DOCSLIB.ORG

The First Structure of HIV-1 Gp120 with CD4 and CCR5 Receptors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The First Structure of HIV-1 Gp120 with CD4 and CCR5 Receptors Guan Cell Biosci (2019) 9:2 https://doi.org/10.1186/s13578-018-0267-6 Cell & Bioscience RESEARCH HIGHLIGHT Open Access The frst structure of HIV‑1 gp120 with CD4 and CCR5 receptors Yongjun Guan* Abstract Shaik et al. recently published online the cryo-electron microscopy structure of HIV-1 gp120 in complex with CD4 and CCR5 receptors. This is the frst structure of the ternary HIV-1 gp120/CD4/CCR5 complex. This breakthrough of Env structure provides insights into HIV-1 fusion mechanism, CCR5 function, co-receptor switch, and, most importantly, the development of co-receptor-targeted therapeutic inhibitor and HIV-1 vaccine. It also shed lights on the immuno- genicity of gp120 by revealing the stably exposed conserved gp41-interactive region of gp120 in the complex. Keywords: gp120, CCR5, Cryo-EM, HIV-1, ADCC, Trogocytosis Main text structural information on previous complexes of gp120 HIV-1 Env, a trimer of gp120–gp41 heterodimers, is the with CD4 and antibodies regarding the conformation of sole target of broadly neutralizing antibodies of which gp120, CCR5 and the interactions between gp120 and is believed to be a primary goal of HIV-1 vaccine devel- CCR5. Te interpretation of the structure, as the authors opment [1]. Env mediates membrane fusion after bind- addressed, provides insights into HIV fusion mechanism, ing CD4 receptor and a co-receptor CCR5/CXCR4. CCR5 function, co-receptor switch, and, most impor- Based on rich structural information of Env with CD4 tantly, the development of co-receptor-targeted thera- and with antibodies, it is well recognized that Env likes peutic inhibitor and HIV-1 vaccine. a conformational machine by transitioning between Te structure revealed details of the interactions conformations of prefusion-closed, CD4-bound, and co- between CCR5 and gp120. It showed that the V3 loop receptor-bound into a postfusion state to facilitate virus/ with its conserved tip inserts into the CCR5 binding target cell membrane fusion. Te initial CD4 receptor pocket, similar to that observed with the CCL5, and an binding displaces V1V2 loops from the Env’s apex, allows extended CCR5N terminus interacts with the gp120 co-receptor binding and opens up Env to enable gp41- bridging sheet. Most importantly, the structure of the mediated membrane fusion [2]. However, a structure of interactions between CCR5 and gp120 indicates that Env with co-receptor had been missing and leaved a gap maraviroc works by directly competing with the bind- in our knowledge of the interaction between Env and ing of gp120 to CCR5, which contrasts with the view in co-receptor.. the feld that maraviroc is an allosteric inhibitor. Based In a recent online article of Nature, Shaik et al. solved on the observation that the gp120 binding site on CCR5 the cryo-electron microscopy (cryo-EM) structure of mainly overlaps with maraviroc in the minor subpocket, a full-length monomeric gp120 in complex with a solu- the authors suggested a new design of more powerful ble CD4 ectodomain and an unmodifed human CCR5 therapeutic drugs by “adding additional groups to the tri- reconstituted into a lipid micelle [3]. Tis is the frst azole ring of maraviroc to enhance its competing potency structure of the ternary HIV-1 gp120/CD4/CCR5 com- with the V3 loop”. plex and a breakthrough in the feld. It adds a wealth of Te overall structural of gp120 in the complex with CD4 and CCR5 is very similar to the CD4-bound struc- *Correspondence: [email protected] tural of Env [2]. Tis surprising observation led the Antibody BioPharm, Inc, 401 Professional Dr. Ste241, Gaithersburg, MD authors to imply that the co-receptor binding does not 20879, USA induce major conformational change of gp120 and the © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Guan Cell Biosci (2019) 9:2 Page 2 of 3 role of CCR5 binding is to stabilize the CD4-bound responses before a conclusive protective role of cluster A conformation of Env and to hold it closer to the cell antibody is evidenced. membrane. However, the structure might represent a In summary, the frst structure of HIV-1gp120 with postfusion state of monomeric gp120 bound to CD4 and CD4 and CCR5 revealed by Shaik et al. is a remarkable CCR5, therefore it may not reveal the changes induced progress in the feld. Te author made import insights by CCR5 binding in the complex of membrane anchored into HIV-1 fusion mechanism, function of CCR5, co- CD4, CCR5 and Env trimer structures. Te observed dif- receptor switch, as well as development of of novel inhib- ference that the N-terminus of the CCR5-bound gp120 itor and vaccine design. It also shed light on immune fips back onto the 7-stranded sheet of gp120 inner response against the conserved immunodominant cluster domain is mostly a late-entry structure as previously A region of gp120. revealed for the epitope structure of the cluster A C11- like antibody N12-i3 [4]. Abbreviations One remarkable highlight of the article is that the cryo-EM: cryo-electron microscopy; RFADCC: “rapid and fuorometric” authors were able to obtain a high-resolution cryo-EM antibody-dependent cellular cytotoxicity. structure of the gp120-CD4/CCR5 complex. Tis tech- Authors’ contributions nical success refects an important feature of the gp120- YG wrote the manuscript. The author read and approved the fnal manuscript. CD4/CCR5 complex that the complex can be stably extracted from target cell membrane. Tis feature shows Acknowledgements that the gp41-interactive region of gp120 in the late viral Not applicable. entry Env structure is well exposed on target cell mem- Competing interests brane and, therefore, is highly vulnerable to antibody YG is CEO of Antibody BioPharm Inc. immune response. Te gp41-interactive region of gp120 is mainly comprised conserved epitopes for the cluster Availability of data and materials Not applicable. A antibodies including A32-like, A32/C11 and C11-like antibodies [4]. Terefore, the article also shed an impor- Consent for publication tant light in immune response against Env in HIV infec- Not applicable. tion and Env vaccine. Ethics approval and consent to participate Antibodies specifc for the cluster A epitopes has been Not applicable. shown to be common and induced early in infection, and Funding may mediate the majority of ADCC activities detected in Not applicable. chronically infected individuals [5]. Tey were also impli- cated in protection for the clinical RV144 vaccine trial Publisher’s Note [6]. However, the role of cluster A antibodies is still not Springer Nature remains neutral with regard to jurisdictional claims in pub- defned. Te epitopes of cluster A antibodies are strictly lished maps and institutional afliations. receptor-binding dependent. Tey are not exposed on Received: 20 December 2018 Accepted: 26 December 2018 native trimer of HIV-1 viruses or productively infected cells [7]. Terefore, the antibodies may not have a direct impact on virus and productively infected cells. Further, a high throughput “rapid and fuorometric” antibody- References dependent cellular cytotoxicity (RFADCC) assay was 1. Sok D, Burton DR. Recent progress in broadly neutralizing antibodies to HIV. Nat Immunol. 2018;19:1179–88. commonly used to measure ADCC activity of cluster 2. Ward AB, Wilson IA. The HIV-1 envelope glycoprotein structure: nailing A antibodies [8]. Te RFADCC assay has been recently down a moving target. Immunol Rev. 2017;275:21–32. revealed to be actually measuring majority an antibody- 3. Shaik MM, Peng H, Lu J, Rits-Volloch S, Xu C, Liao M, Chen B. Structural basis of coreceptor recognition by HIV-1 envelope spike. Natre. 2018;12:1. dependent trogocytosis phenomenon instead of the 4. Tolbert WD, et al. Targeting the late stage of HIV-1 entry for antibody- assumed cell killing function of ADCC [9, 10], which has dependent cellular cytotoxicity: structural basis for Env epitopes in the imposed confusing results for the role of cluster A anti- C11 region. Structure. 2017;25:1719–31. 5. Veillette M, et al. The HIV-1 gp120 CD4-bound conformation is preferen- bodies. Cluster A antibody mediated Trogocytosis will tially targeted by antibody-dependent cellular cytotoxicity-mediating probably remove the well exposed antibody-gp120 com- antibodies in sera from HIV-1-infected individuals. J Virol. 2015;89:545–51. plexes from infected target cell surface by monocytes and 6. Bonsignori M, et al. Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efcacy trial target multiple epitopes may result in escape of infected cells from the immune and preferentially use the VH1 gene family. J Virol. 2012;86:11521–32. surveillance. Terefore, it should be cautious for Env- 7. Lewis GK, et al. Epitope target structures of Fc-mediated efector function based vaccine development targeting cluster A antibody during HIV-1 acquisition. Curr Opin HIV AIDS. 2014;9:263–70. Guan Cell Biosci (2019) 9:2 Page 3 of 3 8. Gomez-Roman VR, et al. A simplifed method for the rapid fuorometric 10. Kramski M, et al. Role of monocytes in mediating HIV-specifc antibody- assessment of antibody-dependent cell-mediated cytotoxicity. J Immu- dependent cellular cytotoxicity. J Immunol Methods. 2012;384:51–61. nol Methods.
Load more

Recommended publications
  • An Overview of Molecular Events Occurring in Human Trophoblast Fusion Pascale Gerbaud, Guillaume Pidoux
    An overview of molecular events occurring in human trophoblast fusion Pascale Gerbaud, Guillaume Pidoux To cite this version: Pascale Gerbaud, Guillaume Pidoux. An overview of molecular events occurring in human trophoblast fusion. Placenta, Elsevier, 2015, 36 (Suppl1), pp.S35-42. 10.1016/j.placenta.2014.12.015. inserm- 02556112v2 HAL Id: inserm-02556112 https://www.hal.inserm.fr/inserm-02556112v2 Submitted on 28 Apr 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 An overview of molecular events occurring in human trophoblast fusion 2 3 Pascale Gerbaud1,2 & Guillaume Pidoux1,2,† 4 1INSERM, U1139, Paris, F-75006 France; 2Université Paris Descartes, Paris F-75006; France 5 6 Running title: Trophoblast cell fusion 7 Key words: Human trophoblast, Cell fusion, Syncytins, Connexin 43, Cadherin, ZO-1, 8 cAMP-PKA signaling 9 10 Word count: 4276 11 12 13 †Corresponding author: Guillaume Pidoux, PhD 14 Inserm UMR-S-1139 15 Université Paris Descartes 16 Faculté de Pharmacie 17 Cell-Fusion group 18 75006 Paris, France 19 Tel: +33 1 53 73 96 02 20 Fax: +33 1 44 07 39 92 21 E-mail: [email protected] 22 1 23 Abstract 24 During human placentation, mononuclear cytotrophoblasts fuse to form a multinucleated syncytia 25 ensuring hormonal production and nutrient exchanges between the maternal and fetal circulation.
    [Show full text]
  • An Overview of Lipid Membrane Models for Biophysical Studies
    biomimetics Review Mimicking the Mammalian Plasma Membrane: An Overview of Lipid Membrane Models for Biophysical Studies Alessandra Luchini 1 and Giuseppe Vitiello 2,3,* 1 Niels Bohr Institute, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark; [email protected] 2 Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Piazzale Tecchio 80, 80125 Naples, Italy 3 CSGI-Center for Colloid and Surface Science, via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy * Correspondence: [email protected] Abstract: Cell membranes are very complex biological systems including a large variety of lipids and proteins. Therefore, they are difficult to extract and directly investigate with biophysical methods. For many decades, the characterization of simpler biomimetic lipid membranes, which contain only a few lipid species, provided important physico-chemical information on the most abundant lipid species in cell membranes. These studies described physical and chemical properties that are most likely similar to those of real cell membranes. Indeed, biomimetic lipid membranes can be easily prepared in the lab and are compatible with multiple biophysical techniques. Lipid phase transitions, the bilayer structure, the impact of cholesterol on the structure and dynamics of lipid bilayers, and the selective recognition of target lipids by proteins, peptides, and drugs are all examples of the detailed information about cell membranes obtained by the investigation of biomimetic lipid membranes. This review focuses specifically on the advances that were achieved during the last decade in the field of biomimetic lipid membranes mimicking the mammalian plasma membrane. In particular, we provide a description of the most common types of lipid membrane models used for biophysical characterization, i.e., lipid membranes in solution and on surfaces, as well as recent examples of their Citation: Luchini, A.; Vitiello, G.
    [Show full text]
  • CHAPTER 11 Lipid Acrobatics in the Membrane Fusion Arena
    CHAPTER 11 Lipid Acrobatics in the Membrane Fusion Arena Albert J. Markvoort1 and Siewert J. Marrink2 1Institute for Complex Molecular Systems & Biomodeling and Bioinformatics Group, Eindhoven University of Technology, Eindhoven, The Netherlands 2Groningen Biomolecular Sciences and Biotechnology Institute & Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands I. Overview II. Introduction III. Historical Background IV. Fusion Pathways at the Molecular Level A. Symmetric Stalk Expansion Pathway B. Alternative Pathways C. Composition Dependence V. Energy Landscape Along the Fusion Pathway A. Stalk and Hemifusion Diaphragm Intermediates B. Lipid Splaying as First Step C. Many Barriers to Cross VI. Fission Pathways in Molecular Detail A. Budding/Neck Formation B. Fission not Just Fusion Reversed VII. Peptide Modulated Fusion A. The Role of Fusion Peptides B. Protein-Induced Fusion VIII. Outlook References I. OVERVIEW In this review, we describe the recent contribution of computer simulation approaches to unravel the molecular details of membrane fusion. Over the past decade, fusion between apposed membranes and vesicles has been studied using a large variety of simulation methods and systems. Despite the variety in techniques, some generic fusion pathways emerge that predict a more complex Current Topics in Membranes, Volume 68 0065-230X/10 $35.00 Copyright 2011, Elsevier Inc. All right reserved. DOI: 10.1016/B978-0-12-385891-7.00011-8 260 Markvoort and Marrink picture beyond the traditional stalk–pore pathway. Indeed the traditional path- way is confirmed in particle-based simulations, but in addition alternative path- ways are observed in which stalks expand linearly rather than radially, leading to inverted-micellar or asymmetric hemifusion intermediates.
    [Show full text]
  • UC Merced UC Merced Electronic Theses and Dissertations
    UC Merced UC Merced Electronic Theses and Dissertations Title Characterizing the P2X4 receptor as a contributor to cell membrane fusion and C. trachomatis L2 vacuole fusion Permalink https://escholarship.org/uc/item/102048cs Author Ahrens-Braunstein, Ashley K. Publication Date 2014 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, MERCED Characterizing the P2X4 receptor as a contributor to cell membrane fusion and C. trachomatis L2 vacuole fusion In Quantitative and Systems Biology by Ashley Ahrens-Braunstein Committee in charge: Professor Masashi Kitazawa, Chair Professor David M. Ojcius Professor Linda S. Hirst 2014 © 2014 Ashley Ahrens-Braunstein All rights reserved. ii The Thesis of Ashley Ahrens-Braunstein is approved, and it is acceptable in quality and form for publication on microfilm and electronically: _______________________________________________ Dr. David M. Ojcius ________________________________________________ Dr. Linda S. Hirst ________________________________________________ Dr. Masashi Kitazawa University of California, Merced 2014 iii DEDICATION I dedicate this thesis to my brothers and sister, Axel Ahrens, Grant Koblis, Christopher Ahrens and Cassandra Koblis for their support and continued understanding throughout my program. Being the oldest, they have looked up to me but it is their accomplishments that have inspired me to continue to persist in my goals. Throughout my years at UC Merced, they have been completely understanding
    [Show full text]
  • Coupling Between Refolding of the Influenza Hemagglutinin and Lipid Rearrangements
    1384 Biophysical Journal Volume 75 September 1998 1384–1396 A Mechanism of Protein-Mediated Fusion: Coupling between Refolding of the Influenza Hemagglutinin and Lipid Rearrangements Michael M. Kozlov* and Leonid V. Chernomordik# *Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel, and #The Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892 USA ABSTRACT Although membrane fusion mediated by influenza virus hemagglutinin (HA) is the best characterized example of ubiquitous protein-mediated fusion, it is still not known how the low-pH-induced refolding of HA trimers causes fusion. This refolding involves 1) repositioning of the hydrophobic N-terminal sequence of the HA2 subunit of HA (“fusion peptide”), and 2) the recruitment of additional residues to the a-helical coiled coil of a rigid central rod of the trimer. We propose here a mechanism by which these conformational changes can cause local bending of the viral membrane, priming it for fusion. In this model fusion is triggered by incorporation of fusion peptides into viral membrane. Refolding of a central rod exerts forces that pull the fusion peptides, tending to bend the membrane around HA trimer into a saddle-like shape. Elastic energy drives self-assembly of these HA-containing membrane elements in the plane of the membrane into a ring-like cluster. Bulging of the viral membrane within such cluster yields a dimple growing toward the bound target membrane. Bending stresses in the lipidic top of the dimple facilitate membrane fusion.
    [Show full text]
  • An Important Regulator of Muscle Cell Fusion Francesco Girardi
    TGFbeta signalling pathway in muscle regeneration : an important regulator of muscle cell fusion Francesco Girardi To cite this version: Francesco Girardi. TGFbeta signalling pathway in muscle regeneration : an important regulator of muscle cell fusion. Cellular Biology. Sorbonne Université, 2019. English. NNT : 2019SORUS114. tel-02944744 HAL Id: tel-02944744 https://tel.archives-ouvertes.fr/tel-02944744 Submitted on 21 Sep 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Sorbonne Université Ecole doctorale Complexité du Vivant Centre of Research in Myology Signaling Pathways & Striated Muscles TGFβ signalling pathway in muscle regeneration: an important regulator of muscle cell fusion Par Francesco GIRARDI Thèse de doctorat en Biologie Cellulaire et Moléculaire Dirigée par Fabien LE GRAND Présentée et soutenue publiquement le 19 septembre 2019 Devant un jury composé de : Président : Pr. Claire Fournier-Thibault Rapporteurs : Dr. Pierre-Yves Rescan Dr. Jerome Feige Examinateurs : Dr. Glenda Comai Dr. Philippos Mourikis Directeur de thèse : Dr. Fabien Le Grand TABLE OF CONTENTS SUMMARY I RÉSUMÉ II LIST OF ABBREVIATIONS III INTRODUCTION 1 I. Skeletal Muscle 1 1. Embryonic Myogenesis 2 1.1. Skeletal muscle formation 2 1.2. Molecular regulators of embryonic myogenesis 4 2.
    [Show full text]
  • Fusion of Cytothrophoblast with Syncytiotrophoblast in the Human Placenta: Factors Involved in Syncytialization Gauster M, Huppertz B J
    Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology – Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie Fusion of Cytothrophoblast with Syncytiotrophoblast in the Human Placenta: Factors Involved in Syncytialization Gauster M, Huppertz B J. Reproduktionsmed. Endokrinol 2008; 5 (2), 76-82 www.kup.at/repromedizin Online-Datenbank mit Autoren- und Stichwortsuche Offizielles Organ: AGRBM, BRZ, DVR, DGA, DGGEF, DGRM, D·I·R, EFA, OEGRM, SRBM/DGE Indexed in EMBASE/Excerpta Medica/Scopus Krause & Pachernegg GmbH, Verlag für Medizin und Wirtschaft, A-3003 Gablitz FERRING-Symposium digitaler DVR 2021 Mission possible – personalisierte Medizin in der Reproduktionsmedizin Was kann die personalisierte Kinderwunschbehandlung in der Praxis leisten? Freuen Sie sich auf eine spannende Diskussion auf Basis aktueller Studiendaten. SAVE THE DATE 02.10.2021 Programm 12.30 – 13.20Uhr Chair: Prof. Dr. med. univ. Georg Griesinger, M.Sc. 12:30 Begrüßung Prof. Dr. med. univ. Georg Griesinger, M.Sc. & Dr. Thomas Leiers 12:35 Sind Sie bereit für die nächste Generation rFSH? Im Gespräch Prof. Dr. med. univ. Georg Griesinger, Dr. med. David S. Sauer, Dr. med. Annette Bachmann 13:05 Die smarte Erfolgsformel: Value Based Healthcare Bianca Koens 13:15 Verleihung Frederik Paulsen Preis 2021 Wir freuen uns auf Sie! Fusion of Cytotrophoblast with Syncytiotrophoblast in the Human Placenta: Factors Involved in Syncytialization M. Gauster, B. Huppertz Human placental villi are covered by a characteristic epithelial-like layer. It consists of mononucleated cytotrophoblasts and an overlying syncytiotrophoblast layer both in contact to the trophoblastic basement membrane. The syncytiotrophoblast mostly lacks DNA replication and seems to transcribe only barely mRNA.
    [Show full text]
  • The Many Mechanisms of Viral Membrane Fusion Proteins
    CTMI (2004) 285:25--66 Springer-Verlag 2004 The Many Mechanisms of Viral Membrane Fusion Proteins L. J. Earp1 · S. E. Delos2 · H. E. Park1 · J. M. White2 ()) 1 Department of Microbiology, University of Virginia, Charlottesville, VA, USA 2 Department of Cell Biology, School of Medicine, UVA Health System, P.O. Box 800732, Charlottesville, VA 22908-0732, USA [email protected] 1 Introduction ................................. 26 2 Activation of Viral Fusion Proteins..................... 27 2.1 Low pH Activation .............................. 28 2.2 Receptor Activation at Neutral pH ..................... 29 2.3 “Two-Step” Activation ............................ 29 3 Classification of Fusion Proteins Based on Structural Criteria ..... 30 4 Examples of Fusion Activation Mechanisms................ 32 4.1 Influenza HA (Class I Fusion Protein, Low pH) .............. 33 4.2 HIV Env (Class I Fusion Protein, Neutral pH) ............... 34 4.3 Paramyxovirus F Proteins (Class I Fusion Protein, Neutral pH, Attachment Protein Assisted) ........................ 36 4.4 TBE E and SFV E1 (Class II Fusion Proteins, Low pH) .......... 38 5 Membrane Dynamics During Fusion.................... 40 6 Membrane-Interacting Regions of Viral Fusion Proteins......... 41 6.1 The Fusion Peptide .............................. 42 6.1.1 Structure of N-terminal Fusion Peptides .................. 43 6.1.2 Structure of Internal Fusion Peptides .................... 44 6.1.3 Roles of Fusion Peptides ........................... 45 6.2 The Transmembrane Domain ........................ 45 6.3 The Juxtamembrane Region of the Ectodomain .............. 46 6.4 The Cytoplasmic Tail ............................. 47 7 Rafts in Viral Membrane Fusion ...................... 48 8 Inhibitors of Viral Fusion .......................... 49 8.1 Inhibition of Helix Bundle Formation ................... 50 8.2 Inhibition of Other Steps in Fusion ..................... 51 9 Perspectives .................................
    [Show full text]
  • Virus-Mediated Cell-Cell Fusion
    International Journal of Molecular Sciences Review Virus-Mediated Cell-Cell Fusion Héloïse Leroy 1,2,3, Mingyu Han 1,2,3 , Marie Woottum 1,2,3 , Lucie Bracq 4 , Jérôme Bouchet 5 , Maorong Xie 6 and Serge Benichou 1,2,3,* 1 Institut Cochin, Inserm U1016, 75014 Paris, France; [email protected] (H.L.); [email protected] (M.H.); [email protected] (M.W.) 2 Centre National de la Recherche Scientifique CNRS, UMR8104, 75014 Paris, France 3 Faculty of Health, University of Paris, 75014 Paris, France 4 Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; lucie.bracq@epfl.ch 5 Laboratory Orofacial Pathologies, Imaging and Biotherapies UR2496, University of Paris, 92120 Montrouge, France; [email protected] 6 Division of Infection and Immunity, University College London, London WC1E 6BT, UK; [email protected] * Correspondence: [email protected] Received: 20 November 2020; Accepted: 14 December 2020; Published: 17 December 2020 Abstract: Cell-cell fusion between eukaryotic cells is a general process involved in many physiological and pathological conditions, including infections by bacteria, parasites, and viruses. As obligate intracellular pathogens, viruses use intracellular machineries and pathways for efficient replication in their host target cells. Interestingly, certain viruses, and, more especially, enveloped viruses belonging to different viral families and including human pathogens, can mediate cell-cell fusion between infected cells and neighboring non-infected cells. Depending of the cellular environment and tissue organization, this virus-mediated cell-cell fusion leads to the merge of membrane and cytoplasm contents and formation of multinucleated cells, also called syncytia, that can express high amount of viral antigens in tissues and organs of infected hosts.
    [Show full text]
  • 1. Introduction 1.1. A. Basic Biology of Membranes and Membrane Fusion. Biological Membranes Consist of Lipids and Proteins
    1. Introduction 1.1. A. Basic biology of membranes and membrane fusion. Biological membranes consist of lipids and proteins, with the lipids self-organized into sheets and the proteins embedded into or bound to the sheets. The lipid sheets are arranged as a “bilayer,” two lipid monolayers with lipid acyl chains (i.e., hydrophobic tails) directly abutted against each other and sequestered from the aqueous solutions bathing the two sides of the membrane by the polar headgroups of the lipid molecules. The lipid bilayer membrane appeared early in evolution (1), and provides the barrier between interiors and exteriors of all eukaryotic (nucleus-containing) cells and their organelles. The architectural organization of the lipid bilayer is critical to life, and the functioning of proteins embedded in membranes is intrinsically connected to the bilayer structure in which they reside. The lipid bilayer also functions as an insulator for all activity within the body: the generation and propagation of action potentials in neurons and heart cells (2), and the voltage across mitochondrial membranes (i.e., batteries) that drives the production of ATP, the currency of cellular energy (3). Bilayer lipids provide extracellular (4) and intracellular molecules (5) that integrate the functioning of cells within body tissues. These and a host of other cellular functions rely on the integrity of the lipid bilayer structure (6). The bilayer membrane is a complex, dynamic structure. Its lipids are asymmetric in all directions, are in rapid motion, rotating, for example, 107 times/sec (7), and both the mass and electron density profiles of each lipid are heterogeneous along its length (1.5 – 2 nm) (8).
    [Show full text]
  • PROTEIN-LIPID INTERPLAY in FUSION and FISSION of BIOLOGICAL MEMBRANES Leonid V. Chernomordik1 and Michael M. Kozlov2
    Annu. Rev. Biochem. 2003. 72:175–207 doi: 10.1146/annurev.biochem.72.121801.161504 PROTEIN-LIPID INTERPLAY IN FUSION AND * FISSION OF BIOLOGICAL MEMBRANES Leonid V. Chernomordik1 and Michael M. Kozlov2 1Section on Membrane Biology, Laboratory of Cellular and Molecular Biophysics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892- 1855; email: [email protected] 2Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; email: [email protected] Key Words hemagglutinin, hemifusion, stalk, fusion pore, membrane curvature f Abstract Disparate biological processes involve fusion of two membranes into one and fission of one membrane into two. To formulate the possible job description for the proteins that mediate remodeling of biological membranes, we analyze the energy price of disruption and bending of membrane lipid bilayers at the different stages of bilayer fusion. The phenomenology and the pathways of the well-charac- terized reactions of biological remodeling, such as fusion mediated by influenza hemagglutinin, are compared with those studied for protein-free bilayers. We briefly consider some proteins involved in fusion and fission, and the dependence of remodeling on the lipid composition of the membranes. The specific hypothetical mechanisms by which the proteins can lower the energy price of the bilayer rearrangement are discussed in light of the experimental data and the requirements imposed by the elastic properties of the bilayer. CONTENTS
    [Show full text]
  • Fusogenic Viruses in Oncolytic Immunotherapy
    cancers Review Fusogenic Viruses in Oncolytic Immunotherapy Teresa Krabbe ID and Jennifer Altomonte * ID 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 München, Germany; [email protected] * Correspondence: [email protected] Received: 4 June 2018; Accepted: 23 June 2018; Published: 26 June 2018 Abstract: Oncolytic viruses are under intense development and have earned their place among the novel class of cancer immunotherapeutics that are changing the face of cancer therapy. Their ability to specifically infect and efficiently kill tumor cells, while breaking immune tolerance and mediating immune responses directed against the tumor, make oncolytic viruses highly attractive candidates for immunotherapy. Increasing evidence indicates that a subclass of oncolytic viruses, which encodes for fusion proteins, could outperform non-fusogenic viruses, both in their direct oncolytic potential, as well as their immune-stimulatory properties. Tumor cell infection with these viruses leads to characteristic syncytia formation and cell death due to fusion, as infected cells become fused with neighboring cells, which promotes intratumoral spread of the infection and releases additional immunogenic signals. In this review, we discuss the potential of fusogenic oncolytic viruses as optimal candidates to enhance immunotherapy and initiate broad antitumor responses. We provide an overview of the cytopathic mechanism of syncytia formation through viral-mediated expression of fusion proteins, either endogenous or engineered, and their benefits for cancer therapy. Growing evidence indicates that fusogenicity could be an important feature to consider in the design of optimal oncolytic virus platforms for combinatorial oncolytic immunotherapy. Keywords: cancer; immunotherapy; oncolytic; virus; fusion; fusogenic; fusogenicity; immunogenic; syncytium 1.
    [Show full text]