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    Late steps of HIV replication cycle

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    Principal instigator : Clarisse Berlioz-Torrent

    Contact : - Phone : +33 1 40 51 65 75

     

    Objective

    AIDS is one of the world’s most devastating diseases, which has killed more than 28 million people and infected an estimated 33 million people worldwide. Production of the Human Immunodeficiency Virus (HIV) involves numerous interactions between viral and cellular proteins at each step of the viral cycle. Identification of new cellular partners is crucial in order to understand the complex interplay between HIV-1 and the host cell, as well as for the development of new anti-viral therapies targeting virus-host protein interactions. Our team is focusing on the identification and functional characterization of cellular co-factors of HIV that are important for viral replication, and more precisely cellular cofactors involved in the late steps of the HIV replication cycle, corresponding to the assembly and release of new infectious HIV particle.

     

    The group

    Olivier Leymarie, post-doc scientist (SIDACTION), Aurelia Kuster, post-doc scientist (ANRS) Ursula Madjo, PhD student (University Paris Descartes), Vanessa Gourhand, engineer assistant (INSERM) and Florian Bakoa, Master 2 student, are involved in these programs.

     

    Research interests

    The aim of our project is to discover and validate new targets acting at the late stage of virus budding, with the ultimate goal to translate the progress in the understanding of the mechanisms involved in HIV-1 assembly, budding and release into innovative anti-viral therapies targeting virus-host protein interactions. To this end, we explore the role of cellular trafficking machineries on Gag and Env trafficking to the budding site and on the formation and production of HIV particles. We define how and when cellular cofactors interplay during the building of the HIV particle. We also decipher the mechanisms underlying the restriction imposed on HIV release by the cellular restriction factor, BST2, as well the viral countermeasures to its antiviral activity. 

     

    Recent advances (2011-2014) – At the end of the viral budding, the accessory protein Vpu of HIV-1 promotes the release of mature viral particles by counteracting the action of the newly identified cellular restriction factor BST2/Tetherin (bone marrow stromal cell antigen 2) that impedes the release of fully assembled HIV-1 particles by physically tethering them to the cell surface. Vpu counteracts this restriction by down-regulating cell surface BST2 (Janvier, Current hiv research 2012)


    In collaboration with Mark Marsh’s lab (MRC, London) and as a part of the collaborative HIV-ACE EU FP7 HEALTH – program (2008-2011), we discovered in 2011 a completely new role for the ESCRT machinery in regulating the release of HIV-1 virions from cells. We found that BST2/Tetherin undergoes constitutive ESCRT-dependent sorting for lysosomal degradation and that this degradation is enhanced by Vpu expression. Vpu-mediated BST2/Tetherin down-modulation and degradation require HRS (ESCRT-0) function. A direct interaction of Vpu, with Tetherin and Hrs is proposed to mediate Tetherin sorting to the lysosome compartment by an ESCRT mediated mechanism (Janvier plos pathogen 2011). In 2011, still in collaboration with Mark Marsh’s lab, we also showed that this viral countermeasure also requires the integrity of the endocytic pathway, and more specifically the activity of Rab7A GTPase (Caillet, plos pathogen 2011).
    In summary, these findings emphasize the intimate interaction between the virus and host cell trafficking and endocytic mechanisms, with possible implications for targeting host cell endocytic components to combat virus infection.          

    These programs were supported by ANR-Young investigator, ANRS, SIDACTION and HIV-ACE FP7-Health program funding.


     

    Main publications and patents

    • Frémont S, Gérard A, Galloux M, Janvier, RE Karess, Berlioz-Torrent C. Beclin-1 is required for  chromosome congression and proper outer kinetochore assembly. EMBO reports 2013 14(4):364-72.

    • Caillet M, Janvier K, Pelchen-Matthews A, Delcroix-Genête D, Camus G, Marsh M, Berlioz-Torrent C.Rab7A is required for efficient production of infectious HIV-1. PloS Pathog.2011 7(11):e1002347.

    • Janvier K, Pelchen-Matthews A, Renaud JB, Caillet M, Marsh M, Berlioz-Torrent C. The ESCRT-0 component HRS is required for HIV-1 Vpu-mediated BST-2/tetherin down-regulation. PloS Pathog.2011 7(2):e1001265.

    • Bauby H, Lopez-Vergès S, Hoeffet G, Delcroix-Genête D, Janvier K, Mammano F, Hosmalin A, Berlioz-Torrent C. TIP47 is required for the production of infectious HIV-1 particles from primary macrophages. Traffic.2010 11(4):455-67.

    • G. Camus, C. Segura-Morales, D. Molle, S.Lopez-Vergès, C. Begon-Pescia, P. Schu, E.Bertrand, C. Berlioz-Torrent* and E. Basyuk*. The clathrin adaptor complex AP-1 bindsHIV-1 and MLV Gag and facilitates their budding. Mol Biol Cell. 2007 Aug;18(8):3193-203. * Co-corresponding authors

    Brevet international WO 2008/08305909.7: Novel substituted aryl derivatives, their process of preparation and their therapeutical uses. Deposited by CellVir at 12/2008.Inventeurs: R. Benarous, S. Berrut, J.M. Paris, S. Barbey, S. Emiliani, C. Berlioz-Torrent.

    Brevet international WO 2007/128806 A3: Methods for in vitro screening of coumpounds inhibiting production of infectious HIV-1 and coumponds selected by said method. Inventeurs: Berlioz-Torrent. C, Benarous. R, Lopez-Vergès.

     

    Financial supports

    These programs are supported by   et  

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