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    Chromatin control of HIV replication

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    Principal investigator: Stephane Emiliani

    Contact : stephane.emiliani@inserm.fr – Phone : +33 1 40 51 66 39

     

     

    The group

    Céline Amadori (PhD student, CIFRE)
    Monica Naughtin (Post-Doc, HIVinnov)

    Collaboration: Marc Ruff (IGBMC, Strasbourg)

     

    Objective

    Most of the currently available ARV drugs and those in development directly target virus components, such as the three viral enzymes (reverse transcriptase (RT), protease (PR), integrase (IN)), with the exception of entry inhibitors that target the cellular co-receptors. HIV requires numerous interactions with cellular proteins and other cellular components, to complete its viral replication cycle and escape the intracellular antiviral innate restriction mechanisms.

     

    Research interests

    Early stages of HIV replication involve the timely disassembly of the viral core, reverse transcription and transport of the pre-integration complex (PIC) to the nucleus where the viral DNA integrates into the host chromosome. Because integrase (IN) remains constantly associated to the PIC, it is likely to engage with cellular cofactors to exploit cellular machineries during these stages. Our lab developed a systematic large-scale yeast 2-hybrid approach to identify HIV cellular interacting proteins. Using this approach, we uncovered important cellular cofactors - including TNPO3, VBP1 and LEDGF/p75 - that bind IN and control the nuclear stages of HIV replication. These host-virus interactions could constitute excellent new targets to expand the scope of development of original ARVs.

    A collaborative project (HIVinnov - Generation of a new class of Anti-RetroVirals Targeting HIV-cofactors) led by MUTABILIS (SA, Romainville, France) has been implemented: our lab aims at identifying new pharmaceutical targets along the intricate pathways and network of interactions involving viral proteins and their cellular partners.


    Partners of HIVinnov consortium are:
    Mutabilis, SA (coordinator), France
    Ariberto Fassati (UCL, MRC), UK
    Peter Cherepanov, (CRUK), UK
    Stéphane Emiliani (INSERM), France
    Alessia Zamborlini (INSERM), France
    Ben Berkhout (AMC), The Netherlands
    Jose Guatell, (FCRB), Spain

     

    References

     

    Le Rouzic E, Bonnard D, Chasset S, Bruneau JM, Chevreuil F, Le Strat F, Nguyen J, Beauvoir R, Amadori C, Brias J, Vomscheid S, Eiler S, Lévy N, Delelis O, Deprez E, Saïb A, Zamborlini A, Emiliani S, Ruff M, Ledoussal B, Moreau F, Benarous R. (2013). Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Retrovirology. 2013 Nov 21;10:144.

    Gérard A, Soler N, Ségéral E, Belshan M, and Emiliani S. (2013). Identification of low molecular weight nuclear complexes containing integrase during the early stages of HIV-1 infection. Retrovirology. Feb 1;10(1):13.

    Cribier A, Segeral E, Delelis O, Parissi V, Simon A, Ruff M, Benarous R, Emiliani S. (2011). Mutations affecting interaction of integrase with TNPO3 do not prevent HIV-1 cDNA nuclear import. Retrovirology. Dec 16;8(1):104.

    Rain JC, Cribier A, Gérard A, Emiliani S* and Benarous R*. (2009) Yeast two-hybrid detection of Integrase-host factor interactions. Methods. Apr;47(4):291-7.

    Michel F, Crucifix C, Granger F, Eiler S, Mouscadet JF, Korolev S, Agapkina J, Ziganshin R, Gottikh M, Nazabal A, Emiliani S, Benarous R, Moras D, Schultz P, Ruff M. Structural basis for HIV-1 DNA integration in the human genome, role of the LEDGF/P75 cofactor. EMBO J. Apr 8;28(7):980-91.

    Christ F, Thys W, De Rijck J, Gijsbers R, Albanese A, Arosio D, Emiliani S, Rain JC, Benarous R, Cereseto A, Debyser Z. Transportin-SR2 imports HIV into the nucleus. (2008) Curr Biol. 18(16):1192-202.

    Cribier A and Emiliani S. Les partenaires cellulaires de l’intégrase du VIH-1 : vers de nouvelles cibles thérapeutiques. (2007) Virologie 11 (n°spécial) : 1-10.

    Mousnier, A., Kubat, N.J., Massias-Simon, A., Ségéral, E., Rain, J.C., Benarous, R., Emiliani, S.* and Dargemont, C.* (2007) VBP1/VHL-mediated degradation of integrase affects HIV 1 gene expression at a post-integration step. Proc Natl Acad Sci U S A, 104(34):13615-20.

    Maroun, M., Delelis, O., Coadou, G., Bader, T., Segeral, E., Mbemba, G., Petit, C., Sonigo, P., Rain, J.C., Mouscadet, J.F., Benarous, R. and Emiliani, S. (2006) Inhibition of early steps of HIV-1 replication by SNF5/Ini1. J Biol Chem 281:22736-43

    Emiliani, S*., Mousnier, A., Busschots, K., Maroun, M., Van Maele, B., Tempe, D., Vandekerckhove, L., Moisant, F., Ben-Slama, L., Witvrouw, M., et al. (2005). Integrase mutants defective for interaction with LEDGF/P75 are impaired in chromosome tethering and HIV-1 replication. J Biol Chem 280 :25517-25523.

     

    Financial supports

     

    This program is supported by ANRS, SIDACTION and FP7.

     

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