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    Mechanisms of HIV latency

    Principal investigator: Stephane Emiliani

    Contact : stephane.emiliani@inserm.fr - Tel : +33 1 40 51 66 39

     

    Objectives

    In Human Immunodeficiency Virus (HIV)-infected individuals on antiretroviral therapy, the persistence of the virus in latently infected cells is the major barrier for the cure of infection. The main latent reservoir is constituted of resting memory CD4+ T lymphocytes containing integrated proviruses that are transcriptionally silent. Inhibition of early elongation is a major reversible block to HIV transcription in peripheral CD4+T latently infected cells from ART-suppressed patients. Whether a successful sterilizing cure will force the reactivation of latent HIV to purge the reservoirs (“shock and kill“ approach) or on the contrary will induce a deep latency stage to block viral rebound (“lock and block“ approach), it is important to better understand the key players controlling of HIV transcriptional silencing and reactivation.

     

    Research interests

    For several years, my group has been interested in understanding the mechanisms controlling HIV expression in infected cells. We identified the functions of key cellular cofactors of HIV integrase during the early steps of the viral life cycle (Gérard Retrovirology, 2013, Cribier Retrovirology 2011, Rain Methods 2009, Maroun JBC 2005, Mousnier PNAS 2007). We also characterized the role of the SWI/SNF complex in Tat-dependent activation of HIV transcription (Tréand EMBOJ 2005).

    Cellular cofactors of HIV integrase

    We identified of a functional role for the interaction between HIV integrase and LEDGF/p75 during HIV integration and replication (Emiliani JBC 2005). Subsequently, LEDGF/p75 was shown to be the main cellular cofactor of HIV integrase responsible for the targeting of HIV integration within transcription units of active genes. These findings led to the development of a new generation of allosteric inhibitors of HIV integrase (Le Rouzic Retrovirology 2013) developed by a spinoff biotech company. Our team was partner of a collaborative EU FP7 project (HIVinnov - Generation of a new class of Anti-RetroVirals Targeting HIV-cofactors) aiming at identifying new pharmaceutical targets along the intricate pathways and network of interactions involving viral proteins and their cellular partners (Le Rouzic Retrovirology 2013, Amadori Retrovirology 2017).

    Mechanisms of HIV Latency

    We also identified a novel cellular complex that consists of LEDGF/p75, Iws1 and Spt6, a histone chaperone that has the ability to reassemble nucleosomes in the wake of the elongating RNAPII in vivo. We showed that the LEDGF/p75:Iws1:Spt6 complex is involved in the control of HIV silencing. (Gerard, Cell Host and Microbe, 2015). In addition, we patented a dual color HIV virus allowing the identification of productively versus latently infected cells (Patent EP14305885.7).

    Our current projects are focusing on transcriptional and post-transcriptional control of HIV and cellular gene expression using genome-wide approaches. We are exploring the mechanisms leading to LTR-proximal pausing and RNAPII premature termination. We are deciphering the role of transcriptional elongation factors in the regulation of gene expression. Finally, we studied the impact of m6A methylation on the fate of viral transcripts.

    The objectives are to understand the molecular mechanisms underlying HIV latency and reactivation.

     

    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. doi: 10.1186/s12977-020-00533-1. PMID: 32807178

    Bonnard D, Le Rouzic E, Eiler S, Amadori C, Orlov I, Bruneau JM, Brias J, Barbion J, Chevreuil F, Spehner D, Chasset S, Ledoussal B, Moreau F, Saïb A, Klaholz BP, Emiliani S, Ruff M, Zamborlini A, Benarous R. Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration. J Biol Chem. 2018 Apr 20;293(16):6172-6186. doi: 10.1074/jbc.M117.816793. Epub 2018 Mar 5. PMID: 29507092

    Amadori C, van der Velden YU, Bonnard D, Orlov I, van Bel N, Le Rouzic E, Miralles L, Brias J, Chevreuil F, Spehner D, Chasset S, Ledoussal B, Mayr L, Moreau F, García F, Gatell J, Zamborlini A, Emiliani S, Ruff M, Klaholz BP, Moog C, Berkhout B, Plana M, Benarous R. The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity. Retrovirology. 2017 Nov 9;14(1):50. doi: 10.1186/s12977-017-0373-2.

    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. NAR. (2016) Dec 20. pii: gkw1289. doi: 10.1093/nar/gkw1289.

    Gérard A, Ségéral E, Naughtin M, Abdouni A, Charmeteau B, Cheynier R, Rain JC, Emiliani S. The Integrase Cofactor LEDGF/p75 Associates with Iws1 and Spt6 for Postintegration Silencing of HIV-1 Gene Expression in Latently Infected Cells. Cell Host & Microbe. (2015) Jan 14;17(1):107-17.

    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. Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Retrovirology. (2013) Nov 21;10:144.

    Maillot B, Lévy N, Eiler S, Crucifix C, Granger F, Richert L, Didier P, Godet J, Pradeau-Aubreton K, Emiliani S, Nazabal A, Lesbats P, Parissi V, Mely Y, Moras D, Schultz P, Ruff M. Structural and functional role of INI1 and LEDGF in the HIV-1 preintegration complex. PLoS One. (2013) Apr 11;8(4):e60734.

    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.

    Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C, Ségéral E, Yatim A, Emiliani S, Schwartz O, Benkirane M. (2011). SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature. May 25;474(7353):654-7.

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

    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 NJ, Massias-Simon A, Ségéral E, Rain JC, 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 USA, 104(34):13615-20. * co-corresponding authors.

    Busschots K, Voet A, De Meyer M, Rain, J-C, Emiliani S, Benarous R, Desender L, Debyser Z, and Christ F (2007). Identification of the LEDGF/p75 binding site in HIV-1 integrase. J. Mol. Biol. 365(5):1480-1492.

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

    Treand C, du Chene I, Bres V, Kiernan R, Benarous R, Benkirane M and Emiliani S. (2006) Requirement for SWI/SNF chromatin-remodeling complex in Tat-mediated activation of the HIV-1 promoter. EMBO J, 25:1690-1699.

     

    Patents

    Methods and means for producing and isolating HIV latently infected cells. Inventors Stéphane EMILIANI and Emmanuel Ségéral. N° 14305885.7 deposited 05.08.14

    Novel substituted aryl derivatives, their process of preparation and their therapeutical uses as anti-HIV agents. Inventors: Benarous R., Barbey S., Paris J-M., Berlioz-Torrent C., Sébastien Berrut and Stéphane EMILIANI. Filed by CellVir, December 14th 2008 (File N° EP08305909)

    Protein-protein interactions in Human Immunodeficiency Virus. Inventors: P. Legrain, J. C. Rain, R. Benarous, G. Blot, S. EMILIANI, C. Berlioz-Torrent. US 60,33346, US  60,385132 (26/11/2001) PCT/EP 2002/013868, (26/11/2002) UE 02792922.3, (01/06/04) WO 03/046176 (05/06/03) EP 1451214  (01/09/04)

     

    Financial Supports

    This program is supported by ANRS, SIDACTION and FP7.

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