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1. Overall Structural Model of NS5A Protein from Hepatitis C Virus and Modulation by Mutations Confering Resistance of Virus Replication to Cyclosporin A

Author

Stéphane Sarrazin, Véronique Receveur-Bréchot, Guy Lippens, Marie-Laure Fogeron, Ralf Bartenschlager, Roland Montserret, Sylvie Ricard-Blum, Volker Lohmann, Aurélie Badillo, Jennifer Molle, François-Xavier Cantrelle, Xavier Hanoulle, François Penin, Anja Böckmann, Frédéric Delolme, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Infectious Diseases [Heidelberg, Germany], Heidelberg University Hospital [Heidelberg], Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS) [A02007-2, A02011-2], French National Agency for Research [ANR-11-JSV8-005], [LABEX ECOFECT ANR-11-LABX-0048], French National Agency for Research (MAPPING Project) [ANR-11-BINF-0003], Deutsche Forschungsgemeinschaft [SFB/TRR83 TP13], CNRS (TGIR RMN THC) [FR-3050], Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)

Subjects
Models, Molecular, 0301 basic medicine, Protein Conformation, [SDV]Life Sciences [q-bio], Hepatitis C virus, Hepacivirus, Microbial Sensitivity Tests, Viral Nonstructural Proteins, Biology, Virus Replication, medicine.disease_cause, Antiviral Agents, Biochemistry, Mass Spectrometry, 03 medical and health sciences, Protein structure, Cyclosporin a, Drug Resistance, Viral, Genotype, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, NS5A, Mutation, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], 3. Good health, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 030104 developmental biology, Viral replication, Phosphoprotein, Cyclosporine
Abstract

International audience; Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a RNA-binding phosphoprotein composed of a N-terminal membrane anchor (AH), a structured domain 1 (D1), and two intrinsically disordered domains (D2 and D3). The knowledge of the functional architecture of this multifunctional protein remains limited. We report here that NS5A-D1D2D3 produced in a wheat germ cell-free system is obtained under a highly phosphorylated state. Its NMR analysis revealed that these phosphorylations do not change the disordered nature of D2 and D3 domains but increase the number of conformers due to partial phosphorylations. By combining NMR and small angle X-ray scattering, we performed a comparative structural characterization of unphosphorylated recombinant D2 domains of JFH1 (genotype 2a) and the Con1 (genotype 1b) strains produced in Escherichia coli. These analyses highlighted a higher intrinsic folding of the latter, revealing the variability of intrinsic conformations in HCV genotypes. We also investigated the effect of D2 mutations conferring resistance of HCV replication to cyclophilin A (CypA) inhibitors on the structure of the recombinant D2 Con1 mutants and their binding to CypA. Although resistance mutations D320E and R318W could induce some local and/or global folding perturbation, which could thus affect the kinetics of conformer interconversions, they do not significantly affect the kinetics of CypA/D2 interaction measured by surface plasmon resonance (SPR). The combination of all our data led us to build a model of the overall structure of NS5A, which provides a useful template for further investigations of the structural and functional features of this enigmatic protein.

Published
2017
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2. Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe

Author

Judd, A, Lodwick, R, Noguera‐Julian, A, Gibb, DM, Butler, K, Costagliola, D, Sabin, C, van Sighem, A, Ledergerber, B, Torti, C, Mocroft, A, Podzamczer, D, Dorrucci, M, De Wit, S, Obel, N, Dabis, F, Cozzi‐Lepri, A, García, F, Brockmeyer, NH, Warszawski, J, Gonzalez‐Tome, MI, Mussini, C, Touloumi, G, Zangerle, R, Ghosn, J, Castagna, A, Fätkenheuer, G, Stephan, C, Meyer, L, Campbell, MA, Chene, G, Phillips, A, Mary Krause, Murielle, Leport, Catherine, Wittkop, Linda, Reiss, Peter, Wit, Ferdinand, Prins, Maria, Bucher, Heiner, Gibb, Diana, Amo, Julia Del, Thorne, Claire, Kirk, Ole, Pérez‐Hoyos, Santiago, Hamouda, Osamah, Bartmeyer, Barbara, Chkhartishvili, Nikoloz, Antinori, Andrea, Monforte, Antonella d'Arminio, Prieto, Luis, Rojo, Pablo, Soriano‐Arandes, Antoni, Battegay, Manuel, Kouyos, Roger, Tookey, Pat, Casabona, Jordi, Miró, Jose M., Konopnick, Deborah, Goetghebuer, Tessa, Sönnerborg, Anders, Teira, Ramon, Garrido, Myriam, Haerry, David, Raben, Dorthe, Chêne, Geneviève, Barger, Diana, Schwimmer, Christine, Termote, Monique, Frederiksen, Casper M., Friis‐Møller, Nina, Kjaer, Jesper, Salbøl Brandt, Rikke, Berenguer, Juan, Bohlius, Julia, Bouteloup, Vincent, Davies, Mary‐Anne, Dunn, David, Egger, Matthias, Furrer, Hansjakob, Guiguet, Marguerite, Grabar, Sophie, Lambotte, Olivier, Leroy, Valériane, Lodi, Sara, Matheron, Sophie, Monge, Susana, Nakagawa, Fumiyo, Paredes, Roger, Puoti, Massimo, Schomaker, Michael, Smit, Colette, Sterne, Jonathan, Thiebaut, Rodolphe, van der Valk, Marc, Wyss, Natasha, The Pursuing Later Treatment Options II (PLATO II) Project Team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord, AII - Infectious diseases, APH - Aging & Later Life, Global Health, AII - Amsterdam institute for Infection and Immunity, Infectious diseases, APH - Global Health, Pursuing Later Treatment Options II (PLATO II) Project Team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord., [Judd,A, Gibb,DM] MRC Clinical Trials Unit, University College London, London, UK. [ Lodwick,R, Sabin,C, Mocroft,A, Cozzi-Lepri,A, Phillips,A] Department of Infection and Population Health, University College London, London, UK. [Noguera-Julian,A] Institut de Recerca Pedi atrica Hospital Sant Joan de Deu, Barcelona, Spain. Departament de Pediatria, Universitat de Barcelona, Barcelona, Spain. CIBER de Epidemiologıa y Salud Publica Ciberesp, Barcelona, Spain. [Butler,K] Department of Infectious Diseases and Immunology, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland. [Costagliola,D] INSERM, UPMC Univ Paris 06, Institut Pierre Louis d’epidemiologie et de Sante Publique (IPLESP UMRS 1136), Sorbonne Universites, Paris, France. [van Sighem,A] Stichting HIV Monitoring, Amsterdam, The Netherlands. [Ledergerber,B] Division of Infectious Diseases and Hospital Epidemiology, University of Zurich, Zurich, Switzerland. [Torti,C] Unit of Infectious and Tropical Diseases, Department of Medical and Surgical Sciences, University 'Magna Graecia', Catanzaro, Italy. [Podzamczer,D[ HUV and STD Unit, Infectious Diseases Service, Hospital Universitari de Bellvitge. L’Hospitalet, Barcelona, Spain. [Dorrucci,M] Istituto Superiore di Sanit a, Rome, Italy. [De Wit,S] Departement of Infectious Diseases, Centre Hospitalier Saint-Pierre, Universite Libre de Bruxelles, Brussels, Belgium. [Obel,N] Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. [Dabis,F, Chene,D] NSERM U1219 – Centre Inserm Bordeaux Population Health, Universite de Bordeaux, Bordeaux, France. ISPED, Centre INSERM U1219-Bordeaux Population Health, Universite de Bordeaux, Bordeaux, France. [Garcia,F] Clinical Microbiology Department, Complejo Hospitalario Universitario Granada, Instituto de Investigacion Biosanitaria ibs.Granada, Granada, Spain. [Brockmeyer,NH] Department of Dermatology, Venerology and Allergology, Center for Sexual Health and Medicine, St. Josef Hospital, Ruhr-Universität Bochum, Bochum, Germany. [Warszawski,J] INSERM CESP U1018, AP-HP Public Health Department, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre Paris, France. [Gonzalez-Tome,MI] HIV and Paeds Infectious Diseases Department, Hospital 12 de Octubre, Madrid, Spain. [Mussini,C] Infectious Diseases Clinics, University Hospital, Modena, Italy. [Touloumi,G] Department Hygiene, Epidemiology & Medical Statistics, Medical School, National & Kapodistrian University of Athens, Athens, Greece. [Zangerle,R] Medical University Innsbruck, Innsbruck, Austria. [Ghosn,J] EA 7327, Faculté de Médecine site Necker, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. APHP, Unité Fonctionnelle de Thérapeutique en Immuno-Infectiologie, Hôpitaux Universitaires Paris Centre site Hôtel Dieu, Paris, France. [Castagna,A] San Raffaele Scientific Institute, Vita-SaLute University, Milan, Italy. [Fätkenheuer,G] Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany. [Stephan,C] Second Medical Department, Infectious Diseases Unit, Goethe-University Hospital, Frankfurt, Germany. [Meyer,L] NSERM CESP U1018, Université Paris-Sud, Université Paris-Saclay, Paris, France. AP-HP Public Health Department, Le Kremlin-Bicêtre, Paris, France. [Campbell,MA] Centre for Health and Infectious Disease Research, University of Copenhagen, Copenhagen, Denmark. [Chene,G]. CHU de Bordeaux, Pole de sante publique, Service d'information medicale, Bordeaux, France., Financial disclosure: The PLATO II project is funded by the UK Medical Research Council (award G0700832). The COHERE study group has received unrestricted funding from: Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS), France, the HIV Monitoring Foundation, The Netherlands, and the Augustinus Foundation, Denmark. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under EuroCoord grant agreement no 260694. The group has also received project-specific funding from the UK Medical Research Council and the Swiss Bridge Foundation., Judd, A, Lodwick, R, Noguera-Julian, A, Gibb, D, Butler, K, Costagliola, D, Sabin, C, van Sighem, A, Ledergerber, B, Torti, C, Mocroft, A, Podzamczer, D, Dorrucci, M, De Wit, S, Obel, N, Dabis, F, Cozzi-Lepri, A, García, F, Brockmeyer, N, Warszawski, J, Gonzalez-Tome, M, Mussini, C, Touloumi, G, Zangerle, R, Ghosn, J, Castagna, A, Fätkenheuer, G, Stephan, C, Meyer, L, Campbell, M, Chene, G, Phillips, A, Puoti, M, Goethe-Universität Frankfurt am Main, Sexualité et soins (Genre, Sexualité, Santé) (CESP - INSERM U1018 - Equipe 7), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, University of Copenhagen = Københavns Universitet (UCPH), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, University College of London [London] (UCL), Universitat Autònoma de Barcelona (UAB), Hospital Sant Joan de Déu [Barcelona], CIBER de Epidemiología y Salud Pública (CIBERESP), Our Lady's Children's Hospital Crumlin (OLCHC), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Stichting HIV Monitoring [Amsterdam], Universiteit van Amsterdam (UvA), University hospital of Zurich [Zurich], Università degli Studi 'Magna Graecia' di Catanzaro = University of Catanzaro (UMG), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Istituto Superiore di Sanita [Rome], Université libre de Bruxelles (ULB), Copenhagen University Hospital, Universidad de Granada = University of Granada (UGR), Ruhr-Universität Bochum [Bochum], Hospital Universitario 12 de Octubre [Madrid], Azienda Ospedaleria Universitaria di Modena, National and Kapodistrian University of Athens (NKUA), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Infection à VIH, réservoirs, diversité génétique et résistance aux antirétroviraux (ARV) (EA 7327), Université Paris Descartes - Paris 5 (UPD5), Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University Hospital of Cologne [Cologne], HAL-SU, Gestionnaire, and The Pursuing Later Treatment Options II (PLATO II) Project Team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in, Eurocoord

Subjects
Male, HIV Infections, Pharmacologie, Santé publique, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Sexual Behavior::Sexuality::Heterosexuality [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Pharmacology (medical), Inhibidores de proteasas, Young adult, Europe, perinatal HIV infection, virological failure, young people, Adolescent, Adult, Anti-Retroviral Agents, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Time Factors, Treatment Failure, Young Adult, Drug Resistance, Viral, Population Groups, Pathologie maladies infectieuses, ComputingMilieux_MISCELLANEOUS, Adolescente, ADN polimerasa dirigida por ADN, Original Research, Health Policy, Enfermedades transmisibles, 3. Good health, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents::Anti-Retroviral Agents::Anti-HIV Agents [Medical Subject Headings], G0700832, Young people, Viral load, Human, Factores de riesgo, medicine.medical_specialty, 030106 microbiology, HIV Infections/drug therapy, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents::Anti-Retroviral Agents::Reverse Transcriptase Inhibitors [Medical Subject Headings], 03 medical and health sciences, Virological failure, Recién nacido, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA [Medical Subject Headings], Heterosexualidad, Persons::Persons::Age Groups::Adult [Medical Subject Headings], Diseases::Bacterial Infections and Mycoses::Infection::Communicable Diseases [Medical Subject Headings], Perinatal HIV infection, RCUK, medicine.disease, Infecciones por VIH, Persons::Persons::Age Groups::Infant::Infant, Newborn [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Microbiological Techniques::Viral Load [Medical Subject Headings], Observational study, Geographical Locations::Geographic Locations::Europe [Medical Subject Headings], 0301 basic medicine, Pediatrics, Science et gestion hospitalières, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Nucleotidyltransferases::DNA Nucleotidyltransferases::DNA-Directed DNA Polymerase [Medical Subject Headings], Diseases::Virus Diseases::RNA Virus Infections::Retroviridae Infections::Lentivirus Infections::HIV Infections [Medical Subject Headings], Anti-Retroviral Agents/therapeutic use, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Confidence Intervals [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings], Interquartile range, Epidemiology, HIV Infection, 030212 general & internal medicine, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Adulto, MRC, Infectious Diseases, Niño, Europa, VIH-1, Population Group, Time Factor, Persons::Persons::Age Groups::Adolescent [Medical Subject Headings], Acquired immunodeficiency syndrome (AIDS), medicine, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protease Inhibitors [Medical Subject Headings], Diseases::Immune System Diseases::Immunologic Deficiency Syndromes::HIV Infections::Acquired Immunodeficiency Syndrome [Medical Subject Headings], Persons::Persons::Age Groups::Child [Medical Subject Headings], ddc:610, Intervalos de confianza, Organisms::Viruses::RNA Viruses::Retroviridae::Lentivirus::Lentiviruses, Primate::HIV::HIV-1 [Medical Subject Headings], business.industry, Inhibidores de la transcriptasa inversa, Confidence interval, Carga viral, Fármacos anti-VIH, Anti-Retroviral Agent, Cohort Studie, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Objectives: The aim of the study was to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection. Methods: We analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged < 20 years at the start of ART for those with perinatal infection and 15–29 years for those with heterosexual infection, with ART containing at least two nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (bPI), were followed from ART initiation until the most recent viral load (VL) measurement. Virological failure of a drug was defined as VL > 500 HIV-1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI. Results: The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4–111) vs. 8 (IQR 2–38) weeks, respectively], and highest in perinatally infected participants aged 10–14 years [49 (IQR 9–267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0−12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9−5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10–14 years when starting ART (27.7%; 95% CI 13.2−42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10–14 years, African origin, pre-ART AIDS, NNRTI-based initial regimens, higher pre-ART viral load and lower pre-ART CD4. Conclusions: The results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development., 0, SCOPUS: ar.j, FLWOA, info:eu-repo/semantics/published

Published
2017
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3. Hepatitis B Virus Evasion From Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase Sensing in Human Hepatocytes

Author

Julie Lucifora, Charlotte Bach, David Durantel, Eloi R. Verrier, Ivan Hirsch, Mirjam B. Zeisel, Seung-Ae Yim, Nicolas Manel, Nathalie Pochet, Laurent Mailly, Sarah C. Durand, Thomas F. Baumert, Patrick Pessaux, Houssein El Saghire, Laura Heydmann, Vincent Turon-Lagot, Catherine Schuster, Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle hépato-digestif [Strasbourg], Nouvel Hôpital Civil, Hospices Civils de Strasbourg-Institut Hospitalo-Universitaire de strasbourg, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de recherche Paris, sciences et lettres [Institut Curie, Paris], Institut Curie [Paris], Department of Genetics and Microbiology [Prague, Czech Republic] (Faculty of Science), Charles University [Prague] (CU), Department of Neurology [Cambridge, MA, USA] (Ann Romney Center for Neurologic Diseases), Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], Cell Circuits Program [Cambridge, MA, USA], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the European Union (ERC-AdG-2014-671231- HEPCIR, EU H2020-667273-HEPCAR, EU-InfectEra HepBccc), the National Institute of Health (NIAID 1R03AI131066-01A1, NCI R21 CA209940 and NIAID U19AI123862), the Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS, 2015/1099), the Fondation ARC pour la Recherche sur le Cancer (TheraHCC IHUARC IHU201301187), GACR 17-15422S, and a PhD fellowship of the Région Alsace, France. The work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and benefits from funding from the state managed by the French National Research Agency as part of the Investments for the future program. E.R.V. was supported by an ANRS fellowship (ECTZ50121)., ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), Baumert, Thomas F., Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Blotting, Western, Cell Culture Techniques, Guanosine, Biology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Hepatocytes/metabolism/*virology, medicine.disease_cause, liver, Real-Time Polymerase Chain Reaction, Virus, Hepatitis B/immunology/*physiopathology, 03 medical and health sciences, chemistry.chemical_compound, Mice, Cyclic guanosine monophosphate–adenosine monophosphate, medicine, capsid, DNA, Viral/immunology, Hepatitis B virus/*pathogenicity, Humans, innate immunity, Hepatitis B virus, Innate immune system, Hepatology, Effector, In Situ Hybridization, Fluorescence/methods, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virology, antiviral, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Nucleotides, Cyclic/*metabolism, 030104 developmental biology, Real-time polymerase chain reaction, chemistry, Cell culture, Host-Pathogen Interactions, Immune Evasion/immunology/*physiology, recognition, Gene Expression Profiling/methods
Abstract

International audience; Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver disease and cancer worldwide. The mechanisms of viral genome sensing and the evasion of innate immune responses by HBV infection are still poorly understood. Recently, the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) was identified as a DNA sensor. In this study, we investigated the functional role of cGAS in sensing HBV infection and elucidate the mechanisms of viral evasion. We performed functional studies including loss-of-function and gain-of-function experiments combined with cGAS effector gene expression profiling in an infectious cell culture model, primary human hepatocytes, and HBV-infected human liver chimeric mice. Here, we show that cGAS is expressed in the human liver, primary human hepatocytes, and human liver chimeric mice. While naked relaxed-circular HBV DNA is sensed in a cGAS-dependent manner in hepatoma cell lines and primary human hepatocytes, host cell recognition of viral nucleic acids is abolished during HBV infection, suggesting escape from sensing, likely during packaging of the genome into the viral capsid. While the hepatocyte cGAS pathway is functionally active, as shown by reduction of viral covalently closed circular DNA levels in gain-of-function studies, HBV infection suppressed cGAS expression and function in cell culture models and humanized mice. Conclusion: HBV exploits multiple strategies to evade sensing and antiviral activity of cGAS and its effector pathways.

Published
2018
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4. TET-Catalyzed 5-Hydroxymethylation Precedes HNF4A Promoter Choice during Differentiation of Bipotent Liver Progenitors

Author

Marie-Pierre Cros, Anne Corlu, Szilvia Ecsedi, Fazlur Rahman Talukdar, Marie-Pierre Lambert, Hector Hernandez-Vargas, Veronique Chauvet, Denise Glaise, Zdenko Herceg, Diana Marcela Devia Narvaez, Pierre-Benoit Ancey, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ligue National (Francaise) Contre le Cancer, IARC Postdoctoral Fellowship and Marie Curie Actions-People-COFUND, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS) [AO 2012-2 CSS4, 12328], La Ligue Contre Le Cancer Comite d'Ille et Vilaine et des Cotes d'Armor, IARC's Junior Investigator Award, Ancey, Pierre-Benoit, and Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, endocrine system, liver progenitor, Biology, Biochemistry, Article, Cell Line, Epigenesis, Genetic, Mixed Function Oxygenases, 03 medical and health sciences, Proto-Oncogene Proteins, Genetics, medicine, Humans, Epigenetics, Progenitor cell, Promoter Regions, Genetic, lcsh:QH301-705.5, Transcription factor, Hepatocyte differentiation, lcsh:R5-920, pluripotent stem-cells, nuclear factor 4-alpha, hepatocyte-like cells, hepatocellular-carcinoma, inflammatory cytokines, dna methylation, expression, transdifferentiation, retrodifferentiation, factor-4-alpha, DNA methylation, Stem Cells, Pioneer factor, 5mC, Gene Expression Regulation, Developmental, Cell Differentiation, Cell Biology, Molecular biology, HNF4A, Cell biology, 030104 developmental biology, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Hepatocyte Nuclear Factor 4, lcsh:Biology (General), Hepatocyte, 5-Methylcytosine, Hepatocytes, 5hmC, FOXA2, lcsh:Medicine (General), Developmental Biology
Abstract

Summary Understanding the processes that govern liver progenitor cell differentiation has important implications for the design of strategies targeting chronic liver diseases, whereby regeneration of liver tissue is critical. Although DNA methylation (5mC) and hydroxymethylation (5hmC) are highly dynamic during early embryonic development, less is known about their roles at later stages of differentiation. Using an in vitro model of hepatocyte differentiation, we show here that 5hmC precedes the expression of promoter 1 (P1)-dependent isoforms of HNF4A, a master transcription factor of hepatocyte identity. 5hmC and HNF4A expression from P1 are dependent on ten-eleven translocation (TET) dioxygenases. In turn, the liver pioneer factor FOXA2 is necessary for TET1 binding to the P1 locus. Both FOXA2 and TETs are required for the 5hmC-related switch in HNF4A expression. The epigenetic event identified here may be a key step for the establishment of the hepatocyte program by HNF4A., Graphical Abstract, Highlights • 5hmC marks HNF4A P1 promoter previous to terminal hepatocyte differentiation • TET1-dependent 5hmC is required to activate P1-driven HNF4A expression • Pioneer factor FOXA2 is necessary for TET1 binding to P1 locus • HNF4A promoter switch is reversible upon hepatocyte dedifferentiation, Hepatocyte identity is impaired in various human chronic liver diseases. Methylation and hydroxymethylation dynamically mark the DNA during development. As shown by Hernandez-Vargas and colleagues, discrete changes in these marks also play a role in establishing hepatocyte identity. Specifically, hydroxymethylation of the hepatocyte promoter HNF4A signals a key switch in expression. Because of its reversibility, this switch is susceptible to experimental manipulation.

Published
2017
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5. Progression of fibrosis in patients with chronic viral hepatitis is associated with IL-17 + neutrophils

Author

Bertrand Huard, Samia Afzal, Zuzana Macek Jilkova, Patrice N. Marche, Thomas Decaens, Nathalie Sturm, Evelyne Jouvin-Marche, Hélène Marche, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), National Center of Excellence in Molecular Biology [ Lahore, Pakistan], University of the Punjab, Département de Gastroentérologie et hépatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Anatomie et de Cytologie Pathologiques [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), This work was supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM) and the Agence Nationale de Recherches sur le Sida et les hepatites virales (ANRS). Part of the works was supported by the Ligue contre le Cancer (CD38 & CD73). ZMJ received financial support from Foundation Finovi and ANRS. SA was supported by a fellowship from the Higher Education Commission of Pakistan and French Embassy in Pakistan., MARCHE, Patrice, and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Liver Cirrhosis, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Hepatitis, Viral, Human, [SDV.IMM] Life Sciences [q-bio]/Immunology, Biopsy, medicine.medical_treatment, Fluorescent Antibody Technique, Immunofluorescence, liver, Flow cytometry, 03 medical and health sciences, neutrophils, Fibrosis, medicine, Humans, Aged, Hepatology, medicine.diagnostic_test, business.industry, Macrophages, Interleukin-17, fibrosis, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Middle Aged, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, IL-17, 030104 developmental biology, Cytokine, Disease Progression, Th17 Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, France, Interleukin 17, Hepatic fibrosis, Viral hepatitis, business
Abstract

International audience; BACKGROUND & AIMS:The pro-inflammatory cytokine IL-17 plays a crucial role in liver diseases associated with hepatic fibrosis and increased risk of cancer development. Nevertheless, the cellular source of this cytokine has never been characterized in patients with liver fibrosis.METHODS:In this study, we investigated liver biopsies from 49 patients with chronic viral hepatitis at different stages of liver fibrosis. We monitored IL-17 production by intracellular flow cytometry, immunofluorescence and immunohistochemical in situ stainings, allowing a precise quantification, characterization and localization of IL-17(+) cells.RESULTS:Density of IL-17(+) cells increased with the stage of liver fibrosis specifically in fibrotic septa and portal areas (correlation coefficient r = 0.7373; P < 0.0001). Data clearly show that the frequency of intrahepatic IL-17(+) lymphocytes (including T, NKT and NK cells) was independent on stage of liver fibrosis, and we observed no statistical differences in number of IL-17(+) macrophages during progression of fibrosis. On the other hand, the number of IL-17(+) neutrophils in fibrotic septa and portal areas strongly correlated with the stages of fibrosis (correlation coefficient r = 0.6986; P < 0.0001), contributing significantly to total IL-17 production in liver tissue.CONCLUSIONS:Our data indicate that neutrophils represent an important source of IL-17 in the human liver, especially in late fibrosis stages. Inhibition of this specific harmful subset of neutrophils may offer therapeutic opportunities in fibrotic liver.© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Published
2016
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6. Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

Author

Olivier Lambotte, Gianfranco Pancino, Javier Martinez-Picado, Camille Lécuroux, Ruth Peña, Annie David, Julia G. Prado, Carine Van Lint, Alain Venet, Itziar Erkizia, Véronique Avettand-Fenoel, Nicolas Noel, Esther Jimenez, Faroudy Boufassa, Asier Sáez-Cirión, Christine Rouzioux, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), IrsiCaixa (Institut de Recerca de la Sida), HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP), Laboratoire de Virologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), U1018, Institut National de la Santé et de la Recherche Médicale (INSERM), Régulation des Infections Rétrovirales, Service de Virologie Moléculaire, IBMM, Université Libre de Bruxelles, Université libre de Bruxelles (ULB), Institució Catalana de Recerca i Estudis Avançats (ICREA), Universitat de Vic, This work was funded by Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS) (2011409). This work, including the efforts of Nicolas Noel, was funded by Foundation pour la Recherche Medicale (PhD grant). This work, including the efforts of Julia G. Prado, was funded by ISCIII (Miguel Servet II [CIIP15/00014], PI11/00249, and PI14/01058). This work, including the efforts of Carine Van Lint, was funded by Belgian Fund for Scientific Research (FRS-FNRS).This work, including the efforts of Esther Jimenez, was funded by Redes Temáticas de Investigación en SIDA, Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008-2011, and Instituto de Salud Carlos III, Fondos FEDER (ISCIII RETIC RD12/0017/0002), ANRS CO21 Cohort, Saez-Cirion, Asier, HIV, Inflammation et persistance, Institut Pasteur [Paris], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris-Sud - Paris 11 (UP11) - Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale, and Université Libre de Bruxelles [Bruxelles] (ULB)

Subjects
0301 basic medicine, Adult, CD4-Positive T-Lymphocytes, Male, Anti-HIV Agents, Immunology, Human immunodeficiency virus (HIV), HIV Infections, Biology, CD8-Positive T-Lymphocytes, medicine.disease_cause, Virus Replication, Microbiology, Virus, 03 medical and health sciences, Virology, Virus latency, medicine, Humans, Aged, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Viral reactivation, Virus Activation, Middle Aged, medicine.disease, 3. Good health, Virus-Cell Interactions, Virus Latency, 030104 developmental biology, Viral replication, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Insect Science, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV-1, RNA, Viral, Female, CD8, Ex vivo
Abstract

HIV establishes reservoirs of infected cells that persist despite effective antiretroviral therapy (ART). In most patients, the virus begins to replicate soon after treatment interruption. However, a low frequency of infected cells at the time of treatment interruption has been associated with delayed viral rebound. Likewise, individuals who control the infection spontaneously, so-called HIV-1 controllers (HICs), carry particularly low levels of infected cells. It is unclear, however, whether and how this small number of infected cells contributes to durable viral control. Here we compared 38 HICs with 12 patients on effective combined antiretroviral therapy (cART) and found that the low frequency of infected cells in the former subjects was associated both with less efficient viral reactivation in resting CD4 + T cells and with less efficient virion production ex vivo . We also found that a potent HIV-specific CD8 + T cell response was present only in those HICs whose CD4 + T cells produced virus ex vivo . Long-term spontaneous control of HIV infection in HICs thus appears to be sustained on the basis of the inefficient reactivation of viruses from a limited number of infected cells and the capacity of HICs to activate a potent HIV-specific CD8 + T cell response to counteract efficient viral reactivation events. IMPORTANCE There is a strong scientific interest in developing strategies to eradicate the HIV-1 reservoir. Very rare HIV-1-infected patients are able to spontaneously control viremia for long periods of time (HIV-1 controllers [HICs]) and are put forward as a model of HIV-1 remission. Here, we show that the low viral reservoirs found in HICs are a critical part of the mechanisms underlying viral control and result in a lower probability of HIV-1 reactivation events, resulting in limited HIV-1 release and spread. We found that those HICs in whom viral reactivation and spread from CD4 + T cells in vitro were the most difficult were those with diminished CD8 + T cell responses. These results suggest that, in some settings, low HIV-1 reservoirs decisively contribute to at least the temporary control of infection without antiretroviral therapy. We believe that this work provides information of relevance in the context of the search for HIV-1 remission.

Published
2016
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7. SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV

Author

Francesca Di Nunzio, Olivier Schwartz, Françoise Porrot, Felipe Diaz-Griffero, Sonia Amraoui, Silvana Opp, Daniel A. Donahue, Camille Kieffer, Nicoletta Casartelli, Virus et Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Virologie moléculaire et vaccinologie, Albert Einstein College of Medicine [New York], Institut de Recherche sur le Vaccin (VRI), PRES Université Paris-Est-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), EU FP7-Health Health-F3-2012-305762 to .Vaccine Research Institute to .Labex IBEID to .Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS) http://dx.doi.org/10.13039/501100003323 to .Sidaction http://dx.doi.org/10.13039/100009060 to .Areva (AREVA NP Company) http://dx.doi.org/10.13039/100006412 to ., European Project: 305762,HEALTH,FP7-HEALTH-2012-INNOVATION-1,HIT HIDDEN HIV(2012), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, MESH: Membrane Proteins/physiology, [SDV]Life Sciences [q-bio], HIV Infections, Cypa, Virus Replication, Interferon, Murine leukemia virus, MESH: Intracellular Signaling Peptides and Proteins/physiology, MESH: Intracellular Signaling Peptides and Proteins/biosynthesis, Intracellular Signaling Peptides and Proteins, MESH: HIV Infections/virology, virus diseases, Virus-Cell Interactions, 3. Good health, medicine.anatomical_structure, MESH: Interferons/metabolism, MESH: HEK293 Cells, Nuclear lamina, MESH: HIV-1/physiology, MESH: HIV-2/physiology, medicine.drug, MESH: Membrane Proteins/biosynthesis, Immunology, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Biology, MESH: Cell Nucleus/pathology, Microbiology, Virus, 03 medical and health sciences, Species Specificity, Virology, medicine, Humans, Inner membrane, MESH: Species Specificity, Nuclear membrane, Cell Nucleus, MESH: Humans, MESH: Virus Replication, Membrane Proteins, biology.organism_classification, HEK293 Cells, 030104 developmental biology, Viral replication, Insect Science, HIV-2, MESH: HeLa Cells, HIV-1, Interferons, HeLa Cells
Abstract

In a previous screen of putative interferon-stimulated genes, SUN2 was shown to inhibit HIV-1 infection in an uncharacterized manner. SUN2 is an inner nuclear membrane protein belonging to the linker of nucleoskeleton and cytoskeleton complex. We have analyzed here the role of SUN2 in HIV infection. We report that in contrast to what was initially thought, SUN2 is not induced by type I interferon, and that SUN2 silencing does not modulate HIV infection. However, SUN2 overexpression in cell lines and in primary monocyte-derived dendritic cells inhibits the replication of HIV but not murine leukemia virus or chikungunya virus. We identified HIV-1 and HIV-2 strains that are unaffected by SUN2, suggesting that the effect is specific to particular viral components or cofactors. Intriguingly, SUN2 overexpression induces a multilobular flower-like nuclear shape that does not impact cell viability and is similar to that of cells isolated from patients with HTLV-I-associated adult T-cell leukemia or with progeria. Nuclear shape changes and HIV inhibition both mapped to the nucleoplasmic domain of SUN2 that interacts with the nuclear lamina. This block to HIV replication occurs between reverse transcription and nuclear entry, and passaging experiments selected for a single-amino-acid change in capsid (CA) that leads to resistance to overexpressed SUN2. Furthermore, using chemical inhibition or silencing of cyclophilin A (CypA), as well as CA mutant viruses, we implicated CypA in the SUN2-imposed block to HIV infection. Our results demonstrate that SUN2 overexpression perturbs both nuclear shape and early events of HIV infection. IMPORTANCE Cells encode proteins that interfere with viral replication, a number of which have been identified in overexpression screens. SUN2 is a nuclear membrane protein that was shown to inhibit HIV infection in such a screen, but how it blocked HIV infection was not known. We show that SUN2 overexpression blocks the infection of certain strains of HIV before nuclear entry. Mutation of the viral capsid protein yielded SUN2-resistant HIV. Additionally, the inhibition of HIV infection by SUN2 involves cyclophilin A, a protein that binds the HIV capsid and directs subsequent steps of infection. We also found that SUN2 overexpression substantially changes the shape of the cell's nucleus, resulting in many flower-like nuclei. Both HIV inhibition and deformation of nuclear shape required the domain of SUN2 that interacts with the nuclear lamina. Our results demonstrate that SUN2 interferes with HIV infection and highlight novel links between nuclear shape and viral infection.

Published
2016
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8. CTIP2 is a negative regulator of P-TEFb

Author

Siavash K. Kurdistani, Thomas Cherrier, Jean-Christophe Paillart, Pedro Bausero, Yannick Goumon, Benoît Van Driessche, Xavier Graña, Wasim Abbas, Carine Van Lint, Olivier Rohr, Mathias Mericskay, Ermanno Candolfi, Arndt Benecke, Georges Herbein, Raphael Riclet, Ara Parlakian, Céline Marban, Christian Schwartz, Valentin Le Douce, Sebastian Eilebrecht, Franck Dequiedt, Institut de Parasitologie et de Pathologie Tropicale (IPPTS), Université de Strasbourg (UNISTRA), Université de Liège, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of California (UC), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Vieillissement, stress, inflammation, Université Pierre et Marie Curie - Paris 6 (UPMC), Ingénierie et biologie cellulaire et tissulaire (IBCT (ex IFR133)), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), University of California [Los Angeles] (UCLA), Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Institut de Biologie et de Médecine Moléculaires [Gosselies] (ULB/IBMM), Faculté des Sciences [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB), Institut des Hautes Etudes Scientifiques (IHES), IHES, Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS), Centre National de la Recherche Scientifique (CNRS, France), Belgian Fund for Scientific Reseach (FRS-FNRS, Belgium), Televie Program of the FRS-FNRS, Walloon Region (Excellence Program `Cibles'), Walloon Region [WALEO 021/5110], European AIDS treatment network (NEAT) integration grant, Internationale Brachet Stiftung, Fondation Roi Baudouin, University of Franche-Comte, National Institute of Mental Health [R21 MH083585], Pennsylvania Department of Health, Agence Nationale de Recherches sur le SIDA et les hepatites virale (ANRS, France), Sidaction, Expression des Gènes et comportement adaptatifs = Molecular Genetics, Neurophysiology and Behavior (NPS-15), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), and Institut des Hautes Études Scientifiques (IHES)

Subjects
Positive Transcriptional Elongation Factor B, Repressor, Cardiomegaly, Biology, Protein Structure, Secondary, 03 medical and health sciences, Mice, 0302 clinical medicine, 7SK RNA, RNA, Small Nuclear, Animals, Humans, Kinase activity, P-TEFb, Promoter Regions, Genetic, Transcription factor, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Myosin Heavy Chains, Tumor Suppressor Proteins, RNA-Binding Proteins, Promoter, Biological Sciences, Molecular biology, Cyclin-Dependent Kinase 9, Repressor Proteins, HEK293 Cells, 030220 oncology & carcinogenesis, Cyclin-dependent kinase 9, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cardiac Myosins, Transcription Factors
Abstract

International audience; The positive transcription elongation factor b (P-TEFb) is involved in physiological and pathological events including inflammation, cancer, AIDS, and cardiac hypertrophy. The balance between its active and inactive form is tightly controlled to ensure cellular integrity. We report that the transcriptional repressor CTIP2 is a major modulator of P-TEFb activity. CTIP2 copurifies and interacts with an inactive P-TEFb complex containing the 7SK snRNA and HEXIM1. CTIP2 associates directly with HEXIM1 and, via the loop 2 of the 7SK snRNA, with P-TEFb. In this nucleoprotein complex, CTIP2 significantly represses the Cdk9 kinase activity of P-TEFb. Accordingly, we show that CTIP2 inhibits large sets of P-TEFb- and 7SK snRNA-sensitive genes. In hearts of hypertrophic cardiomyopathic mice, CTIP2 controls P-TEFb-sensitive pathways involved in the establishment of this pathology. Overexpression of the beta-myosin heavy chain protein contributes to the pathological cardiac wall thickening. The inactive P-TEFb complex associates with CTIP2 at the MYH7 gene promoter to repress its activity. Taken together, our results strongly suggest that CTIP2 controls P-TEFb function in physiological and pathological conditions.

Published
2013
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9. Selective transmigration of monocyte-associated HIV-1 across a human cervical monolayer and its modulation by seminal plasma

Author

Sabine Palle, Philip Lawrence, Bruno Pozzetto, Thomas Olivier, Jacques Fantini, Rachel Terrasse, Didier Portran, Olivier Delézay, Thomas Bourlet, Groupe Immunité des Muqueuses et Agents Pathogènes (GIMAP), Université Jean Monnet - Saint-Étienne (UJM), Centre de Microscopie Confocale Multiphotonique (CMCM), Laboratoire Hubert Curien (LHC), Institut d'Optique Graduate School (IOGS)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Jean Monnet [Saint-Étienne] (UJM), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut National de la Recherche Agronomique (INRA), French Agence Nationale de Recherches sur le SIDA et les hepatites virales (ANRS), Infectiology cluster of Lyon Biopole, Laboratoire Hubert Curien [Saint Etienne] (LHC), and Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS)-Institut d'Optique Graduate School (IOGS)

Subjects
Male, lymphocytes, CD4(+) T-CELLS, GENITAL EPITHELIAL-CELLS, PRIMARY INFECTION, [SDV]Life Sciences [q-bio], Cell, HIV Infections, heterosexual infection, Cervix Uteri, Cell Movement, Leukocytes, Tumor Cells, Cultured, VAGINAL TRANSMISSION, Immunology and Allergy, tropism selection, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Coitus, Phenotype, 3. Good health, Infectious Diseases, medicine.anatomical_structure, HUMAN-IMMUNODEFICIENCY-VIRUS, CORECEPTOR, Female, monocytes, Immunology, Semen, Biology, CELL-ASSOCIATED HIV-1, Andrology, 03 medical and health sciences, Immune system, Carcinoma, medicine, Humans, SEMEN, transmigration, TYPE-1, Tropism, 030304 developmental biology, 030306 microbiology, Monocyte, SEXUAL TRANSMISSION, Transendothelial and Transepithelial Migration, Epithelial Cells, medicine.disease, Endometrial Neoplasms, Microscopy, Fluorescence, Cell culture, HIV-1, seminal plasma
Abstract

Objective: To analyse the transmigration of immune cells infected by HIV-1 across the epithelial monolayer using the endometrial human endometrial carcinoma (HEC)-1A cell line and to study the influence of seminal plasma in this process. Design: After sexual intercourse involving a male partner infected by HIV-1, a selection process has been shown to lead to a predominant transmission of the R5 phenotype despite the presence of X4 and R5 strains in semen. Transmigration of HIV-infected monocytes present in semen may represent a pertinent mechanism that could explain this tropism selection. Methods: Epithelial monolayer crossing was studied by using HEC-1A epithelial cells cultured on permeable support and monocyte-enriched or lymphocyte-enriched populations of cells infected or not by HIV R5 or X4 strains. Transmigrating cells were quantified and analysed for their ability to transmit HIV infection to immune target cells. The effect of HIV-negative seminal plasma on cell transmigration was analysed. Results: A preferential passage of the R5 strain associated with monocyte-enriched populations was observed together with the ability of this strain to transmit infection. Seminal plasma was found able to decrease the epithelial crossing of immune cells by enhancing transepithelial resistance and by increasing the adherence of immune cells to the monolayer. Conclusion: The preferential transmigration of HIV R5 strains associated with monocytes across the endocervical monolayer may explain the predominant transmission of the R5 strains after sexual intercourse. By its capacity to modulate the tightness of the epithelial structure, seminal plasma reinforces this selection process. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Published
2012
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10. Dynamics of innate immunity are key to chronic immune activation in AIDS

Author

Michael G. Katze, Michael Gale, Arndt Benecke, Expression des Gènes et comportement adaptatifs = Molecular Genetics, Neurophysiology and Behavior (NPS-15), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agence Nationale de Recherches sur le SIDA et les hepatites virales (ANRS), NIH [RR00166, RR016354, DA015625], Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Systems biology, animal diseases, Immunology, Simian Acquired Immunodeficiency Syndrome, Biology, medicine.disease_cause, acquired immune deficiency syndrome, Article, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Acquired immunodeficiency syndrome (AIDS), Virology, medicine, natural host, Animals, Humans, 030304 developmental biology, 0303 health sciences, Acquired Immunodeficiency Syndrome, Innate immune system, human immunodeficiency virus, Oncology (nursing), HIV, systems biology, Hematology, Simian immunodeficiency virus, biochemical phenomena, metabolism, and nutrition, medicine.disease, Macaca mulatta, Immunity, Innate, 3. Good health, Vaccination, African green monkey, Infectious Diseases, innate and adaptive immunity, Oncology, Chronic Disease, bacteria, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Simian Immunodeficiency Virus, 030215 immunology, Immune activation, rhesus macaque
Abstract

International audience; Purpose of review We propose here that the dynamics rather than the structure of cellular and viral networks play a determining role in chronic immune activation of HIV-infected individuals. A number of novel avenues of experimental analysis and modeling strategies are discussed to conclusively address these network dynamics in the future. Recent findings Recent insights into the molecular dynamics of immune activation and its control following simian immunodeficiency virus (SIV) infection in natural host primates has provided possible alternate interpretations of SIV and HIV pathogenesis. Concomitant with insights gained in other host-pathogen systems, as well as an increased understanding of innate immune activation mechanisms, these observations lead to a new model for the timing of innate HIV immune responses and a possible primordial role of this timing in programming chronic immune activation. Summary Chronic immune activation is today considered the leading cause of AIDS in HIV-infected individuals. Systems biology has recently lent arguments for considering chronic immune activation a result of untimely innate immune responses by the host to the infection. Future strategies for the analysis, comprehension, and incorporation of the dynamic component of immune activation into HIV vaccination strategies are discussed.

Published
2012
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