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    Role of restriction factor and cellular factors on HIV release and infectivity

     

    Principal investigator     

    Clarisse Berlioz-Torrent

    Tel : +33 1 40 51 65 75

     

    Objectives

    HIV requires numerous interactions with cellular proteins and other cellular components, to complete its viral replication cycle and escape intracellular antiviral innate restriction mechanisms. Our group is studying how HIV counteracts antiviral innate restriction during viral assembly and release, and focus on cellular factors controlling HIV release and infectivity, and the formation of viral containing compartment sequestering viruses in macrophages.

     

    The group

    In 2021, our group will bring together 2 staff members, Clarisse Berlioz-Torrent (Research director) and Margaux Versapuech (Assistant engineer), and 2 non-permanent members, including Delphine Judith (Post-doctoral scientist) and Marjory Palaric (PhD student). We recruit post-doc, PhD and master students on a regular basis. A post-doctoral position is currently open in the group on non conventional autophagy pathway and HIV (Contact: clarisse.berlioz@inserm.fr) (Update: January 2021).


    Research interest

    Cellular restriction factors possessing direct antiviral activities are key players of these intrinsic cellular defenses. During this last 8 years, we made particular efforts to decipher the cellular and anti-viral functions on HIV release of the restriction factor BST2 (bone marrow stromal antigen 2)/Tetherin. BST2 is a restriction factor that considerably reduces enveloped viruses release by physically trapping de novo formed mature viral particles at the surface of infected cells. The antiviral activity of BST2 relies on its presence at the viral budding site and on its ability to be incorporated into nascent budding virions, bridging virions and cellular membranes. Lentiviruses have adopted diverse strategies to antagonize this restriction and further optimize viral release, notably by encoding viral proteins, such as HIV-1 Vpu protein, able to interact with BST2, down-regulate cell surface expression of BST2 and displace it from viral budding sites.

    The interplay of Vpu with the endocytic pathway in the countermeasures against BST2. In 2011, we demonstrated that Vpu downregulates cell surface BST2 by perturbing its intracellular trafficking. Notably, Vpu accelerates Endosomal Sorting Complexes Required for Transport (ESCRT)-mediated sorting of BST2 to lysosomes and decreases the recycling of BST2 to the plasma membrane (PM) (Janvier et al. Plos Pathogens 2011). Marina Caillet (PhD student 2008-2011) also showed that this viral countermeasure also requires the integrity of the endocytic pathway (Caillet et al., Plos Pathogens 2011), and more particularly the activity of Rab7A GTPase, emphasizing the intimate interaction between the virus and host cell trafficking and endocytic machineries (Janvier et al, Curr HIV Res. 2012; Roy et al., Front Microbiol. 2014).

     

     

    The interplay between Vpu and BST2 in HIV production in macrophages. BST2, was present at the budding sites in model cells lines or in T cells, but also found enriched in intracellular plasma membrane-connected structures termed virus-containing compartments (VCCs) in HIV-1 infected macrophages. HIV-1 infection of macrophages leads to the sequestration of newly formed viruses in VCCs, where virions remain infectious and are hidden from the immune system surveillance. Olivier Leymarie (Post-doc 2014-2017) and Leslie Lepont (PhD student, 2017-2020) analyzed this interplay between BST2 and Vpu during HIV production and the formation of the VCC in macrophages. This study revealed that Vpu controls the volume of the VCC, partly by modulating BST2 presence in VCC. However, BST2 is dispensable for the formation of VCC (Leymarie and Lepont, J. Virol 2019).

    Our ongoing work in the group aims to identify new cellular cofactors, related to non-canonical autophagic pathway, required for HIV-1 dissemination, with the ultimate goal to develop innovative strategies to combat the virus. We propose to elucidate the role of ATG and ATG related proteins in the HIV-1 response to restriction factors and in the establishment of a productive viral replication cycle.

     

    Publications

    Nguyen Quang N, Goudey S, Ségéral E, Mohammad A, Lemoine S, Blugeon C, Versapuech M, Paillart JC, Berlioz-Torrent C, Emiliani S, Gallois-Montbrun S. Dynamic nanopore long-read sequencing analysis of HIV-1 splicing events during the early steps of infection. Retrovirology. 2020 Aug 17;17(1):25.

    Leymarie O.*, Lepont L.*, Versapuech M.,  Abelanet S., Judith D., Janvier K. and Berlioz-Torrent C. Contribution of the cytoplasmic determinants of Vpu to the expansion of virus containing compartments in HIV-1 infected macrophages. J Virol. 2019 May 15;93(11). *Co-first authors.

    Dejarnac O, Hafirassou ML, Chazal M, Versapuech M, Gaillard J, Perera-Lecoin M, Umana-Diaz C, Bonnet-Madin L, Carnec X, Tinevez JY, Delaugerre C, Schwartz O, Roingeard P, Jouvenet N, Berlioz-Torrent C, Meertens L, Amara A. TIM-1 Ubiquitination Mediates Dengue Virus Entry. Cell Rep. 2018 May 8;23(6):1779-1793.

    Leymarie O, Lepont L, Berlioz-Torrent C. Canonical and Non-Canonical Autophagy in HIV-1 Replication Cycle. Viruses. 2017 Sep 23;9(10). pii: E270

    RoyN., PaciniG., Berlioz-Torrent C., and Janvier K. Characterization of E3 ligases involved in lysosomal sorting of the HIV-1 restriction factor BST2. J Cell Sci. 2017 May 1; 130(9): 1596-1611

    Eckenfelder,A., Ségéral, E., Pinzón, N.,  Ulveling, D., Amadori, C., Charpentier, M., Nidelet, S., Concordet, J-P., Zagury, J.-F. Paillart, J.-C., Berlioz-Torrent, C., Seitz, H., Emiliani S* and Gallois-Montbrun S*. Argonaute proteins regulate HIV-1 splicing in a Dicer independent manner. Nucleic Acid Res 2017 45 (7): 4158-4173. *corresponding author

    Madjo U.*, Leymarie, O.*, Fremont, F., Kuster, A., Gourhand, V., Gallois-Montbrun, S., Janvier, K. and C. Berlioz-Torrent. LC3C contributes to Vpu-mediated antagonism of BST2/Tetherin restriction on HIV-1 release through a non-canonical autophagy pathway. Cell Rep. 2016 Nov 22;17(9):2221-2233. *Co-first authors.

    Roy, N. *, Pacini, G. *, Berlioz-Torrent, C., Janvier, K. Mechanisms underlying HIV-1 Vpu-mediated viral egress Front Microbiol 2014 5:177. Review. *Co-first authors.

    Fremont, S., Gérard, A., Galloux, M., Janvier, K., Karess, R. E., Berlioz-Torrent, C. Beclin-1 is required for chromosome congression and proper outer kinetochore assembly EMBO Rep 2013 14(4):364-72

    Janvier, K.*, Roy, N., Berlioz-Torrent, C*. Role of the Endosomal ESCRT Machinery in HIV-1 Vpu-Induced Down- Regulation of BST2/Tetherin. Curr HIV Res 2012 10(4):315-20. Review. *Corresponding authors

    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 Nov;7(11):e1002347.

    Janvier K§, Pelchen–Matthews A, Renaud J-B, Caillet M, Marsh M, Berlioz-Torrent C§. The ESCRT-0 component HRS is required for HIV-1 Vpu-mediated BST2/Tetherin down-regulation. PloS Pathog. 2011 7(2): e1001265. §Corresponding authors

     

    Financial supports

    These programs are founded by ANRS and SIDACTION

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