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7 results on '"MESH: Antibodies, Monoclonal/immunology"'

1. Unexpected cross-reactivity of anti-cathepsin B antibodies leads to uncertainties regarding the mechanism of action of anti-CD20 monoclonal antibody GA101

Author

Gilles Salles, Charlène Niogret, Abdel Aouacheria, Romain Jugé, Aurélie Cornut-Thibaut, Wei Wen Chien, Loïc Lionnard, Ariel Savina, Jérôme Kucharczak, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS 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), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), and Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE)

Subjects
Cancer Research, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, MESH: Antibodies, Monoclonal/pharmacology, MESH: Cathepsin B/immunology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humanized antibody, Cathepsin B, 0302 clinical medicine, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, CD20, MESH: Mitochondrial Membranes/metabolism, biology, Antibodies, Monoclonal, Hematology, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Mitochondrial Membranes, MESH: Antigens, CD20/immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Lymphomas, medicine.symptom, Antibody, Lysosomal permeabilization, Cell death, MESH: Cell Line, Tumor, medicine.drug_class, Antibody-based immunotherapy, MESH: Intracellular Membranes/metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cross Reactions, Monoclonal antibody, Antibodies, Monoclonal, Humanized, MESH: Lysosomes/ultrastructure, Permeability, 03 medical and health sciences, MESH: Antibodies, Monoclonal, Humanized/pharmacokinetics, Antigen, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Antibodies, Monoclonal/immunology, medicine, Leukemia, B-Cell, Humans, MESH: Antibodies, Monoclonal, Humanized/therapeutic use, GA101, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Leukemia, B-Cell/drug therapy, MESH: Cross Reactions/immunology, MESH: Humans, MESH: Antibodies, Monoclonal/therapeutic use, MESH: Permeability/drug effects, Actin remodeling, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Intracellular Membranes, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Antigens, CD20, MESH: Cell Death/drug effects, Mechanism of action, Immunology, Cancer research, biology.protein, Lysosomes, 030215 immunology
Abstract

International audience; GA101, also known as obinutuzumab or Gazyva (Gazyvaro), is a glycoengineered type II humanized antibody that targets the CD20 antigen expressed at the surface of B-cells. This novel anti-CD20 antibody is currently assessed in clinical trials with promising results as a single agent or as part of therapeutic combinations for the treatment of B-cell malignancies. Detailed understanding of the mechanisms of GA101-induced cell death is needed to get insight into possible resistance mechanisms occurring in patients. Although multiple in vitro and in vivo mechanisms have been suggested to describe the effects of GA101 on B-cells, currently available data are ambiguous. The aim of our study was to clarify the cellular mechanisms involved in GA101-induced cell death in vitro, and more particularly the respective roles played by lysosomal and mitochondrial membrane permeabilization. Our results confirm previous reports suggesting that GA101 triggers homotypic adhesion and caspase-independent cell death, two processes that are dependent on actin remodeling and involve the production of reactive oxygen species. With respect to lysosomal membrane permeabilization (LMP), our data suggest that lack of specificity of available antibodies directed against cathepsin B may have confounded previously published results, possibly challenging current LMP-driven model of GA101 action mode.

Published
2017
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2. Monoclonal antibody recognizing SLLTEVET epitope of M2 protein potently inhibited the replication of influenza A viruses in MDCK cells

Author

Tianhou Wang, Licheng Zhou, Xu-Guang Xi, Hongwei Xu, Yongjin Wang, Xiaoming Wang, Huiling Shi, Tetsuya Toyoda, Hong Yao, East China Normal University [Shangaï] (ECNU), Génotoxicologie et cycle cellulaire (GCC), Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), Réseau International des Instituts Pasteur (RIIP), This work was supported by grants from Shanghai Municipal Science and Technology Commission (No. 07DZ22940) and Shanghai Municipal Wildlife Administration (No. SBHZ2006_01)., and We thank Dr. Yoshihiro Kawaoka from University of Madison-Wisconsin for providing the reverse genetics system for generating A/WSN/33 (H1N1) viruses.

Subjects
MESH: Virus Replication, [SDV]Life Sciences [q-bio], Peptide binding, Influenza A, MESH: Amino Acid Sequence, Virus Replication, medicine.disease_cause, Biochemistry, Epitope, MESH: Dogs, Epitopes, Influenza A virus, MESH: Animals, Inhibition, chemistry.chemical_classification, 0303 health sciences, Antibodies, Monoclonal, 3. Good health, Amino acid, MESH: Viral Matrix Proteins/immunology, Ectodomain, Influenza Vaccines, M2e8, MESH: Epitopes/genetics, Antibody, MESH: Viral Matrix Proteins/genetics, Monoclonal antibody, MESH: Mutation, medicine.drug_class, MESH: Influenza Vaccines/immunology, Molecular Sequence Data, Biophysics, MESH: Antibodies, Monoclonal/immunology, Biology, Cell Line, Viral Matrix Proteins, 03 medical and health sciences, Dogs, MESH: Epitopes/chemistry, MESH: Viral Matrix Proteins/chemistry, MESH: Influenza A virus/physiology, medicine, Animals, Amino Acid Sequence, Molecular Biology, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Epitopes/immunology, 030306 microbiology, Cell Biology, Virology, Molecular biology, In vitro, MESH: Cell Line, chemistry, Mutation, biology.protein
Abstract

International audience; The ectodomain of influenza A virus M2 protein (M2e) is composed of 24 amino acids and induces antibodies with inhibitory effect against a broad spectrum of influenza A subtypes in vitro and in vivo. Although relatively conserved, 21 M2e variants emerged in recent influenza A strains, most of the mutations appeared in the middle part of M2e domain. In this study, we characterized the in vitro inhibition efficacy of a monoclonal antibody (mAb) M2e8-7 recognizing the N terminus highly conserved epitope SLLTEVET (aa 2-9) which is common for both M1 and M2 proteins. Peptide binding assay showed that mAb M2e8-7 reacted strongly with M2e and 19 M2e variant peptides. The mAb M2e8-7 potently inhibited the replication of influenza A virus H1 and H3 subtypes in MDCK cells. Two important amino acids in M2e epitope, Threonine at position five and the Glutamic acid at position six, were identified to lead antibody-escaping variants. These results brought new insight in developing vaccine and therapeutic agents against influenza A virus infections.

Published
2009
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3. An optical biosensor assay for rapid dual detection of Botulinum neurotoxins A and E

Author

Marie-Pierre Blanchard, Yves Maulet, Michael Seagar, Christelle Mazuet, Michel R. Popoff, Christian Lévêque, Oussama El Far, Géraldine Ferracci, Unité de Neurobiologie des canaux Ioniques et de la Synapse (UNIS - Inserm U1072), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Centre National de Référence des Bactéries Anaérobies et Botulisme - National Reference Center Anaerobic Bacteria and Botulism (CNR), Institut Pasteur [Paris] (IP), This work was supported by INSERM, CNRS and a grant from the DGA (REI N° 0634040), El Far, Oussama, and Institut Pasteur [Paris]

Subjects
0301 basic medicine, Botulinum Toxins, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV]Life Sciences [q-bio], Biosensing Techniques, 01 natural sciences, Epitope, Substrate Specificity, Epitopes, Lab-On-A-Chip Devices, MESH: Microchip Analytical Procedures, Botulinum Toxins, Type A, Surface plasmon resonance, CHIP assay, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Kinetics, Chemistry, Antibodies, Monoclonal, Optical biosensor, MESH: Lab-On-A-Chip Devices, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV] Life Sciences [q-bio], [SDV.TOX]Life Sciences [q-bio]/Toxicology, MESH: Botulinum Toxins, Type A*/immunology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Biosensing Techniques, MESH: Botulinum Toxins*/immunology, MESH: Enzyme Activation, medicine.drug_class, Monoclonal antibody, Sensitivity and Specificity, Article, 03 medical and health sciences, In vivo, Microchip Analytical Procedures, MESH: Antibodies, Monoclonal/immunology, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Humans, MESH: Epitopes/immunology, 010401 analytical chemistry, Serum samples, Molecular biology, MESH: Sensitivity and Specificity, 0104 chemical sciences, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Enzyme Activation, Kinetics, 030104 developmental biology, MESH: Substrate Specificity, Biosensor, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

The enzymatic activity of the pathogenic botulinum neurotoxins type A and E (BoNT/A and E) leads to potentially lethal paralytic symptoms in humans and their prompt detection is of crucial importance. A chip assay based on Surface Plasmon Resonance monitoring of the cleavage products is a simple method that we have previously established to detect BoNT/A activity. We have now developed a similar format assay to measure BoNT/E activity. A monoclonal antibody specifically recognizing SNAP25 cleaved by BoNT/E was generated and used to measure the appearance of the neo-epitope following injection of BoNT/E over SNAP-25 immobilized on a chip. This assay detects BoNT/E activity at 1 LD50/ml within minutes and linear dose-responses curves were obtained using a multiplexed biosensor. A threshold of 0.01 LD50/ml was achieved after 5 h of cleavage. This assay is 10-fold more sensitive than the in vivo assay for direct detection of BoNT/E in serum samples. The SNAP25 chip assay is able to discriminate in an automated manner the presence of BoNT/E, BoNT/A or a combination of both toxins.

Published
2015
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4. Discrimination of agonist and antagonist forms of CXCL10 in biological samples

Author

M. Schmolz, Stanislas Pol, L. Stephen, Matthew L. Albert, James Mapes, Armanda Casrouge, Vincent Mallet, C. Pfister, A. Bisiaux, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Myriad rules based medicine, CHU Rouen, Normandie Université (NU), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Immunologie Humaine (CIH), The work was funded by grants obtained from L'Institut National du Cancer (INCA), the European Research Council (ERC) and a private donation from Caisse de Retraite et de Prévoyance des Clercs et Employés de Notaires (CRPCEN)., The authors would like to thank members of the Centre d'Immunology Humaine (CIH) and the Pôle Integré de Recherche Clinique (PIRC) Institut Pasteur, and the members of the Liver Unit, Hopital Cochin for support of this work., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], and Centre d'Immunologie Humaine ( CIH )

Subjects
Male, MESH: Inflammation, MESH: Carcinoma, Transitional Cell/urine, MESH : Aged, MESH : Hepatitis C, Chronic/blood, Immunoenzyme Techniques, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH : Culture Media, Conditioned/chemistry, MESH: Chemokine CXCL10/analysis, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Protein Isoforms, Multiplex, MESH: Protein Isoforms/immunology, MESH: Culture Media, Conditioned/chemistry, Aged, 80 and over, MESH: Recombinant Fusion Proteins/analysis, 0303 health sciences, MESH: Middle Aged, Antibodies, Monoclonal, Atopic dermatitis, MESH: Enzyme-Linked Immunosorbent Assay/methods, MESH : Protein Isoforms/immunology, Neoplasm Proteins, 3. Good health, MESH : Peptide Fragments/immunology, MESH: Urinary Bladder Neoplasms/urine, MESH : Antibodies, Monoclonal/immunology, bladder cancer, MESH : Protein Structure, Tertiary, Agonist, MESH: Chemokine CXCL10/immunology, MESH: Protein Isoforms/analysis, MESH: Hepatitis C, Chronic/blood, Recombinant Fusion Proteins, Immunology, MESH : Body Fluids/chemistry, 03 medical and health sciences, MESH: Peptide Fragments/immunology, MESH : Immunoenzyme Techniques/methods, MESH: Antibodies, Monoclonal/immunology, Humans, MESH : Middle Aged, MESH : Aged, 80 and over, MESH : Protein Processing, Post-Translational, Aged, MESH : Inflammation, MESH: Humans, MESH : Humans, MESH: Adult, MESH: Peptide Fragments/analysis, medicine.disease, Peptide Fragments, Protein Structure, Tertiary, Chemokine CXCL10, Urinary Bladder Neoplasms, chemokines/monokines, Culture Media, Conditioned, MESH: Dipeptidyl Peptidase 4/metabolism, MESH : Recombinant Fusion Proteins/analysis, MESH: Female, Biomarkers, MESH : Protein Isoforms/analysis, hepatitis C virus, MESH : Carcinoma, Transitional Cell/urine, Translational Studies, MESH: Body Fluids/chemistry, medicine.disease_cause, MESH: Neoplasm Proteins/urine, MESH: Aged, 80 and over, Immunology and Allergy, MESH : Female, BCG, MESH : Biomarkers, MESH: Aged, Predictive marker, MESH : Adult, Middle Aged, Body Fluids, MESH : Neoplasm Proteins/urine, MESH : Enzyme-Linked Immunosorbent Assay/methods, MESH : Chemokine CXCL10/immunology, Biomarker (medicine), [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adult, medicine.drug_class, MESH : Male, Dipeptidyl Peptidase 4, Hepatitis C virus, Enzyme-Linked Immunosorbent Assay, MESH : Chemokine CXCL10/analysis, MESH : Dipeptidyl Peptidase 4/metabolism, medicine, MESH : Urinary Bladder Neoplasms/urine, MESH : Peptide Fragments/analysis, 030304 developmental biology, Inflammation, Carcinoma, Transitional Cell, business.industry, MESH: Immunoenzyme Techniques/methods, Cancer, Hepatitis C, Chronic, MESH: Male, Transplantation, MESH: Protein Processing, Post-Translational, MESH: Biomarkers, business, Protein Processing, Post-Translational, 030215 immunology
Abstract

Summary The ready access to commercially available multiplex assays and the importance of inflammation in disease pathogenesis has resulted in an abundance of studies aimed at identifying surrogate biomarkers for different clinically important questions. Establishing a link between a biomarker and disease pathogenesis, however, is quite complex, and in some instances this complexity is compounded by post-translational modifications and the use of immunoassays that do not always discriminate between the different forms of the same protein. Herein, we provide a detailed description of an assay system that has been established to discriminate the agonist form of CXCL10 from the NH2-terminal truncated form of the molecule generated by dipeptidylpeptidase IV (DPP4) cleavage. We demonstrate the utility of this assay system for monitoring agonist and antagonist forms of CXCL10 in culture supernatant, patient plasma and urine samples. Given the important role of CXCL10 in chronic inflammatory diseases and its suggested role as a predictive marker in managing patients with chronic hepatitis C, asthma, atopic dermatitis, transplantation, tuberculosis, kidney injury, cancer and other diseases, we believe that our method will be of general interest to the research and medical community.

Published
2012
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5. The neutralizing activity of anti-HCV antibodies is modulated by specific glycans on the E2 envelope protein

Author

Helle, Francois, Goffard, Anne, Morel, Virginie, Duverlie, Gilles, Mckeating, Jane, Keck, Zhen-Yong, Foung, Steven, Penin, François, Dubuisson, Jean, Voisset, Cécile, Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, Pathogenèse virale du diabète de type 1 - ULR 3610 (Laboratoire de Virologie), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Amiens-Picardie, University of Birmingham [Birmingham], Department of Pathology [Stanford], Stanford Medicine, Stanford University-Stanford University, 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), This work was supported by the Centre National de la Recherche Scientifique and by the Agence Nationale de Recherche sur le Sida et les Hépatites virales (ANRS) and in part by NIH grants HL079381 and AI47355 to S.F. F.H. and C.V. were supported by fellowships from the French Ministry of Research and the ANRS, respectively. J.D. is an international scholar of the Howard Hughes Medical Institute., We thank Angéline Bilheu and Sophana Ung for their technical assistance. Thanks are also due to Yann Ciczora for his helpful advice and critical comments on the manuscript. We are grateful to B. Bartosch, F. L. Cosset, M. Mondelli, and K. Gustafson for providing us with reagents., and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Epitopes, MESH: Humans, MESH: Hepacivirus/immunology, MESH: Amino Acid Sequence, MESH: Glycosylation, carbohydrates (lipids), MESH: Polysaccharides/immunology, MESH: Viral Envelope Proteins/chemistry, MESH: Antibodies, Monoclonal/immunology, MESH: Viral Envelope Proteins/immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Viral Envelope Proteins/genetics, MESH: Humans Polysaccharides/chemistry, MESH: Hepacivirus/chemistry
Abstract

International audience; Hepatitis C virus (HCV) envelope glycoproteins are highly glycosylated, with up to 5 and 11 N-linked glycans on E1 and E2, respectively. Most of the glycosylation sites on HCV envelope glycoproteins are conserved, and some of the glycans associated with these proteins have been shown to play an essential role in protein folding and HCV entry. Such a high level of glycosylation suggests that these glycans can limit the immunogenicity of HCV envelope proteins and restrict the binding of some antibodies to their epitopes. Here, we investigated whether these glycans can modulate the neutralizing activity of anti-HCV antibodies. HCV pseudoparticles (HCVpp) bearing wild-type glycoproteins or mutants at individual glycosylation sites were evaluated for their sensitivity to neutralization by antibodies from the sera of infected patients and anti-E2 monoclonal antibodies. While we did not find any evidence that N-linked glycans of E1 contribute to the masking of neutralizing epitopes, our data demonstrate that at least three glycans on E2 (denoted E2N1, E2N6, and E2N11) reduce the sensitivity of HCVpp to antibody neutralization. Importantly, these three glycans also reduced the access of CD81 to its E2 binding site, as shown by using a soluble form of the extracellular loop of CD81 in inhibition of entry. These data suggest that glycans E2N1, E2N6, and E2N11 are close to the binding site of CD81 and modulate both CD81 and neutralizing antibody binding to E2. In conclusion, this work indicates that HCV glycans contribute to the evasion of HCV from the humoral immune response.

Published
2007
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6. High-density lipoproteins reduce the neutralizing effect of hepatitis C virus (HCV)-infected patient antibodies by promoting HCV entry

Author

Jean Dubuisson, Marlène Dreux, Anne Op De Beeck, Pauline Horellou, François-Loïc Cosset, Thierry Gustot, Cécile Voisset, Gilles Duverlie, Ngoc Vu-Dac, Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, Virologie moléculaire (HIV-BLV-HTLV) (ULB126), Université libre de Bruxelles (ULB), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Unité de Virologie clinique et fondamentale (UVCF), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, This work was supported by grants from the Agence Nationale de Recherche sur le Sida et les hépatites virales (ANRS), INSERM (ATC ‘hépatite C’) and the Association pour la Recherche sur le Cancer (ARC). C. V. was supported by an ANRS post-doctoral fellowship. J. D. is an international scholar of the Howard Hughes Medical Institute., We thank Czeslaw Wychowski and David Delgrange for their help with the HCVcc system. We also thank Angéline Bilheu, Sophana Ung and André Pillez for excellent technical assistance and Birke Bartosch and Laurence Cocquerel for critical reading of the manuscript. We also thank J. McKeating and T. Wakita for the gift of reagents., Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), and École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Hepacivirus, Hepatitis C virus, In Vitro Techniques, medicine.disease_cause, Neutralization, Virus, MESH: Hepatitis C Antibodies/immunology, 03 medical and health sciences, Flaviviridae, MESH: Hepatitis C/virology, 0302 clinical medicine, Neutralization Tests, Virology, MESH: Antibodies, Monoclonal/immunology, MESH: Hepacivirus/physiology, medicine, Humans, Scavenger receptor, 030304 developmental biology, MESH: In Vitro Techniques, 0303 health sciences, MESH: Hepatitis C/immunology, MESH: Humans, biology, MESH: Hepacivirus/pathogenicity, MESH: Neutralization Tests, Antibodies, Monoclonal, Hepatitis C Antibodies, Scavenger Receptors, Class B, biology.organism_classification, MESH: Lipoproteins, HDL/physiology, Hepatitis C, 3. Good health, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, MESH: Hepatitis C/blood, MESH: Lipoproteins, HDL/immunology, 030211 gastroenterology & hepatology, Antibody, Lipoproteins, HDL, Lipoprotein, MESH: Scavenger Receptors, Class B/physiology
Abstract

The neutralizing activity of anti-hepatitis C virus (HCV) antibodies is attenuated by a factor present in human sera, which has been proposed to be high-density lipoproteins (HDLs). HDLs have also been shown to facilitate the entry of HCV pseudoparticles (HCVpp) into target cells. Here, the aim of the study was to determine whether HDL-mediated facilitation of HCVpp and infectious HCV (HCVcc) entry and attenuation of neutralization are two related phenomena. The data indicated that HDLs attenuate neutralization at a constant rate. In addition, as for HDL-mediated facilitation of HCVpp entry, attenuation of neutralization depended on the expression of the scavenger receptor BI (SR-BI) and its selective lipid-uptake function. Finally, kinetic experiments showed that HDL-mediated facilitation of HCVpp entry is more rapid than virus neutralization. Altogether, these observations indicate that HCV is exploiting the physiological activity of SR-BI for promoting its entry into target cells, which consequently also protects the virus against neutralizing antibodies.

Published
2006
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7. Immunogenicity of HIV Type 1 gp120 CD4 Binding Site Phage Mimotopes

Author

Karim Dorgham, Ismail Dogan, Patrice Debré, Oliver Hartley, Valerie Cardona, Natacha Bitton, Christophe Parizot, Guy Gorochov, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Immunologie cellulaire et tissulaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Européen de Recherche en Virologie et Immunologie [Lyon] (Tour Inserm CERVI), Apoptose et Système Immunitaire (ASI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre médical universitaire de Genève (CMU), and This study was supported by the Swiss National Science Foundation (Project 3339-62032-00), Agence Nationale de Recherche contre le SIDA (ANRS, Paris), INSERM, and Assistance Publique-Hopitaux de Paris.

Subjects
Phage display, MESH: Amino Acid Sequence, HIV Antibodies, HIV Envelope Protein gp120, ddc:616.07, MESH: Base Sequence, Inbred C57BL, Epitope, Bacteriophage, Mice, Bacteriophages, MESH: Animals, MESH: Immunoglobulin G/immunology, Immunoglobulin G/immunology, CD4/metabolism, 0303 health sciences, Mimotope, Immunogenicity, Antibodies, Monoclonal, MESH: CD4 Antigens/metabolism, MESH: Peptides/immunology, 3. Good health, Infectious Diseases, MESH: HIV Antibodies/blood, CD4 Antigens, MESH: Immunization, Female, HIV Envelope Protein gp120/chemistry/immunology/metabolism, medicine.drug_class, Immunology, Molecular Sequence Data, Biology, Monoclonal antibody, Antibodies, MESH: Peptides/chemistry, 03 medical and health sciences, Peptide Library, MESH: Mice, Inbred C57BL, Virology, MESH: Antibodies, Monoclonal/immunology, medicine, Consensus sequence, Animals, Humans, Amino Acid Sequence, Antigens, Peptide library, MESH: Mice, 030304 developmental biology, Peptides/chemical synthesis/chemistry/immunology, Binding Sites, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, 030306 microbiology, MESH: HIV Envelope Protein gp120/immunology, MESH: Peptides/chemical synthesis, Bacteriophages/genetics, biology.organism_classification, Molecular biology, MESH: HIV Envelope Protein gp120/chemistry, Mice, Inbred C57BL, MESH: Bacteriophages/genetics, MESH: Binding Sites, Immunoglobulin G, Immunization, Monoclonal/immunology, MESH: Peptide Library, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Peptides, HIV Antibodies/blood, MESH: HIV Envelope Protein gp120/metabolism, MESH: Female
Abstract

International audience; The conserved domain of the CD4 binding site (CD4bs) on the human immunodeficiency virus type 1 (HIV- 1) envelope represents a potential target for vaccine development. Here we describe selection of peptide mimotopes by panning a phage peptide library on the HIV-1 CD4bs-specific, broadly neutralizing anti-HIV-1 monoclonal antibody, IgG1 b12. We identified an initial consensus sequence for IgG1 b12 binding (M/VΘSD, where Θ represents an aromatic amino acid). A molecular evolution approach, using second- and third-generation libraries, led us to identify a refined consensus sequence (GLLVWSDEL). The resulting IgG1 b12 phage mimotopes compete with gp160 for the IgG1 b12 antigen-binding site, but the phage coat protein (pIII) may play an important structural role, since both free peptides and KLH-conjugated peptides have no detectable binding activity. Mice immunized with IgG1 b12 phage mimotopes elicited a weak but persistent humoral response directed against the HIV-1 envelope. An antibody fragment was isolated from the antibody repertoires of these animals. It is noteworthy that while it has a relatively low affinity for HIV-1 gp160, the antibody targets an epitope that overlaps with that of IgG1 b12. Our data therefore suggest that engineered IgG1 b12 mimotopes share immunogenic features with the CD4bs. However, these peptidic structures will require further improvement in order to generate broad specificity neutralizing antibodies like IgG1 b12.

Published
2005
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