Laboratory of Molecular Virology

Molecular bases of human diseases

Nos projets de recherche s’inscrivent dans une thématique visant à mieux comprendre les interactions entre le VIH et la cellule hôte. Pour cela, nous cherchons à identifier et à étudier la régulation de l’activité des facteurs cellulaires impliqués dans l’activation et la répression de la réplication virale. Nous nous intéressons plus particulièrement à la régulation de l’expression des gènes viraux. En effet, chez les patients infectés par le VIH, le taux de réplication virale, contrôlé en partie par la transcription du génome viral, est un facteur critique, déterminant la progression de la maladie vers le stade SIDA.

La transcription des gènes du VIH est sous le contrôle du transactivateur viral Tat et des facteurs de transcription cellulaires qui interagissent avec sa région promotrice LTR 5’ (“Long Terminal Repeat”). Les déterminants cellulaires impliqués dans la latence transcriptionnelle du VIH, phénomène à l’origine de l’établissement du réservoir viral observé chez les patients infectés, sont mal connus.

Ce réservoir viral, constitué principalement de cellules lymphocytaires T CD4+ mémoires infectées mais non productrices de virus, est un des obstacles majeurs responsables de l’échec des thérapies anti-VIH. Ces cellules stables sont insensibles aux traitements et invisibles pour le système immunitaire. La réactivation du virus dans ces cellules permettra de les rendre accessibles aux traitements anti-viraux. La combinaison d’agents activateurs du virus dans les cellules réservoirs et la tri-thérapie (HAART) permettront de « purger » le réservoir viral et par conséquent, éliminer le virus.

Plusieurs études montrent un rôle important de la structure chromatinienne dans le choix des sites d’intégration et la régulation de la transcription à partir du promoteur viral. De plus, des études récentes suggèrent une interaction physique et fonctionnelle entre le VIH et la machinerie RNAi cellulaire. Afin d’étudier le rôle de la chromatine et de la machinerie RNAi cellulaire dans la réplication du VIH, nous appliquons plusieurs techniques incluant une approche protéomique pour identifier les facteurs cellulaires impliqués dans l’activation et la répression du LTR. Le recrutement de ces facteurs au niveau du LTR est analysé par immunoprécipitation de chromatine et PCR quantitative et par immunofluoresence.

PUBLICATIONS OF THE TEAM

Exploring histone loading on HIV DNA reveals a dynamic nucleosome positioning between unintegrated and integrated viral genome.

Machida S, Depierre D, Chen HC, Thenin-Houssier S, Petitjean G, Doyen CM, Takaku M, Cuvier O, Benkirane M

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FTSJ3 is an RNA 2'-O-methyltransferase recruited by HIV to avoid innate immune sensing.

Ringeard M, Marchand V, Decroly E, Motorin Y, Bennasser Y

Posttranscriptional Regulation of HIV-1 Gene Expression during Replication and Reactivation from Latency by Nuclear Matrix Protein MATR3.

Sarracino A, Gharu L, Kula A, Pasternak AO, Avettand-Fenoel V, Rouzioux C, Bardina M, De Wit S, Benkirane M, Berkhout B, Van Lint C, Marcello A

Descours et al. reply.

Descours B, Petitjean G, Benkirane M

XPC is an RNA polymerase II cofactor recruiting ATAC to promoters by interacting with E2F1.

Bidon B, Iltis I, Semer M, Nagy Z, Larnicol A, Cribier A, Benkirane M, Coin F, Egly JM, Le May N

CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses

Descours B, Petitjean G, López-Zaragoza JL, Bruel T, Raffel R, Psomas C, Reynes J, Lacabaratz C, Levy Y, Schwartz O, Lelievre JD, Benkirane M.

HEXIM1 and NEAT1 lncRNA form a multi subunit complex that regulates DNA-mediated innate immune response

Morchikh, M., Cribier, A., Raffel, R., Amraoui, S., Cau, J., Severac, D., Dubois, E., Schwartz, O., Bennasser, Y., Benkirane, M.

Dasatinib Inhibits HIV-1 Replication through the Interference of SAMHD1 Phosphorylation in CD4+ T Cells

Bermejo M, López-Huertas MR, García-Pérez J, Climent N, Descours B, Ambrosioni J, Mateos E, Rodríguez-Mora S, Rus-Bercial L, Benkirane M, Miró JM, Plana M, Alcamí J, Coiras M.

IL-7 Induces SAMHD1 Phosphorylation in CD4+ T Lymphocytes, Improving Early Steps of HIV-1 Life Cycle

Coiras M, Bermejo M, Descours B, Mateos E, García-Pérez J, López-Huertas MR, Lederman MM, Benkirane M, Alcamí J.

International AIDS Society global scientific strategy: towards an HIV cure 2016

Deeks SG, Lewin SR, Ross AL, Ananworanich J, Benkirane M, Cannon P, Chomont N, Douek D, Lifson JD, Lo YR, Kuritzkes D, Margolis D, Mellors J, Persaud D, Tucker JD, Barre-Sinoussi F; International AIDS Society Towards a Cure Working Group, Alter G, Auerbach J, Autran B, Barouch DH, Behrens G, Cavazzana M, Chen Z, Cohen ÉA, Corbelli GM, Eholié S, Eyal N, Fidler S, Garcia L, Grossman C, Henderson G, Henrich TJ, Jefferys R, Kiem HP, McCune J, Moodley K, Newman PA, Nijhuis M, Nsubuga MS, Ott M, Palmer S, Richman D, Saez-Cirion A, Sharp M, Siliciano J, Silvestri G, Singh J, Spire B, Taylor J, Tolstrup M, Valente S, van Lunzen J, Walensky R, Wilson I, Zack J.

Towards an HBV cure: state-of-the-art and unresolved questions-report of the ANRS workshop on HBV cure

Zeisel MB, Lucifora J, Mason WS, Sureau C, Beck J, Levrero M, Kann M, Knolle PA, Benkirane M, Durantel D, Michel ML, Autran B, Cosset FL, Strick-Marchand H, Trépo C, Kao JH, Carrat F, Lacombe K, Schinazi RF, Barré-Sinoussi F, Delfraissy JF, Zoulim F.

A Testis-Specific Chaperone and the Chromatin Remodeler ISWI Mediate Repackaging of the Paternal Genome

Doyen CM1, Chalkley GE1, Voets O1, Bezstarosti K2, Demmers JA2, Moshkin YM1, Verrijzer CP3.

Phosphorylation of murine SAMHD1 regulates its antiretroviral activity

Wittmann S, Behrendt R, Eissmann K, Volkmann B, Thomas D, Ebert T, Cribier A, Benkirane M, Hornung V, Bouzas NF, Gramberg T.

SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage

Clifford R, Louis T, Robbe P, Ackroyd S, Burns A, Timbs AT, Colopy GW, Dreau H, Sigaux F, Judde JG, Rotger M, Telenti A, Lin YL, Pasero P, Maelfait J, Titsias M, Cohen DR, Henderson SJ, Ross M, Bentley D, Hillmen P, Pettitt A, Rehwinkel J, Knight SJ, Taylor JC, Crow YJ, Benkirane M, Schuh A.

Premature Activation of the SLX4 Complex by Vpr Promotes G2/M Arrest and Escape from Innate Immune Sensing

Laguette,N., Bregnard, C., Hue, P., Basbous, J., Yatim, A., Larroque, M., Kirchhoff, F., Constantinou, A., Sobhian, B., Benkirane, M.

The Tudor Domain Protein Spindlin1 Is Involved in Intrinsic Antiviral Defense against Incoming Hepatitis B Virus and Herpes Simplex Virus Type 1

Ducroux A, Benhenda S, Rivière L, Semmes OJ, Benkirane M, Neuveut C.

Integrator complex regulates NELF-mediated RNA polymerase II pause/release and processivity at coding genes

Stadelmayer B, Micas G, Gamot A, Martin P, Malirat N, Koval S, Raffel R, Sobhian B, Severac D, Rialle S, Parrinello H, Cuvier O, Benkirane M

The PRMT1 methyltransferase is a binding partner of HBx and a negative regulator of hepatitis B virus transcription

Benhenda, S., Ducroux, A., Rivière, L., Sobhian, B., Ward, M., Dion, S., Hantz, O., Protzer, U., Michel, ML., Benkirane, M., Semmes, OJ., Buendia, MA., Neuveut, C.

Monsef Benkirane awarded 2013 Ming K. Jeang Foundation Retrovirology Prize: Landmark HIV-1 research honoured

Berkhout B, Lever A, Wainberg M, Fassati A, Borrow P, Fujii M

Phosphorylation of SAMHD1 by CyclinA2/CDK1 regulates its restriction activity towards HIV-1

Cribier, A., Descours, B., Chaves Valadeo, AL., Laguette, N., Benkirane , M.

SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates

Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, Bloch N, Maudet C, Bertrand M, Gramberg T, Pancino G, Priet S, Canard B, Laguette N, Benkirane M, Transy C, Landau NR, Kim B, Margottin-Goguet F.

NOTCH1 Nuclear Interactome Reveals Key Regulators of Its Transcriptional Activity and Oncogenic Function

Yatim, A., Benne, C., Sobhian, B., Laurent-Chabalier, S., Deas, O., Judde, JG., Lelievre, JD., Levy, Y., Benkirane, M.

SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4+ T-cells

Descours B, Cribier A, Chable-Bessia C, Ayinde D, Rice G, Crow Y, Yatim A, Schawartz O, Laguette N, Benkirane M.

How Samhd1 changes our view of viral restriction

Laguette N, Benkirane M.

Evolutionary and Functional Analyses of the Interaction between the Myeloid Restriction Factor SAMHD1 and the Lentiviral Vpx Protein

Laguette N, Rahm N, Sobhian B, Chable-Bessia C, Münch J, Snoeck, Sauter D, Switzer WM, Heneine W, Kirchhoff F, Delsuc F, Telenti A and Benkirane M.

SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates

Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, Bloch N, Maudet C, Bertrand M, Gramberg T, Pancino G, Priet S, Canard B, Laguette N, Benkirane M, Transy C, Landau NR, Kim B, Margottin-Goguet F.

Role of SAMHD1 nuclear localization in restriction of HIV-1 and SIVmac

Brandariz-Nuñez A, Valle-Casuso JC, White TE, Laguette N, Benkirane M, Brojatsch J, Diaz-Griffero F

Towards an HIV cure: a global scientific strategy

The International AIDS Society Scientific Working Group on HIV Cure, Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, Chomont N, Chun TW, Churchill M, Mascio MD, Katlama C, Lafeuillade A, Landay A, Lederman M, Lewin SR, Maldarelli F, Margolis D, Markowitz M, Martinez-Picado J, Mullins JI, Mellors J, Moreno S, O'Doherty U, Palmer S, Penicaud MC, Peterlin M, Poli G, Routy JP, Rouzioux C, Silvestri G, Stevenson M, Telenti A, Lint CV, Verdin E, Woolfrey A, Zaia J, Barré-Sinoussi F.

Hyperthermia Stimulates HIV-1 Replication

Roesch F, Meziane O, Kula A, Nisole S, Porrot F, Anderson I, Mammano F, Fassati A, Marcello A, Benkirane M, Schwartz O

Competition for XPO5 binding between Dicer mRNA, pre-miRNA and viral RNA regulates human Dicer levels

Bennasser, Y., Chable-Bessia, C., Triboulet, R., Gibbings, D., Gwizdek, C., Dargemont, C., Kremer, EJ., Voinnet, O., Benkirane, M.

SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx.

Laguette, N., Sobhian, B., Casartelli, N., Ringeard, M., Chable-Bessia, C., Ségéral, E., Emiliani, S., Schwartz, O., Benkirane, M

Human Polymerase-Associated Factor complex (PAFc) connects the Super Elongation Complex (SEC) to RNA polymerase II on chromatin

He, N., Chan, CK., Sobhian, B., Chou, S., Xue, Y., Liu, M., Alber, T., Benkirane, M., Zhou, Q

Lessons from interconnected ubiquitylation and acetylation of p53: think metastable networks

Benkirane, M., Sardet, C, Coux,O.

HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP

Sobhian, B., Laguette, N., Yatim, A., Nakamura, M., Levy, Y., Kiernan, R., Benkirane, M.

Epidemiology of HIV infection in the Middle East and North Africa

Abu-Raddad, LJ., Hilmi, N., Mumtaz, G., Benkirane, M., Akala, FA., Riedner, G., Tawil, O., Wilson, D.

Suppression of HIV-1 replication by microRNA effectors

Chable-Bessia, C., Meziane, O., Latreille, D., Triboulet, R., Zamborlini, A., Wagschal, A., Jacquet, JM., Reynes, J., Levy, Y., Saib, A., Bennasser, Y., Benkirane, M.

Endogenous Retroviruses: Thierry Heidmann wins the 2009 Retrovirology prize.

Saib, A., Benkirane, M.

Suv39H1 and HP1gamma are responsible for chromatin-mediated HIV-1 transcriptional silencing and post integration latency.

du Chéné, I., Basyuk, E., Lin,YL., Triboulet, R., Knezevich, A., Chable-Bessia, C., Mettling, C., Baillat, V., Reynes, J., Corbeau, P., Bertrand, E., Marcello, A., Emiliani, S., Kiernan, R., Benkirane, M.

Intrinsic ubiquitylation activity of PCAF controls the stability of the oncoprotein Hdm2

Linares, Laetitia, Rosemary Kiernan, Robinson Triboulet, Christine Chable-Bessia, Daniel Latreille, Olivier Cuvier, Matthieu Lacroix, Laurent Le Cam, Olivier Coux, and Monsef Benkirane.

The Proteasome Regulates HIV-1 Transcription by Both Proteolytic and Non-Proteolytic Mechanisms

Lassot, L., Latreille, D., Rousset, E., Sourisseau, M., Linares, L.K., Chable-Bessia, C., Coux, O., Benkirane, M., Kiernan, R.

Physiological suppression of microRNA-silencing pathway by HIV-1 during virus replication

Triboulet, Robinson., Bernard Mari, Yea-Lih Lin, Christine Chable-Bessia, Yamina Bennasser, Kevin Lebrigand, Bruno Cardinaud, Thomas Maurin, Pascal Barbry, Vincent Baillat, Jacques Reynes, Pierre Corbeau, Kuan-Teh Jeang and Monsef Benkirane.

Interplay between HIV-1 replication and the microRNA-silencing pathway.

Triboulet, R., Benkirane, M.

Small non-coding RNAs, mammalian cells, and viruses: regulatory interactions?

Yeung, ML., Benkirane, M., Jeang, KT.

The HIV-1 Tat protein stimulates reverse transcription in vitro.

Apolloni, A., Meredith, LW., Suhrbier, A., Kiernan, R., Harrich, D

PPAR{gamma} Recruits the P-TEFb Complex to Activate Transcription and Promote Adipogenesis.

Iankova I, Petersen RK, Annicotte JS, Chavey C, Hansen JB, Kratchmarova I, Sarruf D, Benkirane M, Kristiansen K, Fajas L.

Requirement for SWI/SNF chromatin-remodeling complex in Tat-mediated activation of the HIV-1 promoter.

Treand C, du Chene I, Bres V, Kiernan R, Benarous R, Benkirane M, Emiliani S.

ERK5 Activates NF-{kappa}B in Leukemic T Cells and Is Essential for Their Growth In Vivo.

Garaude J, Cherni S, Kaminski S, Delepine E, Chable-Bessia C, Benkirane M, Borges J, Pandiella A, Iniguez MA, Fresno M, Hipskind RA, Villalba M.

Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing

Bennasser Y, Le SY, Benkirane M, Jeang KT

HIV-1 Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses

Col E, Caron C, Chable-Bessia C, Legube G, Gazzeri S, Komatsu Y, Yoshida M, Benkirane M, Trouche D, and Khochbin S

p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain.

Lassot I, Estrabaud E, Emiliani S, Benkirane M, Benarous R, Margottin-Goguet F.

Interferon-induced exonuclease ISG20 exhibits an antiviral activity against human immunodeficiency virus type 1.

Espert L, Degols G, Lin YL, Vincent T, Benkirane M, Mechti N.

Simian Virus 40-Based Replication of Catalytically Inactive Human Immunodeficiency Virus Type 1 Integrase Mutants in Nonpermissive T Cells and Monocyte-Derived Macrophages

Richard Lu, Noriko Nakajima, Wolfgang Hofmann, Monsef Benkirane, Kuan Teh-Jeang, Joseph Sodroski, and Alan Engelman

Ubiquitination of human T-cell leukemia virus type 1 tax modulates its activity

Peloponese JM Jr, Iha H, Yedavalli VR, Miyazato A, Li Y, Haller K, Benkirane M, Jeang KT

Regulation of human SRY subcellular distribution by its acetylation/deacetylation

Thevenet L, Mejean C, Moniot B, Bonneaud N, Galeotti N, Aldrian-Herrada G, Poulat F, Berta P, Benkirane M, Boizet-Bonhoure B

Post-activation turn-off of NF-kB-dependent transcription is regulated by acetylation of p65

Rosemary E. Kiernan, Vanessa Bres, Raymond W.M. Ng, Marie-Pierre Coudart, Selma El Messaoudi, Claude Sardet, Dong-Yan Jin, Stephane Emiliani, and Monsef Benkirane

A non proteolytic role for ubiquitin in Tat-mediated transactivation of the HIV-1 promoter

Vanessa Brès, Rosemary E. Kiernan, Laetitia K. Linares, Christine Chable-Bessia, Olga Plechakova, Céline Tréand, Stephane Emiliani, Jean-Marie Peloponese, Kuan-Teh Jeang, Olivier Coux, Martin Scheffner, and Monsef Benkirane

Tat and TAR RNA independent induction of HIV-1 LTR by Human and Murine cyclin T1 requires Sp1

Venkat S.R.K. Yedavalli, Monsef Benkirane, and Kuan Teh Jeang

Tat acetyl-acceptor lysines are important for Human Immunodeficiency Virus type-1 replication

Brès, V., Rosemary Kiernan, Stéphane Emiliani and Monsef Benkirane

Differential acetylation of Tat coordinates its interaction with the co-activators cyclin T1 and PCAF.

Brès V. Tagami H. Péloponèse J.M. Loret E. Jeang K-T. Nakatani Y. Emiliani S. Benkirane M. and Kiernan ER.

Interaction between cyclin T1 and SCFSKP2 targets CDK9 for ubiquitination and degradation by the proteasome.

Kiernan, R., Emiliani, S., Nakayama, K., Castro, A., Labbé, J.C., Lorca, T., Nakayama, K.-I., and Benkirane, M.

Tat Protein of Human Immunodeficiency Virus Type 1 Induces Interleukin-10 in Human Peripheral Blood Monocytes: Implication of Protein Kinase C-Dependent Pathway

Badou A, Bennasser Y, Moreau M, Leclerc C, Benkirane M, Bahraoui E

Selective CXCR4-antagonism by Tat:Implications for in vivo expansion of co-receptor use by HIV-1

Xiao, H., Neuveut, C., Tiffany, H.L., Murphy, P.M, Benkirane, M., Rich, E.A., and Jeang, K.-T.

HIV-1 Tat transcriptional activity is regulated by acetylation.

Kiernan, R., Vanhulle, C., Schiltz, L., Adam, E., Xiao, H., Maudoux, F., Calomme, C., Burny, A., Nakatani, Y., Jeang, K.-T., Benkirane, M. and Van Lint, C.

Activation of integrated provirus requires histone acetyltransferase. p300 and P/CAF are coactivators for HIV-1 Tat.

Benkirane, M., Chun, R.F., Xiao, H., Ogryzko, V.V., Howard, B.H., Nakatani, Y. and Jeang, K.-T..

Interaction of the second coding exonof Tat withhuman EF-1 delta delineates a mechanism forHIV-1 shut-off of host mRNA translation.

Xiao, H., Neuveut, C., Benkirane, M. and K.T., J.

PUBLICATIONS COMMUNES

Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production

Bregnard, C, Guerra, J, Dejardin, S, Passalacqua, F, Benkirane, M, Laguette, N
2016 - EBioMedicine , 8, 184-194 27428429
Service porteur : Molecular Basis of Inflammation

Shaping of the host cell by viral accessory proteins

Laguette N, Benkirane M.
2015 - Front Microbiol. , 6, 142 25755653
Service porteur : Molecular Basis of Inflammation

Identification of histone 3 variant 2 interacting factors

Latreille D, Bluy L, Benkirane M, Kiernan RE.
2014 - Nucleic Acids Res. , 42,6, 3542-3550 24393775
Service porteur : Gene regulation

DNA damage repair machinery and HIV escape from innate immune sensing

Brégnard C, Benkirane M, Laguette N.
2014 - Front Microbiol , 5:176. eCollection 2014. Review 24795708
Service porteur : Molecular Basis of Inflammation

Premature termination of transcription by RNAP II: The beginning of the end.

Contreras X, Benkirane M, Kiernan R.
2013 - Transcription , 4(2):72-6. 23714697
Service porteur : Gene regulation

Microprocessor, Setx, Xrn2 and Rrp6 Co-Operate to Induce Premature Termination of Transcription by RNAPII

Wagschal, A., Rousset, E., Basavarajaiah, P., Contreras, X. , Harwig, A., Laurent-Chabalier, S. , Nakamura, M., Chen, X., Zhang, K., Meziane, O., Boyer, F., Parrinello, H., Berkhout, B., Terzian, C., Benkirane, M., Kiernan, R.
2012 - CELL , 150, 1147-1157, http://dx.doi.org/10.1016/J.cell.2012.08.004 22980978
Service porteur : Gene regulation

Genome-scale analysis of metazoan replication origins reveals their organization in specific but flexible sites defined by conserved features.

Cayrou C, Coulombe P, Vigneron A, Stanojcic S, Ganier O, Peiffer I, Rivals E, Puy A, Laurent-Chabalier S, Desprat R, Méchali M.
2011 - Genome Res. , 21, 9, 1438-1449 21750104
Service porteur : Replication and Genome Dynamics

Regulation of human SRY subcellular distribution by its acetylation/deacetylation.

Thevenet, L., Mejean, C., Moniot, B., Bonneaud, N., Galeotti, N., Aldrian-Herrada, G., Poulat, F., Berta, P., Benkirane, M., Boizet-Bonhoure, B.
2004 - EMBO J , 23(16):3336-45. 15297880
Service porteur : Development and Pathology of the gonad

LOUIS Tania
LOUIS Tania
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RAHM Nadia
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DOYEN Cécile
DOYEN Cécile
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GAYRAUD Thomas
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YATIM Ahmad
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REY-CADILHAC Felix
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LATREILLE Daniel
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TRIBOULET Robinson
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MEZIANE Oussama
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COUDART Marie-pierre
COUDART Marie-pierre
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EMILIANI Stephane
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INSTITUT COCHIN INSERM U567 CNRS UMR 8104
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HENCKEL Amandine
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LASSOT Irena
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MONTEL Amelie
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WAGSCHAL Alexandre
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KANWAL Shahzina
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ZHANG Ke
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CHABALIER Sabine
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RINGEARD Mathieu
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HUE Pauline
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FORTIER Yasmina
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WURTZ Estelle
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Paving the way toward HIV eradication/control 2010-2015
Acronym: Silent HIV

 

Human Immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, infects primarily cells of the immune system. The outcome of HIV-1 infection results from complex interactions between viral proteins and host cell factors. In most cases, HIV-1 successfully hijacks cellular pathways and bypasses cellular restriction factors for optimal replication leading to continuous rounds of infection, replication and cell death. Continuous viral replication causes the loss of CD4+T cells and progression to immunodeficiency in infected individuals. However, in certain situations virus replication can be successfully controlled. First, HAART (Highly Active AntiRetroviral Therapy) treatment revealed the existence of a pool of resting memory CD4+ T cells harbouring integrated but silent HIV-1 provirus. Although this situation occurs in a small number of cells, it suggests that intracellular defence mechanisms can be effective against HIV. This long-lived viral reservoir is believed to be the major obstacle against HIV-1 eradication by HAART. Second, HIV-infected individuals who are able to control their virus to undetectable levels for many years in absence of any treatment have been identified and referred to as Elite HIV controllers “EC”. Again, this is a rare situation observed in 0.5% of infected patients. Still, it demonstrates that it is possible to naturally and effectively control HIV replication and disease progression. A common feature of these two situations is that virus replication is controlled at the gene expression level. A major challenge in the HIV field is to understand how these naturally occurring situations where intracellular defence and/or immune response win the battle against HIV. Our project aims at identifying the host factors and define the molecular mechanisms involved in the control of virus replication both in HAART-treated and in EC patients.

Major Contribution

Transcription field

He, N., Chan, C.K., Sobhian, B., Chou, S., Xue, Y., Liu, M., Alber, T., Benkirane, M., Zhou, Q., 2011. Human Polymerase-Associated Factor complex (PAFc) connects the Super Elongation Complex (SEC) to RNA polymerase II on chromatin. Proc. Natl. Acad. Sci. U. S. A. 108, E636-645. https://doi.org/10.1073/pnas.1107107108

Latreille, D., Bluy, L., Benkirane, M., Kiernan, R.E., 2014. Identification of histone 3 variant 2 interacting factors. Nucleic Acids Res. 42, 3542–3550. https://doi.org/10.1093/nar/gkt1355

Sobhian, B., Laguette, N., Yatim, A., Nakamura, M., Levy, Y., Kiernan, R., Benkirane, M., 2010. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol. Cell 38, 439–451. https://doi.org/10.1016/j.molcel.2010.04.012

This manuscript, together with the manuscript from Q.Zhou’s Lab and A.Shillatifard’s Lab discovered the Super Elongation Complex (SEC).

Stadelmayer, B., Micas, G., Gamot, A., Martin, P., Malirat, N., Koval, S., Raffel, R., Sobhian, B., Severac, D., Rialle, S., Parrinello, H., Cuvier, O., Benkirane, M., 2014. Integrator complex regulates NELF-mediated RNA polymerase II pause/release and processivity at coding genes. Nat. Commun. 5, 5531. https://doi.org/10.1038/ncomms6531

This manuscript showed for the first time the involvement of Integrator complex in regulating RNPII pausing and termination at coding genes.

Wagschal, A., Rousset, E., Basavarajaiah, P., Contreras, X., Harwig, A., Laurent-Chabalier, S., Nakamura, M., Chen, X., Zhang, K., Meziane, O., Boyer, F., Parrinello, H., Berkhout, B., Terzian, C., Benkirane, M., Kiernan, R., 2012. Microprocessor, Setx, Xrn2, and Rrp6 co-operate to induce premature termination of transcription by RNAPII. Cell 150, 1147–1157. https://doi.org/10.1016/j.cell.2012.08.004

Yatim, A., Benne, C., Sobhian, B., Laurent-Chabalier, S., Deas, O., Judde, J.-G., Lelievre, J.-D., Levy, Y., Benkirane, M., 2012. NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol. Cell 48, 445–458. https://doi.org/10.1016/j.molcel.2012.08.022

Intrinsic immune response field

Bennasser, Y., Chable-Bessia, C., Triboulet, R., Gibbings, D., Gwizdek, C., Dargemont, C., Kremer, E.J., Voinnet, O., Benkirane, M., 2011. Competition for XPO5 binding between Dicer mRNA, pre-miRNA and viral RNA regulates human Dicer levels. Nat. Struct. Mol. Biol. 18, 323–327. https://doi.org/10.1038/nsmb.1987

Brégnard, C., Benkirane, M., Laguette, N., 2014. DNA damage repair machinery and HIV escape from innate immune sensing. Front. Microbiol. 5, 176. https://doi.org/10.3389/fmicb.2014.00176

Brégnard, C., Guerra, J., Déjardin, S., Passalacqua, F., Benkirane, M., Laguette, N., 2016. Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production. EBioMedicine 8, 184–194. https://doi.org/10.1016/j.ebiom.2016.05.005

Clifford, R., Louis, T., Robbe, P., Ackroyd, S., Burns, A., Timbs, A.T., Wright Colopy, G., Dreau, H., Sigaux, F., Judde, J.G., Rotger, M., Telenti, A., Lin, Y.-L., Pasero, P., Maelfait, J., Titsias, M., Cohen, D.R., Henderson, S.J., Ross, M.T., Bentley, D., Hillmen, P., Pettitt, A., Rehwinkel, J., Knight, S.J.L., Taylor, J.C., Crow, Y.J., Benkirane, M., Schuh, A., 2014. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood 123, 1021–1031. https://doi.org/10.1182/blood-2013-04-490847

Laguette, N., Brégnard, C., Hue, P., Basbous, J., Yatim, A., Larroque, M., Kirchhoff, F., Constantinou, A., Sobhian, B., Benkirane, M., 2014. Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing. Cell 156, 134–145. https://doi.org/10.1016/j.cell.2013.12.011

Laguette, N., Rahm, N., Sobhian, B., Chable-Bessia, C., Münch, J., Snoeck, J., Sauter, D., Switzer, W.M., Heneine, W., Kirchhoff, F., Delsuc, F., Telenti, A., Benkirane, M., 2012. Evolutionary and functional analyses of the interaction between the myeloid restriction factor SAMHD1 and the lentiviral Vpx protein. Cell Host Microbe 11, 205–217. https://doi.org/10.1016/j.chom.2012.01.007

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 474, 654–657. https://doi.org/10.1038/nature10117

Lahouassa, H., Daddacha, W., Hofmann, H., Ayinde, D., Logue, E.C., Dragin, L., Bloch, N., Maudet, C., Bertrand, M., Gramberg, T., Pancino, G., Priet, S., Canard, B., Laguette, N., Benkirane, M., Transy, C., Landau, N.R., Kim, B., Margottin-Goguet, F., 2012. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat. Immunol. 13, 223–228. https://doi.org/10.1038/ni.2236

Beyond the seminal discovery of SAMHD1 as the HIV restriction factor, altogether these manuscripts put the bases of the cross talk between DNA repair pathways and innate immune response. Production of proinflammatory cytokine was found to be an intrinsic property of cancer cell.

 

Deciphering the molecular mechanisms of HIV DNA nuclear import and the impact of 3D genome organization
on integration site selection 2019-2024
Acronym: RetroChrom

 

Chromosomes of eukaryotes adopt highly dynamic and complex hierarchical structures in the nucleus. The three-dimensional (3D) organization of chromosomes profoundly affects DNA functions, primarily transcription. During retroviral infection, histone-free viral DNA copy is synthesized from viral genomic RNA. vDNA will ultimately integrate into the host genome to ensure its maintenance and expression.  Understanding retrovirus-host interactions at the genomic level, and the peculiar mechanisms by which lentiviruses, including HIV-1, and their related gene transfer vectors, are imported into the nucleus, loaded with nucleosomes, integrate in, and interact with, the human genome will provide valuable information about lentiviral replication and establish the basis for the development of safer and more efficacious lentiviral vectors for human gene therapy. Our objectives are: 1-To identify and characterize cellular proteins associated with the HIV-1 PIC, and determine their roles in nuclear import and/or integration. 2-To explore the role of the epigenome of unintegrated vDNA in HIV-1 gene expression from unintegrated and integrated vDNA. 3- To determine the impact of nuclear organization on integration site selection and on viral and host transcription. State of the art technologies will be applied to achieve these challenging objectives. If successful, this project will make an outstanding contribution not only to the field of HIV biology but also for the development of safe lentiviral vectors for gene therapy.