Project #526
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#526 : Regulation of HIV replication by cellular DNA topology
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Name of Applicant : Marc Lavigne
Date of application : 11-05-2015
Unit : Molecular Virology and Vaccinology
Location : Lwoff, 4ieme
Phone : 0145688903
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Project context and summary :

HIV-1 replication requires the integration of the viral genome into the cell genome. A viral-encoded enzyme, integrase (IN), performs this critical step of infection and is a promising target for anti-viral therapeutics. If the catalytic properties of INs are well characterized, the mechanisms responsible for their site selectivity are still under investigation. Several cellular proteins, such as the LEDFGF/p75 transcription regulator, the RNA polymerase II machinery, nuclear pore proteins and specific modified histones have been proposed to be involved in IN selectivity at a genomic level. In addition, structural parameters of the target DNA helix (curvature, flexibility and topology) are proposed to regulate IN selectivity at a local level. Our team is studying the role and molecular mechanisms associated with these various parameters (Botbol et al., 2008; Lesbats et al., 2011; Morchikh et al., 2013; Benleulmi et al., 2015; Naughtin et al.,). This project aims to define the role of cellular DNA topology during HIV-1 integration. We will first compare already mapped integration sites and superhelicity profiles and search for possible correlations between these two parameters. We will then modify topoisomerases activity in infected cells and study the consequences on viral replication and integration. Finally, we will study in vitro, the direct effects on integration of two parameters of DNA topology, the twist and writhe of the DNA helix. This project relies on complementary in vivo, in vitro and in silico approaches. Bio-informatics tools are crucial for the correlative and statistical analyses of integration sites and superhelicity maps.

Related team publications :
- Botbol, Y., Raghavendra, N.K., Rahman, S. Engelman, A. & Lavigne, M. (2008) Chromatinized templates reveal the requirement for the LEDGF/p75 PWWP domain during HIV-1 integration in vitro, Nucleic Acids Research 36, 1237-46
- Morchikh, M., Naughtin, M., Di Nunzio, F. Xavier, J., Charneau, P., Jacob, Y. & Lavigne, M. (2013) TOX4 and NOVA1 proteins are partners of the LEDGF PWWP domain and affect HIV-1 replication. PLOS One, 8(11):e81217
- Lesbats, P., Botbol, Y., Chevereau, G., Vaillant, C., Calmels, C., Arnéodo, A., Androlea, M. L., Lavigne, M. & Parissi, V. (2011) Remodeling factors open the way for HIV-1 concerted integration into stable chromatin, PLOS Pathogens 7 ( 2 ), e1001280
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Project Type : Short
Status : Declined

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