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1. The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity

Author

François Moreau, Sophie Chasset, Felipe García, Marc Ruff, Ben Berkhout, Erwann Le Rouzic, Danièle Spehner, Benoit Ledoussal, Laia Miralles, Stéphane Emiliani, Francis Chevreuil, Igor Orlov, Alessia Zamborlini, Christiane Moog, Julie Brias, Bruno P. Klaholz, Nikki van Bel, Céline Amadori, José M. Gatell, Damien Bonnard, Luzia Mayr, Yme U. van der Velden, Richard Benarous, Montserrat Plana, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Laboratoires Biodim-Mutabilis [Romainville], Biocitech, Université Sorbonne Paris Cité (USPC), Laboratory of Experimental Virology - Department of Medical Microbiology [Amsterdam, The Netherlands], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Center for Infection and Immunity Amsterdam - CINIMA [Amsterdam, The Netherlands], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AIDS Research Group [Barcelona, Spain], Hospital Clinic [Barcelona, Spain]-August Pi i Sunyer Biomedical Research Institute - IDIBAPS [Barcelona, Spain], Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by Biodim Mutabilis under the Authorization Number DUO 2145, assigned by the French Ministry of Research for work with genetically modified organisms, and by Grants from EU FP7 to Biodim, BB, SE and AZ under the HIVINNOV consortium, Grant Agreement No. 305137, from the Eurostar Grant ResistAids to Biodim and BB (Grant Agreement No. E!10239) and by the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01, and Instruct as part of the European Strategy Forum on Research Infrastructures (ESFRI). Felipe García team was supported by Grants SAF2015-66193-R, SAF2012-39075, Montserrat Plana by Grant FIS PI15/00480 and Nikki van Bel by NWO-CW (TOP Grant)., ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), European Project: 305137,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,HIVINNOV(2012), Les Laboratoires Biodim-Mutabilis, Centre d'Economie de l'Université Paris Nord (CEPN), Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Centre National de la Recherche Scientifique (CNRS), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF (institution))-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Infection and Immunity Amsterdam (CINIMA), August Pi i Sunyer Biomedical Research Institute - IDIBAPS [Barcelona, Spain]-Hospital Clinic [Barcelona, Spain], Collège de France (CdF (institution))-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CdF)-Université Paris Diderot - Paris 7 (UPD7)-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 Paris Descartes - Paris 5 (UPD5), Immunorhumathologie moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-INBS-05-01/10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Klaholz, Bruno, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, Generation of a new class of antiretrovirals targeting HIV-cellular cofactors interactions - HIVINNOV - - EC:FP7:HEALTH2012-10-01 - 2015-09-30 - 305137 - VALID, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS), AII - Infectious diseases, Medical Microbiology and Infection Prevention, and Amsterdam institute for Infection and Immunity

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, Pyridines, Virus Integration, T cell, [SDV]Life Sciences [q-bio], Aucun, HIV Integrase, Thiophenes, Allosteric integrase inhibitor, HIV Antibodies, Virus Replication, Integrase, Virus, Cell Line, 03 medical and health sciences, INLAI, Immunoreactivity, Virology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Virus maturation, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, LEDGIN, HIV Integrase Inhibitors, LEDGF, Infectivity, biology, Research, Virus Assembly, RNA, virus diseases, Group-specific antigen, Reverse transcriptase, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, biology.protein, HIV-1, Intercellular Signaling Peptides and Proteins, lcsh:RC581-607
Abstract

Background HIV-1 Integrase (IN) interacts with the cellular co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host genome enabling integration. Recently a new class of IN inhibitors was described, the IN-LEDGF allosteric inhibitors (INLAIs). Designed to interfere with the IN-LEDGF interaction during integration, the major impact of these inhibitors was surprisingly found on virus maturation, causing a reverse transcription defect in target cells. Results Here we describe the MUT-A compound as a genuine INLAI with an original chemical structure based on a new type of scaffold, a thiophene ring. MUT-A has all characteristics of INLAI compounds such as inhibition of IN-LEDGF/p75 interaction, IN multimerization, dual antiretroviral (ARV) activities, normal packaging of genomic viral RNA and complete Gag protein maturation. MUT-A has more potent ARV activity compared to other INLAIs previously reported, but similar profile of resistance mutations and absence of ARV activity on SIV. HIV-1 virions produced in the presence of MUT-A were non-infectious with the formation of eccentric condensates outside of the core. In studying the immunoreactivity of these non-infectious virions, we found that inactivated HIV-1 particles were captured by anti-HIV-specific neutralizing and non-neutralizing antibodies (b12, 2G12, PGT121, 4D4, 10-1074, 10E8, VRC01) with efficiencies comparable to non-treated virus. Autologous CD4+ T lymphocyte proliferation and cytokine induction by monocyte-derived dendritic cells (MDDC) pulsed either with MUT-A-inactivated HIV or non-treated HIV were also comparable. Conclusions Although strongly defective in infectivity, HIV-1 virions produced in the presence of the MUT-A INLAI have a normal protein and genomic RNA content as well as B and T cell immunoreactivities comparable to non-treated HIV-1. These inactivated viruses might form an attractive new approach in vaccine research in an attempt to study if this new type of immunogen could elicit an immune response against HIV-1 in animal models. Electronic supplementary material The online version of this article (10.1186/s12977-017-0373-2) contains supplementary material, which is available to authorized users.

Published
2017

2. The invariant arginine within the chromatin-binding motif regulates both nucleolar localization and chromatin binding of Foamy virus Gag

Author

Paris, Joris, Tobaly-Tapiero, Joëlle, Giron, Marie-Lou, Burlaud-Gaillard, Julien, Buseyne, Florence, Roingeard, Philippe, Lesage, Pascale, Zamborlini, Alessia, Saïb, Ali, Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Plateforme IBISA de Microscopie Electronique [CHRU de Tours] (UNIV Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), This study was supported by CNRS, INSERM, Université Paris Diderot Sorbonne Paris Cité, CNAM and ANR (ANR-12-BSV3-0016 to AS, ANR-15-CE15-0008 to AS and FB)., We thank Axel Rethwilm and Dirk Lindemann for FV reagents, Mark Bedford for GFP-PRMTs plasmids, Christelle Doliger, Sophie Duchez and Niclas Setterblad at the Imaging, Cell selection and Genomics Department of the Institut Universitaire d’Hématologie for confocal microscopy, Claudine Pique for critical reading of the manuscript., ANR-12-BSV3-0016,PTPs,Le rôle de l'exportation et de la maturation d'ARN messagers dans la production des produits pionniers de traduction (PTPs) dans la voie du CMH de la classe I.(2012), ANR-15-CE15-0008,REEMFOAMY,L'infection humaine par les virus foamy simiens zoonotiques : rôle des facteurs virologiques et immunologiques dans la restrcition de l'emergence virale(2015), Buseyne, Florence, BLANC - Le rôle de l'exportation et de la maturation d'ARN messagers dans la production des produits pionniers de traduction (PTPs) dans la voie du CMH de la classe I. - - PTPs2012 - ANR-12-BSV3-0016 - BLANC - VALID, L'infection humaine par les virus foamy simiens zoonotiques : rôle des facteurs virologiques et immunologiques dans la restrcition de l'emergence virale - - REEMFOAMY2015 - ANR-15-CE15-0008 - AAPG2015 - VALID, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Université de Tours, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris]

Subjects
Protein-Arginine N-Methyltransferases, viruses, PRMT, MESH: Protein-Arginine N-Methyltransferases, Amino Acid Motifs, Nuclear Localization Signals, MESH: Nuclear Localization Signals, MESH: Amino Acid Sequence, MESH: Amino Acid Motifs, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Evolution, Molecular, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Gag, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Arginine, Chromatin, Nuclear trafficking, Protein Transport, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, MESH: Repressor Proteins, MESH: Gene Products, gag, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, MESH: Retroviridae Infections, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Foamy virus, Post-translational modification, Chromatin-binding, Protein Binding, lcsh:Immunologic diseases. Allergy, MESH: Cell Nucleus, MESH: Protein Transport, Gene Products, gag, Arginine, Methylation, MESH: Chromatin, Evolution, Molecular, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Protein Binding, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Cell Nucleus, MESH: Protein Interaction Domains and Motifs, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, Research, Nucleolus, Repressor Proteins, MESH: Protein Processing, Post-Translational, MESH: Spumavirus, Spumavirus, lcsh:RC581-607, Protein Processing, Post-Translational, Retroviridae Infections
Abstract

Background Nuclear localization of Gag is a property shared by many retroviruses and retrotransposons. The importance of this stage for retroviral replication is still unknown, but studies on the Rous Sarcoma virus indicate that Gag might select the viral RNA genome for packaging in the nucleus. In the case of Foamy viruses, genome encapsidation is mediated by Gag C-terminal domain (CTD), which harbors three clusters of glycine and arginine residues named GR boxes (GRI-III). In this study we investigated how PFV Gag subnuclear distribution might be regulated. Results We show that the isolated GRI and GRIII boxes act as nucleolar localization signals. In contrast, both the entire Gag CTD and the isolated GRII box, which contains the chromatin-binding motif, target the nucleolus exclusively upon mutation of the evolutionary conserved arginine residue at position 540 (R540), which is a key determinant of FV Gag chromatin tethering. We also provide evidence that Gag localizes in the nucleolus during FV replication and uncovered that the viral protein interacts with and is methylated by Protein Arginine Methyltransferase 1 (PRMT1) in a manner that depends on the R540 residue. Finally, we show that PRMT1 depletion by RNA interference induces the concentration of Gag C-terminus in nucleoli. Conclusion Altogether, our findings suggest that methylation by PRMT1 might finely tune the subnuclear distribution of Gag depending on the stage of the FV replication cycle. The role of this step for viral replication remains an open question. Electronic supplementary material The online version of this article (10.1186/s12977-018-0428-z) contains supplementary material, which is available to authorized users.

Published
2018

3. Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage

Author

François Moreau, Richard Benarous, Jean-Michel Bruneau, Erwann Le Rouzic, Marc Ruff, Ali Saïb, Julie Brias, Stéphane Emiliani, Frédéric Le Strat, Olivier Delelis, Eric Deprez, Céline Amadori, Roxane Beauvoir, Nicolas Levy, Alessia Zamborlini, Francis Chevreuil, Juliette Nguyen, Sophie Chasset, Sylvia Eiler, Sophie Vomscheid, Benoit Ledoussal, Damien Bonnard, Les Laboratoires Biodim-Mutabilis, Biocitech, Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie et de Pharmacologie Appliquée ( LBPA ), École normale supérieure - Cachan ( ENS Cachan ) -Centre National de la Recherche Scientifique ( CNRS ), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), EU FP7 provided financial support under the HIVINNOV consortium, grant agreement 305137. Marc Ruff team was supported by grants from the CNRS, the INSERM, SIDACTION, the French National Agency for Research against AIDS (ANRS), the SPINE 2 European Project (FP6 Contract Nu QLG2- CT-2002-00988 and 031220), the French Infrastructure for Integrated Structural Biology (FRISBI, ANR-10-INSB-05-01) and Instruct, part of the European Strategy Forum on Research Infrastructure (ESFRI) supported by national members subscription., Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and BMC, Ed.

Subjects
Protein Conformation, Virus Integration, Allosteric regulation, Integrase inhibitor, HIV Integrase, Plasma protein binding, Crystallography, X-Ray, Virus Replication, Integrase, Cell Line, 03 medical and health sciences, Allosteric inhibition, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, Humans, HIV Integrase Inhibitors, LEDGF, 030304 developmental biology, 0303 health sciences, biology, Drug discovery, Research, 030302 biochemistry & molecular biology, HIV, Antiretroviral activity, Molecular biology, 3. Good health, Chromatin, Cell biology, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Protein-protein interaction inhibitor, Infectious Diseases, Viral replication, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, HIV-1, biology.protein, Intercellular Signaling Peptides and Proteins, Co-crystallization, Protein Binding
Abstract

Background LEDGF/p75 (LEDGF) is the main cellular cofactor of HIV-1 integrase (IN). It acts as a tethering factor for IN, and targets the integration of HIV in actively transcribed gene regions of chromatin. A recently developed class of IN allosteric inhibitors can inhibit the LEDGF-IN interaction. Results We describe a new series of IN-LEDGF allosteric inhibitors, the most active of which is Mut101. We determined the crystal structure of Mut101 in complex with IN and showed that the compound binds to the LEDGF-binding pocket, promoting conformational changes of IN which explain at the atomic level the allosteric effect of the IN/LEDGF interaction inhibitor on IN functions. In vitro, Mut101 inhibited both IN-LEDGF interaction and IN strand transfer activity while enhancing IN-IN interaction. Time of addition experiments indicated that Mut101 behaved as an integration inhibitor. Mut101 was fully active on HIV-1 mutants resistant to INSTIs and other classes of anti-HIV drugs, indicative that this compound has a new mode of action. However, we found that Mut101 also displayed a more potent antiretroviral activity at a post-integration step. Infectivity of viral particles produced in presence of Mut101 was severely decreased. This latter effect also required the binding of the compound to the LEDGF-binding pocket. Conclusion Mut101 has dual anti-HIV-1 activity, at integration and post-integration steps of the viral replication cycle, by binding to a unique target on IN (the LEDGF-binding pocket). The post-integration block of HIV-1 replication in virus-producer cells is the mechanism by which Mut101 is most active as an antiretroviral. To explain this difference between Mut101 antiretroviral activity at integration and post-integration stages, we propose the following model: LEDGF is a nuclear, chromatin-bound protein that is absent in the cytoplasm. Therefore, LEDGF can outcompete compound binding to IN in the nucleus of target cells lowering its antiretroviral activity at integration, but not in the cytoplasm where post-integration production of infectious viral particles takes place.

Published
2013
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