue Léo Saignat, Bordeaux Cedex, France. [email protected].; International Associated Laboratory (LIA) of Microbiology and Immunology, CNRS, University de Bordeaux/Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Bordeaux, France. [email protected].; Viral DNA Integration and Chromatin Dynamics Network (DyNAVir), Bordeaux, France. [email protected].

DOI: 10.1186/s12977-017-0378-x

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MeSH Terms: Cell Line, Transformed, Chromatin, DNA, Viral, HEK293 Cells, HIV Integrase, HIV-1, Histones, Host-Parasite Interactions, Humans, Nucleosomes, Protein Binding, Virus Integration