Project #6826
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#6826 : Regulation of HIV-1 integration selectivity by chromatin
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Name of Applicant : Marc LAVIGNE
Date of application : 21-07-2016
Unit : Department of Virology
Location : Institut Cochin (mission scientifique de deux années)
Phone : 01 40 51 65 77
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Project context and summary :

Integration of the viral reverse-transcribed genome into the genome of infected cells is an essential step of retroviral replication and is performed by a viral-encoded enzyme, named integrase (IN). In the case of HIV-1, IN is a new and efficient anti-viral target. The selectivity of this enzyme for its cellular genomic sites is also a major parameter of HIV replication and is regulated by several cellular parameters. One of them is chromatin, and different levels of this nucleoprotein complex are involved in the regulation of IN selectivity. Using in vitro integration assays, established by our team and collaborators, we have studied this regulation at two levels of chromatin architecture: large poly-nucleosome templates (Botbol et al., 2008; Lesbats et al., 2011; Benleulmi et al., 2015; Naughtin et al., 2015) or nucleosome-induced DNA curvature mimicked by DNA minicircles (Pasi et al., 2016). Our present project is to study IN selectivity into mononucleosomes (MN). These MNs will be used as target substrates of integration and the role of MN structure, histone modifications and IN cofactors will be studied. Results obtained in vitro, will be confronted to structural data obtained by molecular modeling and to integration sites observed in infected cells. This project will benefit from our expertise in integration in chromatin templates and a previous collaboration with the C3BI on the analysis of integration sites (Pasi, M., Mornico, D., S. Volant, S., et al., 2016). This project is funded by the ANRS.

Related team publications :
Pasi M. Mornico, D., Volant, S., Juchet, A., Batisse, J., Bouchier, C., Parissi, V., Ruff, M, Lavery, R. & Lavigne, M. (2016) DNA minicircles clarify the specific role of DNA structure on retroviral integration, Nucleic Acids Research, in press
Naughtin, M., Haftek-Terreau, Z., Xavier, J., Meyer, S., Silvain, M., Jaszczyszyn, Y., Levy, N., Miele, V. Benleulmi, M.S., Ruff, M., Parissi, V., Vaillant, C. & Lavigne, M. (2015), DNA physical properties and nucleosome positions are major determinants of HIV-1 integrase selectivity. PLOS One 10:e0129427
Benleulmi, M., Matysiak, J., Lesbats, P., Calmels, C., Henriquez, D., Leon, O., Skalka, A.M., Ruff, M., Lavigne, M., Andreola, ML. Parissi, V. (2015) Chromatin and intasome structures govern the selectivity of retroviral integration Retrovirology, 12: 13
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Project Type : Short
Status : In Progress

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