45 results on '"Reynard S"'
Search Results
2. One-shot immunization using a Measles/Lassa vaccine fully protects cynomolgus monkeys against Lassa fever
- Author
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Mateo, M., primary, Reynard, S., additional, Baillet, N., additional, Carnec, X., additional, Fizet, A., additional, Jourdain, M., additional, Picard, C., additional, Schaeffer, J., additional, Barrot, L., additional, Barron, S., additional, Vallve, A., additional, Raoul, H., additional, Carbonnelle, C., additional, Tangy, F., additional, and Baize, S., additional
- Published
- 2019
- Full Text
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3. Directed evolution of prenylated FMN-dependent Fdc supports efficient in vivo isobutene production
- Author
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Annica Saaret, Benoît Villiers, François Stricher, Macha Anissimova, Mélodie Cadillon, Reynard Spiess, Sam Hay, and David Leys
- Subjects
Science - Abstract
Isobutene is a high value gaseous alkene that is widely used as fuel additive and a chemical building block. Here, the authors report an alternative pathway for isobutene bioproduction by directed evolution of prenylated FMN-dependent ferulic acid decarboxylase.
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- 2021
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4. Wild birds and West Nile virus in the Western Palearctic: the example of the Camargue area
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Jourdain, Elsa, Sabatier, P., Zeller, H., Schuffenecker, I., Korimbocus, J., Murri, Severine, Reynard, S., Toussaint, Y., Kayser, Y., Leblond, Agnès, Bicout, D., Gauthier-Clerc, M., Centre de Recherche de la Tour du Valat (CRTV), Ecole Nationale Vétérinaire de Lyon (ENVL), Institut Pasteur [Paris], Unité de Recherche d'Épidémiologie Animale (UR EpiA), Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration
- Subjects
[SDV] Life Sciences [q-bio] ,wild bird ,[SDV]Life Sciences [q-bio] ,western paleartic ,west nile virus ,ComputingMilieux_MISCELLANEOUS ,camargue - Abstract
International audience
- Published
- 2007
5. Birds and West Nile virus in a Mediterranean wetland, the Camargue
- Author
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Jourdain, Elsa, Zeller, H, Sabatier, P, Kayser, Y, Grège, O, Murri, S, Toussaint, Y, Reynard, S, Bicout, D, Leblond, A, Gauthier-Clerc, M, Martel, Anne-Sophie, Environnement et Prédiction de la Santé des Populations (TIMC-IMAG-EPSP), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), École nationale vétérinaire - Alfort (ENVA), Centre de Recherche de la Tour du Valat (CRTV), Institut Pasteur de Lyon, Réseau International des Instituts Pasteur (RIIP), Unité biomathématiques et épidémiologie, Ecole Nationale Vétérinaire de Lyon (ENVL), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Institut Pasteur [Paris], and Ecole Nationale Vétérinaire
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[SDV] Life Sciences [q-bio] ,[SDV]Life Sciences [q-bio] ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2006
6. Mission archéologique franco-ouzbèque de Bactriane septentrionale : Rapport 11 (2003)
- Author
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Leriche, Pierre, Pidaev, Sakirdzan Rasulevic, Abdullaev, Kazim, Appert, S., Baudoin, S., Facquez, Dorothée, Gavison, Sarah, Houal, Jean-Baptiste, Leriche, Anne, Lopez Prat, M., Moustafakoulov, Samareddine, Mouradova, D. H., Person, T., Reynard, S., Rohmer, Jérôme, Scherrer-Schaub, Cristina, Archéologies d'Orient et d'Occident et Sciences des textes (AOROC), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut d'Archéologie de l'Académie des Sciences d'Ouzbékistan, Académie des Sciences, Institut de France-Institut de France, Laboratoire des Matériaux Céramiques et Procédés Associés - EA 2443 (LMCPA), Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-INSA Institut National des Sciences Appliquées Hauts-de-France (INSA Hauts-De-France), Archéologies et Sciences de l'Antiquité (ArScAn), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris Nanterre (UPN)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Académie des Sciences [Paris], Université de Valenciennes et du Hainaut-Cambrésis (UVHC), and Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Ministère de la Culture et de la Communication (MCC)-Institut national de recherches archéologiques préventives (Inrap)-Centre National de la Recherche Scientifique (CNRS)
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Tchingiz Tepe ,[SHS.ARCHEO]Humanities and Social Sciences/Archaeology and Prehistory ,bouddhisme ,fortification ,temple (en) ,sépulture ,kiln (en) ,Bactriane ,céramique hellénistique ,burial (en) ,temple ,Buddhism (en) ,lion (en) ,fortification (en) ,lion ,Termez (en) ,citadelle ,Bactria (en) ,four ,Islamic World (en) ,protome (en) ,ép islamique ,Termez ,Tchingiz Tepe (en) ,Payon Kourgane ,protomé ,citadel (en) - Abstract
Rapport de mission illustré (cartes, plans, photographies).; This report describes the excavations at Termez, in the citadel (Hellenistic ware, burial in the Islamic World) ; at Tchingiz Tepe (fortification, temple, kiln, lion's protome). It deals with the Bactrian buddhism.; Ce rapport décrit les fouilles de Termez, dans la citadelle (céramique hellénistique, sépultures de l'époque islamique) ; à Tchingiz Tepe (fortifications, temple, four, protomé de lion) et à Payon Kourgane. Il traite aussi du bouddhisme en Bactriane.
- Published
- 2003
7. Characterization of Melan-A reactive memory CD8+ T cells in a healthy donor
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Voelter, V., primary, Rufer, N., additional, Reynard, S., additional, Greub, G., additional, Brookes, R., additional, Guillaume, P., additional, Grosjean, F., additional, Fagerberg, T., additional, Michelin, O., additional, Rowland-Jones, S., additional, Pinilla, C., additional, Leyvraz, S., additional, Romero, P., additional, and Appay, V., additional
- Published
- 2008
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8. West Nile Virus in Wild Resident Birds, Southern France, 2004
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Jourdain, E., primary, Schuffenecker, I., additional, Korimbocus, J., additional, Reynard, S., additional, Murri, S., additional, Kayser, Y., additional, Gauthier-Clerc, M., additional, Sabatier, P., additional, and Zeller, H.G., additional
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- 2007
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9. Optimumin vitroexpansion of human antigen-specific CD8+ T cells for adoptive transfer therapy
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Montes, M, primary, Rufer, N, additional, Appay, V, additional, Reynard, S, additional, Pittet, M J, additional, Speiser, D E, additional, Guillaume, P, additional, Cerottini, J-C, additional, Romero, P, additional, and Leyvraz, S, additional
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- 2005
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10. Optimum in vitro expansion of human antigen-specific CD8+ T cells for adoptive transfer therapy.
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Montes, M., Rufer, N., Appay, V., Reynard, S., Pittet, M. J., Speiser, D. E., Guillaume, P., Cerottini, J.-C., Romero, P., and Leyvraz, S.
- Subjects
T cells ,ANTIGENS ,VIRUS diseases ,CYTOKINES ,LYMPHOCYTES - Abstract
Increasing evidence suggests that adoptive transfer of antigen-specific CD8
+ T cells could represent an effective strategy in the fight against chronic viral infections and malignancies such as melanoma. None the less, a major limitation in the implementation of such therapy resides in the difficulties associated with achieving rapid and efficient expansion of functional T cells in culture necessary to obtain the large numbers required for intravenous infusion. Recently, the critical role of the cytokines interleukin (IL)-2, IL-7 and IL-15 in driving T cell proliferation has been emphasized, thus suggesting their use in the optimization of expansion protocols. We have used major histocompatibility complex (MHC) class I/peptide multimers to monitor the expansion of antigen-specific CD8 T lymphocytes from whole blood, exploring the effect of antigenic peptide dose, IL-2, IL-7 and IL-15 concentrations on the magnitude and functional characteristics of the antigen-specific CD8+ T cells generated. We show here that significant expansions of antigen-specific T cells, up to 50% of the CD8+ T cell population, can be obtained after a single round of antigen/cytokine (IL-2 or IL-15) stimulation, and that these cells display good cytolytic and interferon (IFN)-γ secretion capabilities. Our results provide an important basis for the rapid in vitro expansion of autologous T cells from the circulating lymphocyte pool using a simple procedure, which is necessary for the development of adoptive transfer therapies. [ABSTRACT FROM AUTHOR]- Published
- 2005
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11. The Dona Marika Oil Spill
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Baker, J. M., Blackman, R. A. A., Jelly, J., and Reynard, S.
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- 1973
12. A vaccine targeting antigen-presenting cells through CD40 induces protective immunity against Nipah disease.
- Author
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Pastor Y, Reynard O, Iampietro M, Surenaud M, Picard F, El Jahrani N, Lefebvre C, Hammoudi A, Dupaty L, Brisebard É, Reynard S, Moureaux É, Moroso M, Durand S, Gonzalez C, Amurri L, Gallouët AS, Marlin R, Baize S, Chevillard E, Raoul H, Hocini H, Centlivre M, Thiébaut R, Horvat B, Godot V, Lévy Y, and Cardinaud S
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- Animals, Chlorocebus aethiops, T-Lymphocytes, Antibody Formation, Antigen-Presenting Cells, Virus Replication, Viral Vaccines
- Abstract
Nipah virus (NiV) has been recently ranked by the World Health Organization as being among the top eight emerging pathogens likely to cause major epidemics, whereas no therapeutics or vaccines have yet been approved. We report a method to deliver immunogenic epitopes from NiV through the targeting of the CD40 receptor of antigen-presenting cells by fusing a selected humanized anti-CD40 monoclonal antibody to the Nipah glycoprotein with conserved NiV fusion and nucleocapsid peptides. In the African green monkey model, CD40.NiV induces specific immunoglobulin A (IgA) and IgG as well as cross-neutralizing responses against circulating NiV strains and Hendra virus and T cell responses. Challenge experiments using a NiV-B strain demonstrate the high protective efficacy of the vaccine, with all vaccinated animals surviving and showing no significant clinical signs or virus replication, suggesting that the CD40.NiV vaccine conferred sterilizing immunity. Overall, results obtained with the CD40.NiV vaccine are highly promising in terms of the breadth and efficacy against NiV., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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13. Hemostasis defects underlying the hemorrhagic syndrome caused by mammarenaviruses in a cynomolgus macaque model.
- Author
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Lafoux B, Baillet N, Picard C, Fourcaud G, Borges-Cardoso V, Reynard S, Journeaux A, Germain C, Perthame E, Mateo M, Hortion J, Carnec X, Pietrosemoli N, Moroso M, Lacroix O, Jourjon O, Barron S, Vallve A, Duthey A, Jacquot F, Barrot L, Dirheimer M, Raoul H, Nougier C, and Baize S
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- Animals, Hemorrhage etiology, Hemostasis, Macaca, Arenaviridae, Arenavirus, Hemorrhagic Fevers, Viral pathology, Hemostatics
- Abstract
Viral hemorrhagic fevers (HF) are a group of acute febrile diseases with high mortality rates. Although hemostatic dysfunction appears to be a major determinant of the severity of the disease, it is still unclear what pathogenic mechanisms lead to it. In clinical studies it is found that arenaviruses, such as Lassa, Machupo, and Guanarito viruses cause HF that vary in symptoms and biological alterations. In this study we aimed to characterize the hemostatic dysfunction induced by arenaviral HF to determine its implication in the severity of the disease and to elucidate the origin of this syndrome. We found that lethal infection with Machupo, Guanarito, and Lassa viruses is associated with cutaneomucosal, cerebral, digestive, and pulmonary hemorrhages. The affected animals developed a severe alteration of the coagulation system, which was concomitant with acute hepatitis, minor deficit of hepatic factor synthesis, presence of a plasmatic inhibitor of coagulation, and dysfunction of the fibrinolytic system. Despite signs of increased vascular permeability, endothelial cell infection was not a determinant factor of the hemorrhagic syndrome. There were also alterations of the primary hemostasis during lethal infection, with moderate to severe thrombocytopenia and platelet dysfunction. Finally, we show that lethal infection is accompanied by a reduced hematopoietic potential of the bone marrow. This study provides an unprecedented characterization of the hemostasis defects induced by several highly pathogenic arenaviruses., (© 2023 by The American Society of Hematology.)
- Published
- 2023
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14. Endoscopic submucosal dissection of esophageal squamous cell carcinoma with superficial capillary changes and epithelialization after chemotherapy for pancreatic adenocarcinoma.
- Author
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Lupu A, Reynard S, Rivory J, Lafeuille P, Grimaldi J, Yzet C, and Pioche M
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- Humans, Treatment Outcome, Retrospective Studies, Pancreatic Neoplasms, Esophageal Squamous Cell Carcinoma surgery, Adenocarcinoma drug therapy, Adenocarcinoma surgery, Adenocarcinoma pathology, Esophageal Neoplasms surgery, Esophageal Neoplasms pathology, Endoscopic Mucosal Resection adverse effects, Pancreatic Neoplasms surgery
- Abstract
Competing Interests: The authors declare that they have no conflict of interest.
- Published
- 2023
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15. Immunogenicity, safety, and tolerability of a recombinant measles-vectored Lassa fever vaccine: a randomised, placebo-controlled, first-in-human trial.
- Author
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Tschismarov R, Van Damme P, Germain C, De Coster I, Mateo M, Reynard S, Journeaux A, Tomberger Y, Withanage K, Haslwanter D, Terler K, Schrauf S, Müllner M, Tauber E, Ramsauer K, and Baize S
- Subjects
- Adult, Humans, Measles Vaccine, Vaccines, Synthetic, Vaccines, Attenuated, Double-Blind Method, Antibodies, Viral, Lassa Fever, Measles
- Abstract
Background: Lassa fever is a substantial health burden in west Africa. We evaluated the safety, tolerability, and immunogenicity of a recombinant, live-attenuated, measles-vectored Lassa fever vaccine candidate (MV-LASV)., Methods: This first-in-human phase 1 trial-consisting of an open-label dose-escalation stage and an observer-blinded, randomised, placebo-controlled treatment stage-was conducted at a single site at the University of Antwerp, Antwerp, Belgium, and involved healthy adults aged 18-55 years. Participants in the dose-escalation stage were sequentially assigned to a low-dose group (two intramuscular doses of MV-LASV at 2 × 10
4 times the median tissue culture infectious dose) or a high-dose group (two doses at 1 × 105 times the median tissue culture infectious dose). Participants in the double-blinded treatment stage were randomly assigned in a 2:2:1 ratio to receive low dose, high dose, or placebo. The primary endpoint was the rate of solicited and unsolicited adverse events up to study day 56 and was assessed in all participants who received at least one dose of investigational product. The trial is registered with ClinicalTrials.gov, NCT04055454, and the European Union Drug Regulating Authorities Clinical Trials Database, 2018-003647-40, and is complete., Findings: Between Sept 26, 2019, and Jan 20, 2020, 60 participants were enrolled and assigned to receive placebo (n=12) or MV-LASV (n=48). All 60 participants received at least one study treatment. Most adverse events occurred during the treatment phase, and frequencies of total solicited or unsolicited adverse events were similar between treatment groups, with 96% of participants in the low-dose group, 100% of those in the high-dose group, and 92% of those in the placebo group having any solicited adverse event (p=0·6751) and 76% of those in the low-dose group, 70% of those in the high-dose group, and 100% of those in the placebo group having any unsolicited adverse event (p=0·1047). The only significant difference related to local solicited adverse events, with higher frequencies observed in groups receiving MV-LASV (24 [96%] of 25 participants in the low-dose group; all 23 [100%] participants in the high-dose group) than in the placebo group (6 [50%] of 12 participants; p=0·0001, Fisher-Freeman-Halton test). Adverse events were mostly of mild or moderate severity, and no serious adverse events were observed. MV-LASV also induced substantial concentrations of LASV-specific IgG (geometric mean titre 62·9 EU/ml in the low-dose group and 145·9 EU/ml in the high-dose group on day 42)., Interpretation: MV-LASV showed an acceptable safety and tolerability profile, and immunogenicity seemed to be unaffected by pre-existing immunity against the vector. MV-LASV is therefore a promising candidate for further development., Funding: Coalition for Epidemic Preparedness Innovations., Competing Interests: Declaration of interests RT, YT, DH, SS, KT, MMü, ET, and KR are employees of Themis Bioscience, a subsidiary of Merck & Co, Rahway, NJ, USA. SB and MMa are inventors of US patent 20200308555 protecting the MV-LASV vaccine candidate. RT, MMü, ET, SS, YT, and KR possess stock options of Merck & Co, Rahway, NJ, USA., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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16. Rapid protection induced by a single-shot Lassa vaccine in male cynomolgus monkeys.
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Mateo M, Reynard S, Pietrosemoli N, Perthame E, Journeaux A, Noy K, Germain C, Carnec X, Picard C, Borges-Cardoso V, Hortion J, Lopez-Maestre H, Regnard P, Fellmann L, Vallve A, Barron S, Jourjon O, Lacroix O, Duthey A, Dirheimer M, Daniau M, Legras-Lachuer C, Carbonnelle C, Raoul H, Tangy F, and Baize S
- Subjects
- Lassa virus immunology, Male, Animals, Macaca fascicularis, Viral Vaccines administration & dosage, Viral Vaccines immunology, Nucleoproteins immunology, Immunity, Humoral, Virus Replication, T-Lymphocytes immunology, Killer Cells, Natural immunology, Transcriptome, Lassa Fever immunology, Lassa Fever prevention & control
- Abstract
Lassa fever hits West African countries annually in the absence of licensed vaccine to limit the burden of this viral hemorrhagic fever. We previously developed MeV-NP, a single-shot vaccine protecting cynomolgus monkeys against divergent strains one month or more than a year before Lassa virus infection. Given the limited dissemination area during outbreaks and the risk of nosocomial transmission, a vaccine inducing rapid protection could be useful to protect exposed people during outbreaks in the absence of preventive vaccination. Here, we test whether the time to protection can be reduced after immunization by challenging measles virus pre-immune male cynomolgus monkeys sixteen or eight days after a single shot of MeV-NP. None of the immunized monkeys develop disease and they rapidly control viral replication. Animals immunized eight days before the challenge are the best controllers, producing a strong CD8 T-cell response against the viral glycoprotein. A group of animals was also vaccinated one hour after the challenge, but was not protected and succumbed to the disease as the control animals. This study demonstrates that MeV-NP can induce a rapid protective immune response against Lassa fever in the presence of MeV pre-existing immunity but can likely not be used as therapeutic vaccine., (© 2023. The Author(s).)
- Published
- 2023
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17. A MOPEVAC multivalent vaccine induces sterile protection against New World arenaviruses in non-human primates.
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Reynard S, Carnec X, Picard C, Borges-Cardoso V, Journeaux A, Mateo M, Germain C, Hortion J, Albrecht L, Perthame E, Pietrosemoli N, Vallvé A, Barron S, Duthey A, Lacroix O, Jourjon O, Moroso M, Fellmann L, Moreau PH, Daniau M, Legras-Lachuer C, Dirheimer M, Carbonnelle C, Raoul H, and Baize S
- Subjects
- Animals, Vaccines, Combined, Macaca fascicularis metabolism, Antibodies, Neutralizing, Glycoproteins, Arenaviruses, New World metabolism
- Abstract
Pathogenic New World arenaviruses (NWAs) cause haemorrhagic fevers and can have high mortality rates, as shown in outbreaks in South America. Neutralizing antibodies (Abs) are critical for protection from NWAs. Having shown that the MOPEVAC vaccine, based on a hyperattenuated arenavirus, induces neutralizing Abs against Lassa fever, we hypothesized that expression of NWA glycoproteins in this platform might protect against NWAs. Cynomolgus monkeys immunized with MOPEVAC
MAC , targeting Machupo virus, prevented the lethality of this virus and induced partially NWA cross-reactive neutralizing Abs. We then developed the pentavalent MOPEVACNEW vaccine, expressing glycoproteins from all pathogenic South American NWAs. Immunization of cynomolgus monkeys with MOPEVACNEW induced neutralizing Abs against five NWAs, strong innate followed by adaptive immune responses as detected by transcriptomics and provided sterile protection against Machupo virus and the genetically distant Guanarito virus. MOPEVACNEW may thus be efficient to protect against existing and potentially emerging NWAs., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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18. Pathogenesis of recent Lassa virus isolates from lineages II and VII in cynomolgus monkeys.
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Mateo M, Hortion J, Perthame E, Picard C, Reynard S, Journeaux A, Germain C, Carnec X, Baillet N, Borges-Cardoso V, Pietrosemoli N, Vallve A, Barron S, Jourjon O, Lacroix O, Duthey A, Dirheimer M, Daniau M, Legras-Lachuer C, Jouvion G, Carbonnelle C, Raoul H, and Baize S
- Subjects
- Animals, Humans, Macaca fascicularis, Virus Replication, Lassa Fever, Lassa virus genetics
- Abstract
The area of Lassa virus (LASV) circulation is expanding, with the emergence of highly pathogenic new LASV lineages. Benin recently became an endemic country for LASV and has seen the emergence of a new LASV lineage (VII). The first two outbreaks in 2014 and 2016 showed a relatively high mortality rate compared to other outbreaks. We infected cynomolgus monkeys with two strains belonging to lineage II and lineage VII that were isolated from deceased patients during the 2016 outbreak in Benin. The lineage VII strain (L7) caused uniform mortality. Death was associated with uncontrolled viral replication, unbalanced inflammatory responses characterized by increased concentrations of pro- and anti-inflammatory mediators, and the absence of efficient immune responses, resembling the pathogenesis associated with the prototypic Josiah strain in monkeys. The lineage II strain (L2) showed apparently lower virulence than its counterpart, with a prolonged time to death and a lower mortality rate. Prolonged survival was associated with better control of viral replication, a moderate inflammatory response, and efficient T -cell responses. Transcriptomic analyses also highlighted important differences in the immune responses associated with the outcome. Both strains caused strong inflammation in several organs. Notably, meningitis and encephalitis were observed in the cerebral cortex and cerebellum in all monkeys, independently of the outcome. Due to their apparently high pathogenicity, emerging strains from lineage VII should be considered in preclinical vaccine testing. Lineage II would also be beneficial in pathogenesis studies to study the entire spectrum of Lassa fever severity.
- Published
- 2022
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19. Digital Interventions for Emotion Regulation in Children and Early Adolescents: Systematic Review and Meta-analysis.
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Reynard S, Dias J, Mitic M, Schrank B, and Woodcock KA
- Abstract
Background: Difficulties in emotion regulation are common in adolescence and are associated with poor social and mental health outcomes. However, psychological therapies that promote adaptive emotion regulation may be inaccessible and unattractive to youth. Digital interventions may help address this need., Objective: The aim of this systematic review and meta-analysis was to synthesize evidence on the efficacy, feasibility, and acceptability of emotion regulation digital interventions in children and early adolescents aged 8 to 14 years., Methods: Systematic searches of Web of Science, MEDLINE, PsycINFO, EMBASE, Education Resources Information Centre, ACM Digital Library, and IEEE Xplore up to July 2020 identified 39 studies, of which 11 (28%) were included in the meta-analyses (n=2476 participants). A bespoke tool was used to assess risk of bias., Results: The studies evaluated digital games (27/39, 69%), biofeedback (4/39, 10%), virtual or augmented reality (4/39, 10%), and program or multimedia (4/39, 10%) digital interventions in samples classified as diagnosed, at risk, healthy, and universal. The most consistent evidence came from digital games, which reduced negative emotional experience with a small significant effect, largely in youth at risk of anxiety (Hedges g=-0.19, 95% CI -0.34 to -0.04). In general, digital interventions tended to improve emotion regulation, but this effect was not significant (Hedges g=0.19, 95% CI -0.16 to 0.54)., Conclusions: Most feasibility issues were identified in diagnosed youth, and acceptability was generally high across intervention types and samples. Although there is cause to be optimistic about digital interventions supporting the difficulties that youth experience in emotion regulation, the predominance of early-stage development studies highlights the need for more work in this area., (©Sally Reynard, Joao Dias, Marija Mitic, Beate Schrank, Kate Anne Woodcock. Originally published in JMIR Serious Games (https://games.jmir.org), 19.08.2022.)
- Published
- 2022
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20. A single-shot Lassa vaccine induces long-term immunity and protects cynomolgus monkeys against heterologous strains.
- Author
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Mateo M, Reynard S, Journeaux A, Germain C, Hortion J, Carnec X, Picard C, Baillet N, Borges-Cardoso V, Merabet O, Vallve A, Barron S, Jourjon O, Lacroix O, Duthey A, Dirheimer M, Jouvion G, Moreau PH, Fellmann L, Carbonnelle C, Raoul H, Tangy F, and Baize S
- Subjects
- Africa, Western, Animals, Lassa virus, Macaca fascicularis, Nucleoproteins, Lassa Fever prevention & control, Viral Vaccines immunology
- Abstract
A safe and protective Lassa virus vaccine is crucially needed in Western Africa to stem the recurrent outbreaks of Lassa virus infections in Nigeria and the emergence of Lassa virus in previously unaffected countries, such as Benin and Togo. Major challenges in developing a Lassa virus vaccine include the high diversity of circulating strains and their reemergence from 1 year to another. To address each of these challenges, we immunized cynomolgus monkeys with a measles virus vector expressing the Lassa virus glycoprotein and nucleoprotein of the prototypic Lassa virus strain Josiah (MeV-NP). To evaluate vaccine efficacy against heterologous strains of Lassa virus, we challenged the monkeys a month later with heterologous strains from lineage II or lineage VII, finding that the vaccine was protective against these strains. A second cohort of monkeys was challenged 1 year later with the homologous Josiah strain, finding that a single dose of MeV-NP was sufficient to protect all vaccinated monkeys. These studies demonstrate that MeV-NP can generate both long-lasting immune responses and responses that are able to protect against diverse strains of Lassa virus., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2021
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21. Early control of viral load by favipiravir promotes survival to Ebola virus challenge and prevents cytokine storm in non-human primates.
- Author
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Reynard S, Gloaguen E, Baillet N, Madelain V, Guedj J, Raoul H, de Lamballerie X, Mullaert J, and Baize S
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- Animals, Cytokines blood, Disease Models, Animal, Hemorrhagic Fever, Ebola pathology, Hemorrhagic Fever, Ebola veterinary, Macaca fascicularis, T-Lymphocytes immunology, Viremia blood, Viremia pathology, Virus Replication drug effects, Amides pharmacology, Antiviral Agents pharmacology, Cytokine Release Syndrome prevention & control, Ebolavirus drug effects, Hemorrhagic Fever, Ebola drug therapy, Pyrazines pharmacology, Viral Load drug effects
- Abstract
Ebola virus has been responsible for two major epidemics over the last several years and there has been a strong effort to find potential treatments that can improve the disease outcome. Antiviral favipiravir was thus tested on non-human primates infected with Ebola virus. Half of the treated animals survived the Ebola virus challenge, whereas the infection was fully lethal for the untreated ones. Moreover, the treated animals that did not survive died later than the controls. We evaluated the hematological, virological, biochemical, and immunological parameters of the animals and performed proteomic analysis at various timepoints of the disease. The viral load strongly correlated with dysregulation of the biological functions involved in pathogenesis, notably the inflammatory response, hemostatic functions, and response to stress. Thus, the management of viral replication in Ebola virus disease is of crucial importance in preventing the immunopathogenic disorders and septic-like shock syndrome generally observed in Ebola virus-infected patients., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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22. Systemic viral spreading and defective host responses are associated with fatal Lassa fever in macaques.
- Author
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Baillet N, Reynard S, Perthame E, Hortion J, Journeaux A, Mateo M, Carnec X, Schaeffer J, Picard C, Barrot L, Barron S, Vallve A, Duthey A, Jacquot F, Boehringer C, Jouvion G, Pietrosemoli N, Legendre R, Dillies MA, Allan R, Legras-Lachuer C, Carbonnelle C, Raoul H, and Baize S
- Subjects
- Adaptive Immunity, Animals, Biomarkers metabolism, Female, Immunity, Innate, Lassa Fever blood, Lassa Fever pathology, Lung pathology, Lymphoid Tissue pathology, Male, Transcriptome, Disease Models, Animal, Lassa Fever immunology, Lassa Fever virology, Macaca fascicularis
- Abstract
Lassa virus (LASV) is endemic in West Africa and induces a viral hemorrhagic fever (VHF) with up to 30% lethality among clinical cases. The mechanisms involved in control of Lassa fever or, in contrast, the ensuing catastrophic illness and death are poorly understood. We used the cynomolgus monkey model to reproduce the human disease with asymptomatic to mild or fatal disease. After initial replication at the inoculation site, LASV reached the secondary lymphoid organs. LASV did not spread further in nonfatal disease and was rapidly controlled by balanced innate and T-cell responses. Systemic viral dissemination occurred during severe disease. Massive replication, a cytokine/chemokine storm, defective T-cell responses, and multiorgan failure were observed. Clinical, biological, immunological, and transcriptomic parameters resembled those observed during septic-shock syndrome, suggesting that similar pathogenesis is induced during Lassa fever. The outcome appears to be determined early, as differentially expressed genes in PBMCs were associated with fatal and non-fatal Lassa fever outcome very early after infection. These results provide a full characterization and important insights into Lassa fever pathogenesis and could help to develop early diagnostic tools.
- Published
- 2021
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23. Vaccines inducing immunity to Lassa virus glycoprotein and nucleoprotein protect macaques after a single shot.
- Author
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Mateo M, Reynard S, Carnec X, Journeaux A, Baillet N, Schaeffer J, Picard C, Legras-Lachuer C, Allan R, Perthame E, Hillion KH, Pietrosemoli N, Dillies MA, Barrot L, Vallve A, Barron S, Fellmann L, Gaillard JC, Armengaud J, Carbonnelle C, Raoul H, Tangy F, and Baize S
- Subjects
- Animals, Cell Line, Flow Cytometry, Humans, Lassa Fever immunology, Lassa Fever prevention & control, Lassa Fever virology, Lassa virus, Macaca fascicularis, Male, Proteomics, Transcriptome, Vaccination methods, Glycoproteins immunology, Nucleoproteins immunology, Viral Proteins immunology
- Abstract
Lassa fever is a major threat in Western Africa. The large number of people living at risk for this disease calls for the development of a vaccine against Lassa virus (LASV). We generated live-attenuated LASV vaccines based on measles virus and Mopeia virus platforms and expressing different LASV antigens, with the aim to develop a vaccine able to protect after a single shot. We compared the efficacy of these vaccines against LASV in cynomolgus monkeys. The vaccines were well tolerated and protected the animals from LASV infection and disease after a single immunization but with varying efficacy. Analysis of the immune responses showed that complete protection was associated with robust secondary T cell and antibody responses against LASV. Transcriptomic and proteomic analyses showed an early activation of innate immunity and T cell priming after immunization with the most effective vaccines, with changes detectable as early as 2 days after immunization. The most efficacious vaccine candidate, a measles vector simultaneously expressing LASV glycoprotein and nucleoprotein, has been selected for further clinical evaluation., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2019
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24. Non-Pathogenic Mopeia Virus Induces More Robust Activation of Plasmacytoid Dendritic Cells than Lassa Virus.
- Author
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Schaeffer J, Reynard S, Carnec X, Pietrosemoli N, Dillies MA, and Baize S
- Subjects
- Cells, Cultured, Humans, Interferon Type I immunology, Dendritic Cells virology, Lassa virus immunology, Lymphocyte Activation, Virus Replication immunology
- Abstract
Lassa virus (LASV) causes a viral haemorrhagic fever in humans and is a major public health concern in West Africa. An efficient immune response to LASV appears to rely on type I interferon (IFN-I) production and T-cell activation. We evaluated the response of plasmacytoid dendritic cells (pDC) to LASV, as they are an important and early source of IFN-I. We compared the response of primary human pDCs to LASV and Mopeia virus (MOPV), which is very closely related to LASV, but non-pathogenic. We showed that pDCs are not productively infected by either MOPV or LASV, but produce IFN-I. However, the activation of pDCs was more robust in response to MOPV than LASV. In vivo, pDC activation may support the control of viral replication through IFN-I production, but also improve the induction of a global immune response. Therefore, pDC activation could play a role in the control of LASV infection.
- Published
- 2019
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25. Immune parameters and outcomes during Ebola virus disease.
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Reynard S, Journeaux A, Gloaguen E, Schaeffer J, Varet H, Pietrosemoli N, Mateo M, Baillet N, Laouenan C, Raoul H, Mullaert J, and Baize S
- Abstract
Background: The West African Ebola virus epidemic from 2014-2016 highlighted the lack of knowledge about the pathogenicity of the virus and the factors responsible for outcome. A performant and rapid diagnosis is of crucial importance, as is overcoming the difficulty of providing high-quality patient management during such an extensive outbreak. Here, we propose to study the role of the immune mediators during Ebola virus disease and to define some molecules of importance in the outcome., Methods: Plasma from Guinean patients sampled during the outbreak were analyzed using RT-qPCR, magnetic bead assay, ELISA, and high-quality statistical analyses. We also performed a transcriptomic analysis in leukocytes samples. Therefore, we deeply characterized the immune responses involved in Ebola virus disease., Results: We evaluated the immune patterns depending on the outcome of the disease. Survivors presented an efficient and well-balanced immune response, whereas fatalities were characterized by an intense inflammatory response, overexpression of multiple cytokines, and a "chemokine storm." The plasma concentration of most of the parameters tested increased until death. Statistical analyses also allowed us to define a panel of markers highly predictive of outcome., Conclusion: The immune response observed in fatalities was highly similar to that characterizing septic shock syndrome. Our results suggest that immune responses can play a major pathogenic role during severe Ebola virus infection and argue in favor of therapeutic approaches that act on both viral replication and the induction of shock syndrome., Funding: French Ministry of Foreign Affairs, the Agence Française de Développement, and the Institut Pasteur.
- Published
- 2019
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26. Lassa virus activates myeloid dendritic cells but suppresses their ability to stimulate T cells.
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Schaeffer J, Carnec X, Reynard S, Mateo M, Picard C, Pietrosemoli N, Dillies MA, and Baize S
- Subjects
- Antiviral Agents, Arenaviridae immunology, Dendritic Cells virology, Healthy Volunteers, Hemorrhagic Fevers, Viral virology, Humans, Interferon Type I, Interferon-alpha metabolism, Interferon-beta metabolism, Lassa Fever virology, Lassa virus pathogenicity, Lymphocyte Activation immunology, Lymphocyte Activation physiology, Myeloid Cells virology, Nucleoproteins metabolism, Primary Cell Culture, T-Lymphocytes immunology, Dendritic Cells immunology, Lassa virus immunology, Myeloid Cells immunology
- Abstract
Lassa virus (LASV) is responsible for a viral hemorrhagic fever in humans and the death of 3,000 to 5,000 people every year. The immune response to LASV is poorly understood, but type I interferon (IFN-I) and T-cell responses appear to be critical for the host. We studied the response of myeloid dendritic cells (mDC) to LASV, as mDCs are involved in both IFN-I production and T-cell activation. We compared the response of primary human mDCs to LASV and Mopeia virus (MOPV), which is similar to LASV, but non-pathogenic. We showed that mDCs produced substantial amounts of IFN-I in response to both LASV and MOPV. However, only MOPV-infected mDCs were able to activate T cells. More surprisingly, coculture with T cells completely inhibited the activation of LASV-infected mDCs. These differences between LASV and MOPV were mostly due to the LASV nucleoprotein, which has major immunosuppressive properties, but the glycoprotein was also involved. Overall, these results suggest that mDCs may be important for the global response to LASV and play a role in the outcome of Lassa fever., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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27. Ebola viral dynamics in nonhuman primates provides insights into virus immuno-pathogenesis and antiviral strategies.
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Madelain V, Baize S, Jacquot F, Reynard S, Fizet A, Barron S, Solas C, Lacarelle B, Carbonnelle C, Mentré F, Raoul H, de Lamballerie X, and Guedj J
- Subjects
- Amides pharmacology, Amides therapeutic use, Animals, Antiviral Agents pharmacology, Cytokines metabolism, Disease Models, Animal, Ebolavirus drug effects, Female, Hemorrhagic Fever, Ebola virology, Host-Pathogen Interactions drug effects, Interferon-alpha pharmacology, Interferon-alpha therapeutic use, Macaca, Models, Theoretical, Pyrazines pharmacology, Pyrazines therapeutic use, Survival Analysis, Time Factors, Viral Load drug effects, Viral Load immunology, Antiviral Agents therapeutic use, Ebolavirus immunology, Ebolavirus pathogenicity, Hemorrhagic Fever, Ebola drug therapy, Hemorrhagic Fever, Ebola immunology, Host-Pathogen Interactions immunology
- Abstract
Despite several clinical trials implemented, no antiviral drug could demonstrate efficacy against Ebola virus. In non-human primates, early initiation of polymerase inhibitors favipiravir and remdesivir improves survival, but whether they could be effective in patients is unknown. Here we analyze the impact of antiviral therapy by using a mathematical model that integrates virological and immunological data of 44 cynomolgus macaques, left untreated or treated with favipiravir. We estimate that favipiravir has a ~50% efficacy in blocking viral production, which results in reducing virus growth and cytokine storm while IFNα reduces cell susceptibility to infection. Simulating the effect of delayed initiations of treatment, our model predicts survival rates of 60% for favipiravir and 100% for remdesivir when treatment is initiated within 3 and 4 days post infection, respectively. These results improve the understanding of Ebola immuno-pathogenesis and can help optimize antiviral evaluation in future outbreaks.
- Published
- 2018
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28. A Vaccine Platform against Arenaviruses Based on a Recombinant Hyperattenuated Mopeia Virus Expressing Heterologous Glycoproteins.
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Carnec X, Mateo M, Page A, Reynard S, Hortion J, Picard C, Yekwa E, Barrot L, Barron S, Vallve A, Raoul H, Carbonnelle C, Ferron F, and Baize S
- Subjects
- Animals, Arenaviridae genetics, Cell Line, Chlorocebus aethiops, Cricetinae, Exoribonucleases metabolism, HEK293 Cells, Hemorrhagic Fevers, Viral pathology, Hemorrhagic Fevers, Viral transmission, Hemorrhagic Fevers, Viral virology, Humans, Interferon Type I immunology, Lassa Fever prevention & control, Lassa Fever virology, Macaca fascicularis, Monkey Diseases virology, Vaccination, Vero Cells, Arenaviridae immunology, Hemorrhagic Fevers, Viral immunology, Lassa Fever immunology, Lassa virus immunology, Monkey Diseases immunology, Monkey Diseases prevention & control, Vaccines, Attenuated immunology, Viral Vaccines immunology
- Abstract
Several Old World and New World arenaviruses are responsible for severe endemic and epidemic hemorrhagic fevers, whereas other members of the Arenaviridae family are nonpathogenic. To date, no approved vaccines, antivirals, or specific treatments are available, except for Junín virus. However, protection of nonhuman primates against Lassa fever virus (LASV) is possible through the inoculation of the closely related but nonpathogenic Mopeia virus (MOPV) before challenge with LASV. We reasoned that this virus, modified by using reverse genetics, would represent the basis for the generation of a vaccine platform against LASV and other pathogenic arenaviruses. After showing evidence of exoribonuclease (ExoN) activity in NP of MOPV, we found that this activity was essential for multiplication in antigen-presenting cells. The introduction of multiple mutations in the ExoN site of MOPV NP generated a hyperattenuated strain (MOPV
ExoN6b ) that is (i) genetically stable over passages, (ii) has increased immunogenic properties compared to those of MOPV, and (iii) still promotes a strong type I interferon (IFN) response. MOPVExoN6b was further modified to harbor the envelope glycoproteins of heterologous pathogenic arenaviruses, such as LASV or Lujo, Machupo, Guanarito, Chapare, or Sabia virus in order to broaden specific antigenicity while preserving the hyperattenuated characteristics of the parental strain. Our MOPV-based vaccine candidate for LASV, MOPEVACLASV , was used in a one-shot immunization assay in nonhuman primates and fully protected them from a lethal challenge with LASV. Thus, our hyperattenuated strain of MOPV constitutes a promising new live-attenuated vaccine platform to immunize against several, if not all, pathogenic arenaviruses. IMPORTANCE Arenaviruses are emerging pathogens transmitted to humans by rodents and responsible for endemic and epidemic hemorrhagic fevers of global concern. Nonspecific symptoms associated with the onset of infection make these viruses difficult to distinguish from other endemic pathogens. Moreover, the unavailability of rapid diagnosis in the field delays the identification of the virus and early care for treatment and favors spreading. The vaccination of exposed populations would be of great help to decrease morbidity and human-to-human transmission. Using reverse genetics, we generated a vaccine platform for pathogenic arenaviruses based on a modified and hyperattenuated strain of the nonpathogenic Mopeia virus and showed that the Lassa virus candidate fully protected nonhuman primates from a lethal challenge. These results showed that a rationally designed recombinant MOPV-based vaccine is safe, immunogenic, and efficacious in nonhuman primates., (Copyright © 2018 American Society for Microbiology.)- Published
- 2018
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29. Interference with the production of infectious viral particles and bimodal inhibition of replication are broadly conserved antiviral properties of IFITMs.
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Tartour K, Nguyen XN, Appourchaux R, Assil S, Barateau V, Bloyet LM, Burlaud Gaillard J, Confort MP, Escudero-Perez B, Gruffat H, Hong SS, Moroso M, Reynard O, Reynard S, Decembre E, Ftaich N, Rossi A, Wu N, Arnaud F, Baize S, Dreux M, Gerlier D, Paranhos-Baccala G, Volchkov V, Roingeard P, and Cimarelli A
- Subjects
- Cell Line, HIV-1 physiology, Host-Pathogen Interactions, Humans, Virus Internalization, Antigens, Differentiation metabolism, Virion, Virus Replication
- Abstract
IFITMs are broad antiviral factors that block incoming virions in endosomal vesicles, protecting target cells from infection. In the case of HIV-1, we and others reported the existence of an additional antiviral mechanism through which IFITMs lead to the production of virions of reduced infectivity. However, whether this second mechanism of inhibition is unique to HIV or extends to other viruses is currently unknown. To address this question, we have analyzed the susceptibility of a broad spectrum of viruses to the negative imprinting of the virion particles infectivity by IFITMs. The results we have gathered indicate that this second antiviral property of IFITMs extends well beyond HIV and we were able to identify viruses susceptible to the three IFITMs altogether (HIV-1, SIV, MLV, MPMV, VSV, MeV, EBOV, WNV), as well as viruses that displayed a member-specific susceptibility (EBV, DUGV), or were resistant to all IFITMs (HCV, RVFV, MOPV, AAV). The swapping of genetic elements between resistant and susceptible viruses allowed us to point to specificities in the viral mode of assembly, rather than glycoproteins as dominant factors of susceptibility. However, we also show that, contrarily to X4-, R5-tropic HIV-1 envelopes confer resistance against IFITM3, suggesting that viral receptors add an additional layer of complexity in the IFITMs-HIV interplay. Lastly, we show that the overall antiviral effects ascribed to IFITMs during spreading infections, are the result of a bimodal inhibition in which IFITMs act both by protecting target cells from incoming viruses and in driving the production of virions of reduced infectivity. Overall, our study reports for the first time that the negative imprinting of the virion particles infectivity is a conserved antiviral property of IFITMs and establishes IFITMs as a paradigm of restriction factor capable of interfering with two distinct phases of a virus life cycle.
- Published
- 2017
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30. Clinical, virological, and biological parameters associated with outcomes of Ebola virus infection in Macenta, Guinea.
- Author
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Vernet MA, Reynard S, Fizet A, Schaeffer J, Pannetier D, Guedj J, Rives M, Georges N, Garcia-Bonnet N, Sylla AI, Grovogui P, Kerherve JY, Savio C, Savio-Coste S, de Séverac ML, Zloczewski P, Linares S, Harouna S, Abdoul BM, Petitjean F, Samake N, Shepherd S, Kinda M, Koundouno FR, Joxe L, Mateo M, Lecine P, Page A, Tchamdja TM, Schoenhals M, Barbe S, Simon B, Tran-Minh T, Longuet C, L'Hériteau F, and Baize S
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Cohort Studies, Ebolavirus, Female, Guinea epidemiology, Hemorrhagic Fever, Ebola epidemiology, Humans, Infant, Male, Middle Aged, Prognosis, Survivors, Viral Load, Young Adult, Hemorrhagic Fever, Ebola physiopathology, Hemorrhagic Fever, Ebola virology, Outcome Assessment, Health Care
- Abstract
BACKGROUND. The pathogenesis of Ebola virus (EBOV) disease (EVD) is poorly characterized. The establishment of well-equipped diagnostic laboratories close to Ebola treatment centers (ETCs) has made it possible to obtain relevant virological and biological data during the course of EVD and to assess their association with the clinical course and different outcomes of the disease. METHODS. We were responsible for diagnosing EBOV infection in patients admitted to two ETCs in forested areas of Guinea. The pattern of clinical signs was recorded, and an etiological diagnosis was established by RT-PCR for EBOV infection or a rapid test for malaria and typhoid fever. Biochemical analyses were also performed. RESULTS. We handled samples from 168 patients between November 29, 2014, and January 31, 2015; 97 patients were found to be infected with EBOV, with Plasmodium falciparum coinfection in 18%. Overall mortality for EVD cases was 58%, rising to 86% if P . falciparum was also present. Viral load was higher in fatal cases of EVD than in survivors, and fatal cases were associated with higher aspartate aminotransferase (AST) and alanine aminotransferase (ALT), C-reactive protein (CRP), and IL-6 levels. Furthermore, regardless of outcome, EVD was characterized by higher creatine kinase (CPK), amylase, and creatinine levels than in febrile patients without EVD, with higher blood urea nitrogen (BUN) levels in fatal cases of EVD only. CONCLUSION. These findings suggest that a high viral load at admission is a marker of poor EVD prognosis. In addition, high AST, ALT, CRP, and IL-6 levels are associated with a fatal outcome of EVD. Damage to the liver and other tissues, with massive rhabdomyolysis and, probably, acute pancreatitis, is associated with EVD and correlated with disease severity. Finally, biochemical analyses provide substantial added value at ETCs, making it possible to improve supportive rehydration and symptomatic care for patients. FUNDING. The French Ministry of Foreign Affairs, the Agence Française de Développement, and Institut Pasteur., Competing Interests: Conflict of interest: The authors have declared that no conflict of interest exists.
- Published
- 2017
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31. The exonuclease domain of Lassa virus nucleoprotein is involved in antigen-presenting-cell-mediated NK cell responses.
- Author
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Russier M, Reynard S, Carnec X, and Baize S
- Subjects
- Animals, Capsid Proteins genetics, Cell Degranulation, Cell Survival, Cells, Cultured, Coculture Techniques, Dendritic Cells immunology, Exonucleases genetics, Humans, Immune Tolerance, Interferon-gamma metabolism, Interleukins metabolism, Macrophages immunology, Mutant Proteins genetics, Mutant Proteins immunology, Mutation, Missense, Antigen-Presenting Cells immunology, Capsid Proteins immunology, Exonucleases immunology, Killer Cells, Natural immunology, Lassa virus immunology
- Abstract
Unlabelled: Lassa virus is an Old World Arenavirus which causes Lassa hemorrhagic fever in humans, mostly in West Africa. Lassa fever is an important public health problem, and a safe and effective vaccine is urgently needed. The infection causes immunosuppression, probably due to the absence of activation of antigen-presenting cells (dendritic cells and macrophages), low type I interferon (IFN) production, and deficient NK cell function. However, a recombinant Lassa virus carrying D389A and G392A substitutions in the nucleoprotein that abolish the exonuclease activity and IFN activation loses its inhibitory activity and induces strong type I IFN production by dendritic cells and macrophages. We show here that during infection by this mutant Lassa virus, antigen-presenting cells trigger efficient human NK cell responses in vitro, including production of IFN-γ and cytotoxicity. NK cell activation involves close contact with both antigen-presenting cells and soluble factors. We report that infected dendritic cells and macrophages express the NKG2D ligands major histocompatibility complex (MHC) class I-related chains A and B and that they may produce interleukin-12 (IL-12), IL-15, and IL-18, all involved in NK cell functions. NK cell degranulation is significantly increased in cocultures, suggesting that NK cells seem to kill infected dendritic cells and macrophages. This work confirms the inhibitory function of Lassa virus nucleoprotein. Importantly, we demonstrate for the first time that Lassa virus nucleoprotein is involved in the inhibition of antigen-presenting cell-mediated NK cell responses., Importance: The pathogenesis and immune responses induced by Lassa virus are poorly known. Recently, an exonuclease domain contained in the viral nucleoprotein has been shown to be able to inhibit the type I IFN response by avoiding the recognition of viral RNA by cell sensors. Here, we studied the responses of NK cells to dendritic cells and macrophages infected with a recombinant Lassa virus in which the exonuclease functions have been abolished and demonstrated that NK cells are strongly activated and presented effective functions. These results show that the strategy developed by Lassa virus to evade innate immunity is also effective on NK cells, explaining the weak NK cell activation observed with the wild-type virus. By providing a better understanding of the interactions between Lassa virus and the host immune system, these results are important for the field of arenavirus biology and may be useful for a vaccine approach against Lassa fever., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Published
- 2014
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32. Exonuclease domain of the Lassa virus nucleoprotein is critical to avoid RIG-I signaling and to inhibit the innate immune response.
- Author
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Reynard S, Russier M, Fizet A, Carnec X, and Baize S
- Subjects
- Cells, Cultured, DEAD Box Protein 58, DEAD-box RNA Helicases metabolism, Exonucleases metabolism, Humans, Nucleoproteins metabolism, Receptors, Immunologic, Exonucleases immunology, Immune Tolerance, Immunity, Innate, Lassa virus immunology, Lassa virus physiology, Nucleoproteins immunology, Signal Transduction
- Abstract
Lassa virus (LASV), which causes a viral hemorrhagic fever, inhibits the innate immune response. The exonuclease (ExoN) domain of its nucleoprotein (NP) is implicated in the suppression of retinoic acid-inducible gene I (RIG-I) signaling. We show here that a LASV in which ExoN function has been abolished strongly activates innate immunity and that this effect is dependent on RIG-I signaling. These results highlight the key role of NP ExoN function in the immune evasion that occurs during LASV infection., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Published
- 2014
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33. Production of CXC and CC chemokines by human antigen-presenting cells in response to Lassa virus or closely related immunogenic viruses, and in cynomolgus monkeys with lassa fever.
- Author
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Pannetier D, Reynard S, Russier M, Carnec X, and Baize S
- Subjects
- Animals, Humans, Immune Evasion, Male, Nucleoproteins immunology, Viral Proteins immunology, Antigen-Presenting Cells metabolism, Chemokines, CC metabolism, Chemokines, CXC metabolism, Lassa Fever immunology, Lassa Fever veterinary, Lassa virus immunology, Primate Diseases immunology
- Abstract
The pathogenesis of Lassa fever (LF), a hemorrhagic fever endemic to West Africa, remains unclear. We previously compared Lassa virus (LASV) with its genetically close, but nonpathogenic homolog Mopeia virus (MOPV) and demonstrated that the strong activation of antigen-presenting cells (APC), including type I IFN production, observed in response to MOPV probably plays a crucial role in controlling infection. We show here that human macrophages (MP) produce large amounts of CC and CXC chemokines in response to MOPV infection, whereas dendritic cells (DC) release only moderate amounts of CXC chemokines. However, in the presence of autologous T cells, DCs produced CC and CXC chemokines. Chemokines were produced in response to type I IFN synthesis, as the levels of both mediators were strongly correlated and the neutralization of type I IFN resulted in an inhibition of chemokine production. By contrast, LASV induced only low levels of CXCL-10 and CXCL-11 production. These differences in chemokine production may profoundly affect the generation of virus-specific T-cell responses and may therefore contribute to the difference of pathogenicity between these two viruses. In addition, a recombinant LASV (rLASV) harboring the NP-D389A/G392A mutations, which abolish the inhibition of type I IFN response by nucleoprotein (NP), induced the massive synthesis of CC and CXC chemokines in both DC and MP, confirming the crucial role of arenavirus NP in immunosuppression and pathogenicity. Finally, we confirmed, using PBMC samples and lymph nodes obtained from LASV-infected cynomolgus monkeys, that LF was associated with high levels of CXC chemokine mRNA synthesis, suggesting that the very early synthesis of these mediators may be correlated with a favourable outcome.
- Published
- 2014
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34. NK cells are strongly activated by Lassa and Mopeia virus-infected human macrophages in vitro but do not mediate virus suppression.
- Author
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Russier M, Reynard S, Tordo N, and Baize S
- Subjects
- Animals, Cell Growth Processes immunology, Chlorocebus aethiops, Coculture Techniques, Fas Ligand Protein genetics, Fas Ligand Protein immunology, Gene Expression Regulation, Viral, Granzymes genetics, Granzymes immunology, Humans, Interferon-gamma genetics, Interferon-gamma immunology, K562 Cells, Killer Cells, Natural virology, Lassa Fever virology, Lymphocyte Activation immunology, Macrophages virology, RNA chemistry, RNA genetics, Reverse Transcriptase Polymerase Chain Reaction, Statistics, Nonparametric, TNF-Related Apoptosis-Inducing Ligand genetics, TNF-Related Apoptosis-Inducing Ligand immunology, Vero Cells, Killer Cells, Natural immunology, Lassa Fever immunology, Lassa virus immunology, Macrophages immunology
- Abstract
Lassa virus (LASV) and Mopeia virus (MOPV) are closely related Arenaviruses. LASV causes hemorrhagic fever, whereas MOPV is not pathogenic. Both viruses display tropism for APCs such as DCs and macrophages. During viral infections, NK cells are involved in the clearance of infected cells and promote optimal immune responses by interacting with APCs. We used an in vitro model of human NK and APC coculture to study the role of NK cells and to characterize their interactions with APCs during LASV and MOPV infections. As expected, NK cells alone were neither infected nor activated by LASV and MOPV, and infected DCs did not activate NK cells. By contrast, LASV- and MOPV-infected macrophages activated NK cells, as shown by the upregulation of CD69, NKp30, and NKp44, the downregulation of CXCR3, and an increase in NK-cell proliferation. NK cells acquired enhanced cytotoxicity, as illustrated by the increase in granzyme B (GrzB) expression and killing of K562 targets, but did not produce IFN-γ. Contact between NK cells and infected macrophages and type I IFNs were essential for activation; however, NK cells could not kill infected cells and control infection. Overall, these findings show that MOPV- as well as pathogenic LASV-infected macrophages mediate NK-cell activation., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2012
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35. Lassa virus nucleoprotein mutants generated by reverse genetics induce a robust type I interferon response in human dendritic cells and macrophages.
- Author
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Carnec X, Baize S, Reynard S, Diancourt L, Caro V, Tordo N, and Bouloy M
- Subjects
- Amino Acid Substitution, Animals, Chlorocebus aethiops, Dendritic Cells virology, Lassa virus growth & development, Macrophages virology, Molecular Sequence Data, Mutant Proteins genetics, Mutant Proteins immunology, Mutation, Missense, Sequence Analysis, DNA, Vero Cells, Viral Load, Viral Plaque Assay, Capsid Proteins genetics, Capsid Proteins immunology, Dendritic Cells immunology, Interferon Type I metabolism, Lassa virus genetics, Lassa virus immunology, Macrophages immunology
- Abstract
Lassa virus (LASV; Arenaviridae) is responsible for severe hemorrhagic fevers in Africa. LASV nucleoprotein (NP) plays important roles in regulating viral transcription and replication and in inhibiting type I interferon (IFN) production. The NP C-terminal domain contains a 3'-to-5' exonuclease activity involved in suppressing IFN induction. We have established a murine polymerase (Pol) I reverse genetics system for LASV, showing that residues D389 and G392 of NP were critical for LASV viability, while the D389A/G392A and D389T/392A double mutants were severely altered in the ability to suppress IFN in macrophages and dendritic cells. Assessing their attenuation in vivo may open new perspectives in vaccinology.
- Published
- 2011
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36. Human dendritic cells infected with the nonpathogenic Mopeia virus induce stronger T-cell responses than those infected with Lassa virus.
- Author
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Pannetier D, Reynard S, Russier M, Journeaux A, Tordo N, Deubel V, and Baize S
- Subjects
- Cell Proliferation, Cells, Cultured, Coculture Techniques, Cytokines biosynthesis, Dendritic Cells immunology, Enzyme-Linked Immunosorbent Assay, Enzyme-Linked Immunospot Assay, Flow Cytometry, Humans, Immunologic Memory, Lassa virus immunology, Lymphocyte Activation, Reverse Transcriptase Polymerase Chain Reaction, Arenaviruses, Old World immunology, CD4-Positive T-Lymphocytes immunology, Dendritic Cells virology, T-Lymphocytes, Cytotoxic immunology
- Abstract
The events leading to death in severe cases of Lassa fever (LF) are unknown. Fatality seems to be linked to high viremia and immunosuppression, and cellular immunity, rather than neutralizing antibodies, appears to be essential for survival. We previously compared Lassa virus (LV) with its genetically close but nonpathogenic homolog Mopeia virus (MV), which was used to model nonfatal LF. We showed that strong and early activation of antigen-presenting cells (APC) may play a crucial role in controlling infection. Here we developed an in vitro model of dendritic-cell (DC)-T-cell coculture in order to characterize human T-cell responses induced by MV- or LV-infected DCs. Our results show very different responses to infection with LV and MV. MV strongly and durably stimulated CD8(+) and CD4(+) T cells, showing early and high activation, a strong proliferative response, and acquisition of effector and memory phenotypes. Furthermore, robust and functional CD4(+) and CD8(+) cytotoxic T lymphocytes (CTL) were generated. LV, however, induced only weak memory responses. Thus, this study allows an improved understanding of the pathogenesis and immune mechanisms involved in the control of human LV.
- Published
- 2011
- Full Text
- View/download PDF
37. KAP1 controls endogenous retroviruses in embryonic stem cells.
- Author
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Rowe HM, Jakobsson J, Mesnard D, Rougemont J, Reynard S, Aktas T, Maillard PV, Layard-Liesching H, Verp S, Marquis J, Spitz F, Constam DB, and Trono D
- Subjects
- 5' Untranslated Regions genetics, Acetylation, Animals, DNA Methylation, Embryo, Mammalian metabolism, Embryo, Mammalian virology, Embryonic Stem Cells virology, Fibroblasts, Genes, Reporter, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Histones metabolism, Leukemia Virus, Murine genetics, Leukemia Virus, Murine physiology, Lysine metabolism, Methylation, Mice, Nuclear Proteins deficiency, Nuclear Proteins genetics, Promoter Regions, Genetic genetics, Repressor Proteins deficiency, Repressor Proteins genetics, Tripartite Motif-Containing Protein 28, Embryonic Stem Cells metabolism, Endogenous Retroviruses genetics, Gene Silencing, Genes, Intracisternal A-Particle genetics, Nuclear Proteins metabolism, Repressor Proteins metabolism
- Abstract
More than forty per cent of the mammalian genome is derived from retroelements, of which about one-quarter are endogenous retroviruses (ERVs). Some are still active, notably in mice the highly polymorphic early transposon (ETn)/MusD and intracisternal A-type particles (IAP). ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation (and reviewed in ref. 7), although the initiators of this process, which is essential to protect genome integrity, remain largely unknown. KAP1 (KRAB-associated protein 1, also known as tripartite motif-containing protein 28, TRIM28) represses genes by recruiting the histone methyltransferase SETDB1, heterochromatin protein 1 (HP1) and the NuRD histone deacetylase complex, but few of its physiological targets are known. Two lines of evidence suggest that KAP1-mediated repression could contribute to the control of ERVs: first, KAP1 can trigger permanent gene silencing during early embryogenesis, and second, a KAP1 complex silences the retrovirus murine leukaemia virus in embryonic cells. Consistent with this hypothesis, here we show that KAP1 deletion leads to a marked upregulation of a range of ERVs, in particular IAP elements, in mouse embryonic stem (ES) cells and in early embryos. We further demonstrate that KAP1 acts synergistically with DNA methylation to silence IAP elements, and that it is enriched at the 5' untranslated region (5'UTR) of IAP genomes, where KAP1 deletion leads to the loss of histone 3 lysine 9 trimethylation (H3K9me3), a hallmark of KAP1-mediated repression. Correspondingly, IAP 5'UTR sequences can impose in cis KAP1-dependent repression on a heterologous promoter in ES cells. Our results establish that KAP1 controls endogenous retroelements during early embryonic development.
- Published
- 2010
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- View/download PDF
38. Early and strong immune responses are associated with control of viral replication and recovery in lassa virus-infected cynomolgus monkeys.
- Author
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Baize S, Marianneau P, Loth P, Reynard S, Journeaux A, Chevallier M, Tordo N, Deubel V, and Contamin H
- Subjects
- Animals, Arenaviridae Infections blood, Arenaviridae Infections pathology, Chlorocebus aethiops, Cytokines biosynthesis, Cytokines immunology, Macaca fascicularis blood, Male, Time Factors, Vero Cells, Viremia virology, Arenaviridae Infections immunology, Arenaviridae Infections virology, Lassa virus immunology, Macaca fascicularis immunology, Macaca fascicularis virology, Virus Replication
- Abstract
Lassa virus causes a hemorrhagic fever endemic in West Africa. The pathogenesis and the immune responses associated with the disease are poorly understood, and no vaccine is available. We followed virological, pathological, and immunological markers associated with fatal and nonfatal Lassa virus infection of cynomolgus monkeys. The clinical picture was characterized by fever, weight loss, depression, and acute respiratory syndrome. Transient thrombocytopenia and lymphopenia, lymphadenopathy, splenomegaly, infiltration of mononuclear cells, and alterations of the liver, lungs, and endothelia were observed. Survivors exhibited fewer lesions and a lower viral load than nonsurvivors. Although all animals developed strong humoral responses, antibodies appeared more rapidly in survivors and were directed against GP(1), GP(2), and NP. Type I interferons were detected early after infection in survivors but only during the terminal stages in fatalities. The mRNAs for CXCL10 (IP-10) and CXCL11 (I-TAC) were abundant in peripheral blood mononuclear cells and lymph nodes from infected animals, but plasma interleukin-6 was detected only in fatalities. In survivors, high activated-monocyte counts were followed by a rise in the total number of circulating monocytes. Activated T lymphocytes circulated in survivors, whereas T-cell activation was low and delayed in fatalities. In vitro stimulation with inactivated Lassa virus induced activation of T lymphocytes from all infected monkeys, but only lymphocytes from survivors proliferated. Thus, early and strong immune responses and control of viral replication were associated with recovery, whereas fatal infection was characterized by major alterations of the blood formula and, in organs, weak immune responses and uncontrolled viral replication.
- Published
- 2009
- Full Text
- View/download PDF
39. Interfering residues narrow the spectrum of MLV restriction by human TRIM5alpha.
- Author
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Maillard PV, Reynard S, Serhan F, Turelli P, and Trono D
- Subjects
- Amino Acid Substitution, Animals, Antiviral Restriction Factors, Capsid metabolism, Carrier Proteins chemistry, Carrier Proteins genetics, Cells, Fibroblasts cytology, Fibroblasts immunology, HIV Infections immunology, HIV Infections virology, HIV-1 genetics, HIV-1 growth & development, Humans, Kidney cytology, Leukemia Virus, Murine genetics, Leukemia Virus, Murine immunology, Mice, Molecular Sequence Data, Protein Structure, Tertiary, Retroviridae Infections immunology, Tripartite Motif Proteins, Tumor Virus Infections immunology, Ubiquitin-Protein Ligases, Carrier Proteins metabolism, Fibroblasts virology, Leukemia Virus, Murine growth & development, Retroviridae Infections virology, Tumor Virus Infections virology
- Abstract
TRIM5alpha is a restriction factor that limits infection of human cells by so-called N- but not B- or NB-tropic strains of murine leukemia virus (MLV). Here, we performed a mutation-based functional analysis of TRIM5alpha-mediated MLV restriction. Our results reveal that changes at tyrosine(336) of human TRIM5alpha, within the variable region 1 of its C-terminal PRYSPRY domain, can expand its activity to B-MLV and to the NB-tropic Moloney MLV. Conversely, we demonstrate that the escape of MLV from restriction by wild-type or mutant forms of huTRIM5alpha can be achieved through interdependent changes at positions 82, 109, 110, and 117 of the viral capsid. Together, our results support a model in which TRIM5alpha-mediated retroviral restriction results from the direct binding of the antiviral PRYSPRY domain to the viral capsid, and can be prevented by interferences exerted by critical residues on either one of these two partners.
- Published
- 2007
- Full Text
- View/download PDF
40. West Nile virus in wild resident birds, Southern France, 2004.
- Author
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Jourdain E, Schuffenecker I, Korimbocus J, Reynard S, Murri S, Kayser Y, Gauthier-Clerc M, Sabatier P, and Zeller HG
- Subjects
- Animals, Animals, Wild, Antibodies, Viral blood, Cell Line, France, Immunoglobulin G blood, Molecular Sequence Data, Phylogeny, West Nile Fever epidemiology, West Nile Fever virology, West Nile virus classification, West Nile virus genetics, West Nile virus isolation & purification, Bird Diseases epidemiology, Bird Diseases virology, Passeriformes virology, West Nile Fever veterinary, West Nile virus physiology
- Abstract
An equine West Nile virus (WNV) outbreak occurred in 2004 in the Camargue, a wetland area in the south of France where the virus was first reported in 1962 and re-emerged in 2000. WNV neutralizing antibodies were detected in resident birds and two isolates from a House Sparrow (Passer domesticus) and a Common Magpie (Pica pica) were completely sequenced. Phylogenetic analyses revealed that these isolates are closely related to strains previously found in horses in southern Europe and North Africa. More extensive investigation is required to determine whether WNV has been re-introduced or has become endemic in the Camargue.
- Published
- 2007
- Full Text
- View/download PDF
41. Combination of transient lymphodepletion with busulfan and fludarabine and peptide vaccination in a phase I clinical trial for patients with advanced melanoma.
- Author
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Appay V, Voelter V, Rufer N, Reynard S, Jandus C, Gasparini D, Lienard D, Speiser DE, Schneider P, Cerottini JC, Romero P, and Leyvraz S
- Subjects
- Adult, Aged, Antigens, Neoplasm chemistry, Antigens, Neoplasm immunology, Antineoplastic Agents pharmacology, Busulfan pharmacology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Combined Modality Therapy, Female, Humans, Lymphocyte Depletion, MART-1 Antigen, Male, Melanoma pathology, Middle Aged, Neoplasm Proteins chemistry, Neoplasm Proteins immunology, Peptides chemistry, Peptides therapeutic use, Skin Neoplasms pathology, T-Lymphocyte Subsets drug effects, T-Lymphocyte Subsets immunology, Vaccination, Vaccines, Subunit therapeutic use, Vidarabine pharmacology, Vidarabine therapeutic use, Antigens, Neoplasm therapeutic use, Antineoplastic Agents therapeutic use, Busulfan therapeutic use, Cancer Vaccines therapeutic use, Melanoma drug therapy, Neoplasm Proteins therapeutic use, Skin Neoplasms drug therapy, Vidarabine analogs & derivatives
- Abstract
Taking advantage of homeostatic mechanisms to boost tumor-specific cellular immunity is raising increasing interest in the development of therapeutic strategies in the treatment of melanoma. Here, we have explored the potential of combining homeostatic proliferation, after transient immunosuppression, and antigenic stimulation of Melan-A/Mart-1 specific CD8 T-cells. In an effort to develop protocols that could be readily applicable to the clinic, we have designed a phase I clinical trial, involving lymphodepleting chemotherapy with Busulfan and Fludarabine, reinfusion of Melan-A specific CD8 T-cell containing peripheral blood mononuclear cells (exempt of growth factors), and Melan-A peptide vaccination. Six patients with advanced melanoma were enrolled in this outpatient regimen that demonstrated good feasibility combined with low toxicity. Consistent depletion of lymphocytes with persistent increased CD4/CD8 ratios was induced, although the proportion of circulating CD4 regulatory T-cells remained mostly unchanged. The study of the immune reconstitution period showed a steady recovery of whole T-cell numbers overtime. However, expansion of Melan-A specific CD8 T-cells, as measured in peripheral blood, was mostly inconsistent, accompanied with marginal phenotypic changes, despite vaccination with Melan-A/Mart-1 peptide. On the clinical level, 1 patient presented a partial but objective antitumor response following the beginning of the protocol, even though a direct effect of Busulfan/Fludarabine cannot be completely ruled out. Overall, these data provide further ground for the development of immunotherapeutic approaches to be both effective against melanoma and applicable in clinic.
- Published
- 2007
- Full Text
- View/download PDF
42. New generation vaccine induces effective melanoma-specific CD8+ T cells in the circulation but not in the tumor site.
- Author
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Appay V, Jandus C, Voelter V, Reynard S, Coupland SE, Rimoldi D, Lienard D, Guillaume P, Krieg AM, Cerottini JC, Romero P, Leyvraz S, Rufer N, and Speiser DE
- Subjects
- Adult, Aged, Antigens, Neoplasm, CD8-Positive T-Lymphocytes virology, Cancer Vaccines administration & dosage, Cell Movement immunology, Clone Cells, CpG Islands immunology, Cytomegalovirus immunology, Herpesvirus 4, Human immunology, Humans, Immunophenotyping, Lymphocyte Count, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating pathology, MART-1 Antigen, Melanoma prevention & control, Melanoma secondary, Oligodeoxyribonucleotides administration & dosage, Oligodeoxyribonucleotides immunology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory pathology, Tumor Cells, Cultured, Vaccines, Subunit administration & dosage, Vaccines, Subunit immunology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Cancer Vaccines immunology, Epitopes, T-Lymphocyte immunology, Lymphocyte Activation immunology, Melanoma immunology, Melanoma pathology, Neoplasm Proteins immunology
- Abstract
Although increasing evidence suggests that CTL are important to fight the development of some cancers, the frequency of detectable tumor-specific T cells is low in cancer patients, and these cells have generally poor functional capacities, compared with virus-specific CD8(+) T cells. The generation with a vaccine of potent CTL responses against tumor Ags therefore remains a major challenge. In the present study, ex vivo analyses of Melan-A-specific CD8(+) T cells following vaccination with Melan-A peptide and CpG oligodeoxynucleotides revealed the successful induction in the circulation of effective melanoma-specific T cells, i.e., with phenotypic and functional characteristics similar to those of CTL specific for immunodominant viral Ags. Nonetheless, the eventual impact on tumor development in vaccinated melanoma donors remained limited. The comprehensive study of vaccinated patient metastasis shows that vaccine-driven tumor-infiltrating lymphocytes, although activated, still differed in functional capacities compared with blood counterparts. This coincided with a significant increase of FoxP3(+) regulatory T cell activity within the tumor. The consistent induction of effective tumor-specific CD8(+) T cells in the circulation with a vaccine represents a major achievement; however, clinical benefit may not be achieved unless the tumor environment can be altered to enable CD8(+) T cell efficacy.
- Published
- 2006
- Full Text
- View/download PDF
43. Decreased specific CD8+ T cell cross-reactivity of antigen recognition following vaccination with Melan-A peptide.
- Author
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Appay V, Speiser DE, Rufer N, Reynard S, Barbey C, Cerottini JC, Leyvraz S, Pinilla C, and Romero P
- Subjects
- Antigens, Neoplasm, Cancer Vaccines administration & dosage, Cells, Cultured, Humans, MART-1 Antigen, Melanoma immunology, Melanoma therapy, Neoplasm Proteins administration & dosage, Peptide Fragments administration & dosage, Vaccines, Subunit administration & dosage, Vaccines, Subunit immunology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cancer Vaccines immunology, Cross-Priming immunology, Epitopes, T-Lymphocyte immunology, Neoplasm Proteins immunology, Peptide Fragments immunology
- Abstract
The aim of T cell vaccines is the expansion of antigen-specific T cells able to confer immune protection against pathogens or tumors. Although increase in absolute cell numbers, effector functions and TCR repertoire of vaccine-induced T cells are often evaluated, their reactivity for the cognate antigen versus their cross-reactive potential is rarely considered. In fact, little information is available regarding the influence of vaccines on T cell fine specificity of antigen recognition despite the impact that this feature may have in protective immunity. To shed light on the cross-reactive potential of vaccine-induced cells, we analyzed the reactivity of CD8(+) T cells following vaccination of HLA-A2(+) melanoma patients with Melan-A peptide, incomplete Freund's adjuvant and CpG-oligodeoxynucleotide adjuvant, which was shown to induce strong expansion of Melan-A-reactive CD8(+) T cells in vivo. A collection of predicted Melan-A cross-reactive peptides, identified from a combinatorial peptide library, was used to probe functional antigen recognition of PBMC ex vivo and Melan-A-reactive CD8(+) T cell clones. While Melan-A-reactive CD8(+) T cells prior to vaccination are usually constituted of widely cross-reactive naive cells, we show that peptide vaccination resulted in expansion of memory T cells displaying a reactivity predominantly restricted to the antigen of interest. Importantly, these cells are tumor-reactive.
- Published
- 2006
- Full Text
- View/download PDF
44. Immuno-monitoring of CD8+ T cells in whole blood versus PBMC samples.
- Author
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Appay V, Reynard S, Voelter V, Romero P, Speiser DE, and Leyvraz S
- Subjects
- Blood Cells cytology, Blood Cells immunology, CD8-Positive T-Lymphocytes cytology, Cancer Vaccines therapeutic use, Cell Separation, Flow Cytometry, Humans, Immunity, Innate, Immunotherapy, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear immunology, Longitudinal Studies, Melanoma immunology, Melanoma therapy, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets immunology, CD8-Positive T-Lymphocytes immunology
- Abstract
The study of natural T cell responses against pathogens or tumors, as well as the assessment of new immunotherapy strategies aimed at boosting these responses, requires increasingly precise ex vivo analysis of blood samples. For practical reasons, studies are often performed using purified PBMC samples, usually cryopreserved. Here, we report on FACS analyses of peripheral blood T cells, performed by direct antibody staining of non-purified total blood. For comparison, fresh PBMC, purified by Ficoll, were analysed. Our results show that the latter method can induce a bias in subpopulation distribution, in particular of CD8+ T cells, and sometimes lead to inaccurate measurement of antigen specific CD8+ T cell responses. Direct analysis of total blood can be applied to longitudinal immuno-monitoring of T cell-based therapy. While the need to purify and cryopreserve PBMC for subsequent studies is obvious, the use of whole blood has the advantage of providing unbiased results and only small amounts of blood are used.
- Published
- 2006
- Full Text
- View/download PDF
45. TRAIL receptor-2 signals apoptosis through FADD and caspase-8.
- Author
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Bodmer JL, Holler N, Reynard S, Vinciguerra P, Schneider P, Juo P, Blenis J, and Tschopp J
- Subjects
- Caspase 3, Caspase 8, Caspase 9, Humans, Jurkat Cells chemistry, Jurkat Cells cytology, Jurkat Cells enzymology, Receptors, TNF-Related Apoptosis-Inducing Ligand, Apoptosis physiology, Arabidopsis Proteins, Caspases metabolism, Fatty Acid Desaturases metabolism, Receptors, Tumor Necrosis Factor metabolism, Signal Transduction physiology
- Published
- 2000
- Full Text
- View/download PDF
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