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1. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization

Author: Najiby Kassis-Chikhani, Samira Fafi-Kremer, Olivier Schwartz, Laurent Bélec, Matthieu Prot, Cyril Planchais, Timothée Bruel, Laura Courtellemont, Florence Guivel-Benhassine, Artem Baidaliuk, Isabelle Staropoli, Julien Le Guen, Etienne Simon-Loriere, Laurent Hocqueloux, Delphine Planas, David Veyer, Pierre Gantner, Maaran Michael Rajah, Aurélie Velay, Thierry Prazuck, Dhiaeddine Edriss, Félix A. Rey, Françoise Porrot, Hélène Péré, Floriane Gallais, Aymeric Sève, Nicolas Robillard, Julien Puech, Hugo Mouquet, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP), Université Paris Cité (UPCité), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Strasbourg, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional d'Orléans (CHRO), Virologie Structurale - Structural Virology, The Opera system was co-funded by the Institut Pasteur and the Région Île de France (DIM1Health). Work in the O.S. laboratory is funded by the Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale (FRM), ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR. Work in UPBI is funded by grant ANR-10-INSB-04-01 and the Région Île-de-France program DIM1-Health. D.P. is supported by the Vaccine Research Institute. The H.M. laboratory is funded by the Institut Pasteur, the Milieu Intérieur Program (ANR-10-LABX-69-01), INSERM, REACTing, EU (RECOVER) and Fondation de France (00106077) grants. The S.F.K. laboratory is funded by Strasbourg University Hospitals (SeroCoV-HUS, PRI 7782), the Programme Hospitalier de Recherche Clinique (PHRC N 2017–HUS no. 6997), the Agence Nationale de la Recherche (ANR-18-CE17-0028), Laboratoire d’Excellence TRANSPLANTEX (ANR-11-LABX-0070_TRANSPLANTEX) and the Institut National de la Santé et de la Recherche Médicale (UMR_S 1109). The E.S.-L. laboratory is funded by the Institut Pasteur and the French Government’s Investissement d’Avenir programme, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant no. ANR-10-LABX-62-IBEID)., We thank N. Casartelli for critical reading of the manuscript, P. Guardado Calvo for discussion, the individuals who participated in the study, members of the Virus and Immunity Unit for discussions and help, N. Aulner and the UTechS Photonic BioImaging (UPBI) core facility (Institut Pasteur), a member of the France BioImaging network, for image acquisition and analysis, and the DRCI, CIC, Médecine du Travail and Pôle de Biologie teams (CHU de Strasbourg) for the management of the Strasbourg cohort and serology testing., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-18-CE17-0028,HuMABK,Les anticorps monoclonaux humains : une Nouvelle approche thérapeutique contre l'infection par le virus BK et les maladies associées(2018), ANR-11-LABX-0070,TRANSPLANTEX,Nouveaux loci d'histocompatibilité/biomarqueurs en transplantation humaine: de la découverte à l'app(2011), European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute (VRI), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), and Université Paris Cité (UPC)
Subjects: Male, Delta, COVID-19 Vaccines, medicine.drug_class, India, Alpha (ethology), Biology, Antibodies, Monoclonal, Humanized, Antibodies, Viral, Monoclonal antibody, Neutralization, Epitope, Epitopes, Immune system, Neutralization Tests, medicine, Humans, Immune Evasion, Multidisciplinary, COVID-19, Convalescence, Middle Aged, Antibodies, Neutralizing, Virology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Spike Glycoprotein, Coronavirus, Monoclonal, biology.protein, France, Antibody
Abstract: The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India1–5. Since then, it has become dominant in some regions of India and in the UK, and has spread to many other countries6. The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), which contain diverse mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein that may increase the immune evasion potential of these variants. B.1.617.2—also termed the Delta variant—is believed to spread faster than other variants. Here we isolated an infectious strain of the Delta variant from an individual with COVID-19 who had returned to France from India. We examined the sensitivity of this strain to monoclonal antibodies and to antibodies present in sera from individuals who had recovered from COVID-19 (hereafter referred to as convalescent individuals) or who had received a COVID-19 vaccine, and then compared this strain with other strains of SARS-CoV-2. The Delta variant was resistant to neutralization by some anti-NTD and anti-RBD monoclonal antibodies, including bamlanivimab, and these antibodies showed impaired binding to the spike protein. Sera collected from convalescent individuals up to 12 months after the onset of symptoms were fourfold less potent against the Delta variant relative to the Alpha variant (B.1.1.7). Sera from individuals who had received one dose of the Pfizer or the AstraZeneca vaccine had a barely discernible inhibitory effect on the Delta variant. Administration of two doses of the vaccine generated a neutralizing response in 95% of individuals, with titres three- to fivefold lower against the Delta variant than against the Alpha variant. Thus, the spread of the Delta variant is associated with an escape from antibodies that target non-RBD and RBD epitopes of the spike protein. The SARS-CoV-2 Delta variant partially evades neutralization by several monoclonal antibodies and by sera from individuals who have had COVID-19, but two doses of anti-COVID-19 vaccines still generate a strong neutralizing response.
Published: 2021

2. Tracking receptor motions at the plasma membrane reveals distinct effects of ligands on CCR5 dynamics depending on its dimerization status

Author: Fanny Momboisse, Giacomo Nardi, Philippe Colin, Melanie Hery, Nelia Cordeiro, Simon Blachier, Olivier Schwartz, Fernando Arenzana-Seisdedos, Nathalie Sauvonnet, Jean-Christophe Olivo-Marin, Bernard Lagane, Thibault Lagache, Anne Brelot, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Pathogénie Virale - Viral Pathogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biologie cellulaire et infection - Department of Cell Biology and infection (BCI), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), This work was supported by grants from Agence National de Recherche sur le SIDA et les hepatitis virales (ANRS), the French Government’s Investissement d’Avenir program, Laboratoire d’excellence 'Integrative Biology of Emerging Infectious Diseases’ (grant ANR-10-LABX-62- IBEID), INCEPTION (ANR-16-CONV-0005) and GET-REDI (ANR-21-CE44-0030). UTechS PBI is part of theFrance–BioImaging infrastructure network (FBI) supported by the French National Research Agency (ANR-10- INBS- 04, Investments for the Future), and acknowledges support from Institut Pasteur, ANR/ FBI, the Région Ile-de- France (program ‘Domaine d'Intérêt Majeur-Malinf’ and DIM1HEALTH), and the French Government Investissement d'Avenir Programme—Laboratoire d'Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (ANR-10-LABX-62-IBEID) for the use of ELYRA PS1 LSM780and ELYRA7 microscopes. FM was the recipient of ANR-10-LABX-62-IBEID fellowship, GN of INCEPTION (ANR-16- CONV-0005) fellowship and PC of an ANRS fellowship, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-21-CE44-0030,GET-REDI,Cibler la dimérisation des récepteurs de chimiokines CCR2 et CCR5: vers une meilleure régulation de l'inflammation(2021), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Virus et Immunité - Virus and immunity, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brelot, Anne, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID, Cibler la dimérisation des récepteurs de chimiokines CCR2 et CCR5: vers une meilleure régulation de l'inflammation - - GET-REDI2021 - ANR-21-CE44-0030 - AAPG2021 - VALID, and Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID
Subjects: Receptors, CCR5, General Immunology and Microbiology, none, single-particle-tracking, [SDV]Life Sciences [q-bio], General Neuroscience, Cell Membrane, chemokine receptor, imaging, General Medicine, Ligands, General Biochemistry, Genetics and Molecular Biology, Receptors, G-Protein-Coupled, [SDV] Life Sciences [q-bio], GPCR, statistics, cell biology, physics of living systems, HIV-1, Humans, Protein Multimerization, CCR5, Dimerization
Abstract: International audience; G-protein-coupled receptors (GPCR) are present at the cell surface in different conformational and oligomeric states. However, how these states impact GPCRs biological function and therapeutic targeting remains incompletely known. Here, we investigated this issue in living cells for the CC chemokine receptor 5 (CCR5), a major receptor in inflammation and the principal entry co-receptor for Human Immunodeficiency Viruses type 1 (HIV-1). We used TIRF microscopy and a statistical method to track and classify the motion of different receptor subpopulations. We showed a diversity of ligand-free forms of CCR5 at the cell surface constituted of various oligomeric states and exhibiting transient Brownian and restricted motions. These forms were stabilized differently by distinct ligands. In particular, agonist stimulation restricted the mobility of CCR5 and led to its clustering, a feature depending on β-arrestin, while inverse agonist stimulation exhibited the opposite effect. These results suggest a link between receptor activation and immobilization. Applied to HIV-1 envelope glycoproteins gp120, our quantitative analysis revealed agonist-like properties of gp120s. Distinct gp120s influenced CCR5 dynamics differently, suggesting that they stabilize different CCR5 conformations. Then, using a dimerization-compromized mutant, we showed that dimerization (i) impacts CCR5 precoupling to G proteins, (ii) is a pre-requisite for the immobilization and clustering of receptors upon activation, and (iii) regulates receptor endocytosis, thereby impacting the fate of activated receptors. This study demonstrates that tracking the dynamic behavior of a GPCR is an efficient way to link GPCR conformations to their functions, therefore improving the development of drugs targeting specific receptor conformations.
Published: 2022

3. Sex Differences in the Evolution of Neutralizing Antibodies to Severe Acute Respiratory Syndrome Coronavirus 2

Author: Cyril Planchais, David Rey, Aurélie Velay, Ludivine Grzelak, Yoann Madec, Yves Hansmann, Isabelle Staropoli, Marie-Josée Wendling, Samira Fafi-Kremer, Arnaud Fontanet, Catherine Schmidt-Mutter, Timothée Bruel, Hugo Mouquet, Nathalie Reix, Ludovic Glady, Floriane Gallais, Olivier Schwartz, María González, Nicolas Meyer, Jérôme De Seze, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Cité (UPCité), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Strasbourg, Groupe Méthodes en Recherche Clinique [Strasbourg] (GMRC), Nouvel Hôpital Civil [Strasbourg], CHU Strasbourg-CHU Strasbourg, Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), S. F. K.’s laboratory is funded by Strasbourg University Hospitals (Hôpitaux Universitaires de Strasbourg, PRI 7782), Agence Nationale de la Recherche (ANR-18-CE17-0028), Laboratoire d’Excellence TRANSPLANTEX (ANR-11-LABX-0070_TRANSPLANTEX), and Institut National de la Santé et de la Recherche Médicale (UMR_S 1109). O. S.’s laboratory is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Agence Nationale de recherches sur le sida, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), 'TIMTAMDEN' Agence Nationale de la Recherche ANR-14-CE14-0029, 'CHIKV-Viro-Immuno' ANR-14-CE14-0015-01, the Gilead HIV cure program, and ANR/Fondation Pour la Recherche Médicale Flash COVID. L. Gr., is supported by the French Ministry of Higher Education, Research and Innovation., ANR-18-CE17-0028,HuMABK,Les anticorps monoclonaux humains : une Nouvelle approche thérapeutique contre l'infection par le virus BK et les maladies associées(2018), ANR-11-LABX-0070,TRANSPLANTEX,Nouveaux loci d'histocompatibilité/biomarqueurs en transplantation humaine: de la découverte à l'app(2011), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute [Créteil, France] (VRI), univOAK, Archive ouverte, APPEL À PROJETS GÉNÉRIQUE 2018 - Les anticorps monoclonaux humains : une Nouvelle approche thérapeutique contre l'infection par le virus BK et les maladies associées - - HuMABK2018 - ANR-18-CE17-0028 - AAPG2018 - VALID, Nouveaux loci d'histocompatibilité/biomarqueurs en transplantation humaine: de la découverte à l'app - - TRANSPLANTEX2011 - ANR-11-LABX-0070 - LABX - VALID, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Appel à projets générique - Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue - - TIMTAMDEN2014 - ANR-14-CE14-0029 - Appel à projets générique - VALID, and Appel à projets générique - Multiplication et Relation avec l'hôte du virus Chikungunya - - CHIKV-Viro-Immuno2014 - ANR-14-CE14-0015 - Appel à projets générique - VALID
Subjects: 0301 basic medicine, sex-related differences, MESH: Spike Glycoprotein, Coronavirus, medicine.disease_cause, Immunoglobulin G, MESH: Antibodies, Neutralizing, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, antibodies, MESH: COVID-19, Immunology and Allergy, Medicine, MESH: SARS-CoV-2, 030212 general & internal medicine, Polymerase chain reaction, Coronavirus, MESH: Immunoglobulin G, 2. Zero hunger, MESH: Humans, MESH: Middle Aged, biology, SARS-CoV-2, business.industry, COVID-19, MESH: Adult, MESH: Immunoglobulin M, MESH: Male, 3. Good health, 030104 developmental biology, Infectious Diseases, Real-time polymerase chain reaction, [INFO.INFO-TI] Computer Science [cs]/Image Processing [eess.IV], Immunoglobulin M, MESH: HEK293 Cells, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Immunology, biology.protein, MESH: Health Personnel, Antibody, business, MESH: Female, Body mass index, MESH: Antibodies, Viral, MESH: Sex Characteristics, Sex characteristics
Abstract: We measured anti-spike (S), nucleoprotein (N), and neutralizing antibodies in sera from 308 healthcare workers with a positive reverse-transcription quantitative polymerase chain reaction result for severe acute respiratory syndrome coronavirus 2 and with mild disease, collected at 2 timepoints up to 6 months after symptom onset. At month 1, anti-S and -N antibody levels were higher in male participants aged >50 years and participants with a body mass index (BMI) >25 kg/m2. At months 3–6, anti-S and anti-N antibodies were detected in 99% and 59% of individuals, respectively. Anti-S antibodies and neutralizing antibodies declined faster in men than in women, independent of age and BMI, suggesting an association of sex with evolution of the humoral response.
Published: 2021

4. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization

Author: Delphine Planas, Nell Saunders, Piet Maes, Florence Guivel-Benhassine, Cyril Planchais, Julian Buchrieser, William-Henry Bolland, Françoise Porrot, Isabelle Staropoli, Frederic Lemoine, Hélène Péré, David Veyer, Julien Puech, Julien Rodary, Guy Baele, Simon Dellicour, Joren Raymenants, Sarah Gorissen, Caspar Geenen, Bert Vanmechelen, Tony Wawina-Bokalanga, Joan Martí-Carreras, Lize Cuypers, Aymeric Sève, Laurent Hocqueloux, Thierry Prazuck, Félix A. Rey, Etienne Simon-Loriere, Timothée Bruel, Hugo Mouquet, Emmanuel André, Olivier Schwartz, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Université libre de Bruxelles (ULB), University Hospitals Leuven [Leuven], Centre Hospitalier Régional d'Orléans (CHRO), Virologie Structurale - Structural Virology, Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, The Opera system was co-funded by Institut Pasteur and the Région ile de France (DIM1Health). Work in the O.S. laboratory is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale (FRM), ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR. Work in the UPBI is funded by grant ANR-10-INSB-04-01 and Région Ile-de-France program DIM1-Health. D.P. is supported by the Vaccine Research Institute. The H.M. laboratory is funded by the Institut Pasteur, the Milieu Intérieur Program (ANR-10-LABX-69-01), the INSERM, REACTing, EU (RECOVER) and Fondation de France (00106077) grants. The E.S.-L. laboratory is funded by Institut Pasteur, the INCEPTION program (Investissements d’Avenir grant ANR-16-CONV-0005) and the French Government’s Investissement d’Avenir programme, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant no. ANR-10-LABX-62-IBEID). G.B. acknowledges support from the Internal Funds KU Leuven under grant agreement C14/18/094, and the Research Foundation–Flanders (Fonds voor Wetenschappelijk Onderzoek–Vlaanderen, G0E1420N, G098321N). P.M. acknowledges support from a COVID-19 research grant of ‘Fonds Wetenschappelijk Onderzoek’/Research Foundation–Flanders (grant no. G0H4420N). S.D. is supported by the Fonds National de la Recherche Scientifique (FNRS, Belgium) and also acknowledges support from the Research Foundation–Flanders (Fonds voor Wetenschappelijk Onderzoek–Vlaanderen, G098321N) and from the European Union Horizon 2020 project MOOD (grant no. 874850)., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), European Project: 874850,H2020-SC1-2019-Single-Stage-RTD,MOOD(2020), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute (VRI), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris]-Université Paris Cité (UPCité), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), and European Project: 874850,MOOD
Subjects: MESH: Humans, MESH: Mutation, Multidisciplinary, MESH: ChAdOx1 nCoV-19, MESH: Neutralization Tests, MESH: Adult, MESH: Convalescence, MESH: Male, MESH: Antibodies, Monoclonal, MESH: Antibodies, Neutralizing, MESH: Belgium, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: COVID-19, MESH: Immunization, Secondary, MESH: SARS-CoV-2, MESH: Immune Evasion, MESH: BNT162 Vaccine, MESH: Phylogeny, MESH: Travel, MESH: Female, MESH: Antibodies, Viral
Abstract: The SARS-CoV-2 Omicron variant was first identified in November 2021 in Botswana and South Africa1-3. It has since spread to many countries and is expected to rapidly become dominant worldwide. The lineage is characterized by the presence of around 32 mutations in spike-located mostly in the N-terminal domain and the receptor-binding domain-that may enhance viral fitness and enable antibody evasion. Here we isolated an infectious Omicron virus in Belgium from a traveller returning from Egypt. We examined its sensitivity to nine monoclonal antibodies that have been clinically approved or are in development4, and to antibodies present in 115 serum samples from COVID-19 vaccine recipients or individuals who have recovered from COVID-19. Omicron was completely or partially resistant to neutralization by all monoclonal antibodies tested. Sera from recipients of the Pfizer or AstraZeneca vaccine, sampled five months after complete vaccination, barely inhibited Omicron. Sera from COVID-19-convalescent patients collected 6 or 12 months after symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titres 6-fold to 23-fold lower against Omicron compared with those against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and, to a large extent, vaccine-elicited antibodies. However, Omicron is neutralized by antibodies generated by a booster vaccine dose. ispartof: NATURE vol:602 issue:7898 pages:671-+ ispartof: location:England status: published
Published: 2021

5. COVID-19 outbreak in vaccinated patients from a haemodialysis unit: antibody titres as a marker of protection from infection

Author: Idris Boudhabhay, Alexandra Serris, Aude Servais, Delphine Planas, Aurélie Hummel, Bruno Guery, Perrine Parize, Claire Aguilar, Myriam Dao, Claire Rouzaud, Elsa Ferriere, Bertrand Knebelmann, Hamza Sakhi, Marianne Leruez, Dominique Joly, Olivier Schwartz, Fanny Lanternier, Timothée Bruel, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Maladies infectieuses et tropicales [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service Néphrologie et transplantation rénale Adultes [CHU Necker], Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de néphrologie adultes [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Virologie [CHU Necker], We thank William Henry Bolland for his critical reading of the manuscript and members of the Virus and Immunity Unit for discussions and help, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: Transplantation, COVID-19 outbreak, hemodialysis, SARS-CoV-2, COVID-19, Viral Vaccines, Antibodies, Monoclonal, Humanized, Antibodies, Viral, Disease Outbreaks, Hemodialysis Units, Hospital, Nephrology, BNT162b2 mRNA vaccination, Renal Dialysis, Immunoglobulin G, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Humans, monoclonal antibodies, humoral response, BNT162 Vaccine, Retrospective Studies
Abstract: Background Patients on maintenance haemodialysis (HD) have an increased risk of severe coronavirus disease 2019 (COVID-19) and a reduced response to vaccines. Data are needed to identify immune correlates of protection in this population. Methods Following a COVID-19 outbreak among vaccinated patients in a HD unit, clinical data and serological response to BNT162b2 vaccine were retrospectively recorded. Results Among 53 patients present in the dialysis room, 14 were infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) alpha variant (COVID_Pos) and 39 were not. Compared with uninfected patients, COVID_Pos patients more frequently had additional causes of immunosuppression (50% versus 21%; P = .046) and were more often scheduled on the Monday–Wednesday–Friday (MWF) shift (86% versus 39%; P = .002). Moreover, COVID_Pos had lower anti-spike (S) immunoglobulin G (IgG) titres than uninfected patients {median 24 BAU/mL [interquartile range (IQR) 3–1163] versus 435 [99–2555]; P = .001} and lower neutralization titres [median 108 (IQR 17–224) versus 2483 (481–43 908); P = .007]. Anti-S and neutralization antibody titres are correlated (r = 0.92, P 284 BAU/mL got infected. Ten of 14 COVID_Pos patients were treated with casirivimab and imdevimab. No patient developed severe disease. Conclusions Anti-S IgG titre measured prior to exposure correlates to protection from SARS-CoV-2 infection in HD patients. BNT162b2 vaccination alone or in combination with monoclonal antibodies prevented severe COVID-19.
Published: 2021

6. SARS-CoV-2 Alpha, Beta, and Delta variants display enhanced Spike-mediated syncytia formation

Author: Mathieu Hubert, Jérémy Dufloo, Rémy Robinot, Hugo Mouquet, Olivier Schwartz, Ludivine Grzelak, Nell Saunders, Elodie Bishop, Françoise Porrot, Delphine Planas, Maaran Michael Rajah, Julian Buchrieser, Lisa A. Chakrabarti, Marija Zivaljic, Alice Bongers, Stacy Gellenoncourt, Florence Guivel-Benhassine, Cyril Planchais, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Cité (UPCité), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Sorbonne Université (SU), Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Institut Pasteur [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ecole doctorale Cerveau Cognition et Comportement [Paris] (ED 158 - 3C), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Work in OS lab is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Fondation Pour la Recherche Médicale (FRM), Labex IBEID (ANR-10-LABX62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, ANR CoronaMito AAP RA-COVID-19 V14, and IDISCOVR. Work in UPBI is funded by grant ANR-10-INSB-04-01 and Région Ile-de-France program DIM1-Health. MMR and MZ are supported by the Pasteur-Paris University (PPU) International Doctoral Program. MMR is also supported by Institut Pasteur Department of Virology 'Bourse de Soudure' fellowship. DP is supported by the Vaccine Research Institute. LG is supported by the French Ministry of Higher Education, Research and Innovation. EB is supported by the Medecine-Sciences ENS-PSL Program. HM laboratory is funded by the Institut Pasteur, the Milieu Intérieur Program (ANR-10-LABX-69- 01), the INSERM, REACTing, EU (RECOVER), and Fondation de France (#00106077) grants., We thank members of the Virus and Immunity Unit for helpful discussions, Dr. Nicoletta Casartelli for her critical reading of the manuscript, and Nathalie Aulner and the UtechS Photonic BioImaging (UPBI) core facility (Institut Pasteur), a member of the France BioImaging network, for image acquisition and analysis support., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), ANR-21-CO14-0007,CoronaMito,Conséquences de l'infection par le SRAS-CoV-2 sur la fonction mitochondriale(2021), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute [Créteil, France] (VRI), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ziani, Isma, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Protéomique du SARS-CoV-2 - - PROTEO-SARS-CoV-22020 - ANR-20-COVI-0059 - COVID-19 - VALID, Conséquences de l'infection par le SRAS-CoV-2 sur la fonction mitochondriale - - CoronaMito2021 - ANR-21-CO14-0007 - COVID-19 - VALID, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, and Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID
Subjects: fusion, coronavirus, MESH: Spike Glycoprotein, Coronavirus, MESH: Angiotensin-Converting Enzyme 2, medicine.disease_cause, Virus Replication, Giant Cells, SARS‐CoV‐2, MESH: Antibodies, Monoclonal, MESH: Giant Cells, MESH: Chlorocebus aethiops, Chlorocebus aethiops, MESH: Animals, Receptor, Coronavirus, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Syncytium, Strain (chemistry), General Neuroscience, Antibodies, Monoclonal, Articles, Transmembrane protein, Microbiology, Virology & Host Pathogen Interaction, Cell biology, MESH: HEK293 Cells, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Spike Glycoprotein, Coronavirus, MESH: Caco-2 Cells, Angiotensin-Converting Enzyme 2, MESH: Mutation, medicine.drug_class, Immunology, Alpha (ethology), MESH: Vero Cells, Biology, Monoclonal antibody, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, medicine, Animals, Humans, MESH: SARS-CoV-2, Beta (finance), syncytia, Molecular Biology, Vero Cells, MESH: Humans, General Immunology and Microbiology, SARS-CoV-2, MESH: Virus Replication, spike, MESH: Cell Line, HEK293 Cells, Mutation, Caco-2 Cells
Abstract: Severe COVID‐19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when SARS‐CoV‐2 spike protein expressed on the surface of infected cells interacts with the ACE2 receptor on neighboring cells. The syncytia forming potential of spike variant proteins remain poorly characterized. Here, we first assessed Alpha (B.1.1.7) and Beta (B.1.351) spread and fusion in cell cultures, compared with the ancestral D614G strain. Alpha and Beta replicated similarly to D614G strain in Vero, Caco‐2, Calu‐3, and primary airway cells. However, Alpha and Beta formed larger and more numerous syncytia. Variant spike proteins displayed higher ACE2 affinity compared with D614G. Alpha, Beta, and D614G fusion was similarly inhibited by interferon‐induced transmembrane proteins (IFITMs). Individual mutations present in Alpha and Beta spikes modified fusogenicity, binding to ACE2 or recognition by monoclonal antibodies. We further show that Delta spike also triggers faster fusion relative to D614G. Thus, SARS‐CoV‐2 emerging variants display enhanced syncytia formation., Spike protein mutations expressed by emerging SARS‐CoV‐2 variants‐of‐concern differentially affect host cell‐to‐cell fusion, ACE2 receptor binding, and antibody escape.
Published: 2021

7. The FDA-approved drug Auranofin has a dual inhibitory effect on SARS-CoV-2 entry and NF-κB signaling

Author: Emmanuel Laplantine, Christine Chable-Bessia, Anne Oudin, Jitendryia Swain, Adèle Soria, Peggy Merida, Manon Gourdelier, Sarra Mestiri, Indira Besseghe, Erwan Bremaud, Aymeric Neyret, Sebastien Lyonnais, Cyril Favard, Philippe Benaroch, Mathieu Hubert, Olivier Schwartz, Maryse Guerin, Anne Danckaert, Elaine Del Nery, Delphine Muriaux, Robert Weil, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d’études des Maladies Infectieuses et Pharmacologie Anti-Infectieuse - [Montpellier] (CEMIPAI), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de génétique humaine (IGH), Institut de Recherche en Infectiologie de Montpellier (IRIM), BioImaging Cell and Tissue Core Facility (PICT-IBiSA), Institut Curie [Paris], Institut Curie, PSL Research University, INSERM U932., Institut Pasteur [Paris], Virologie (CNRS - UMR3569), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Virus et Immunité - Virus and immunity, Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Institut Pasteur [Paris]-Université Paris Cité (UPCité), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laplantine, Emmanuel, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Institut Pasteur [Paris] (IP), Institut Pasteur, UTechS Photonic BioImaging (PBI), a member of the national infrastructure France-BioImaging supported by the French National Research Agency (ANR-10-INBS-04), kindly acknowledges the financial support of the Région Ile-de France (program DIM1Health) and the Institut Pasteur. This study was supported by the CNRS and Montpellier University through a Montpellier Université d’Excellence (MUSE) support, and the French Agency for Research through the Fondation de la Recherche Médicale (ANR COVID19 to DM) and Cancéropôle Ile-de-France (Emergence Grant, to EL)., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Virus et Immunité - Virus and immunity (CNRS-UMR3569), and Vaccine Research Institute [Créteil, France] (VRI)
Subjects: Chemistry, Multidisciplinary, Molecular biology, [SDV]Life Sciences [q-bio], [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Medical biochemistry, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Biochemistry
Abstract: International audience; Patients with severe COVID-19 show an altered immune response that fails to control the viral spread and suffer from exacerbated inflammatory response, which eventually can lead to death. A major challenge is to develop an effective treatment for COVID-19. NF-κB is a major player in innate immunity and inflammatory process. By a high-throughput screening approach, we identified FDA-approved compounds that inhibit the NF-κB pathway and thus dampen inflammation. Among these, we show that Auranofin prevents post-translational modifications of NF-κB effectors and their recruitment into activating complexes in response to SARS-CoV-2 infection or cytokine stimulation. In addition, we demonstrate that Auranofin counteracts several steps of SARS-CoV-2 infection. First, it inhibits a raft-dependent endocytic pathway involved in SARS-CoV-2 entry into host cells; Second, Auranofin alters the ACE2 mobility at the plasma membrane. Overall, Auranofin should prevent SARS-CoV-2 infection and inflammatory damages, offering new opportunities as a repurposable drug candidate to treat COVID-19.
Published: 2022

8. Distinct systemic and mucosal immune responses during acute SARS-CoV-2 infection

Author: Smith, Nikaïa, Goncalves, Pedro, Charbit, Bruno, Grzelak, Ludivine, Beretta, Maxime, Planchais, Cyril, Bruel, Timothée, Rouilly, Vincent, Bondet, Vincent, Hadjadj, Jérôme, Yatim, Nader, Pere, Helene, Merkling, Sarah H., Ghozlane, Amine, Kernéis, Solen, Rieux-Laucat, Frederic, Terrier, Benjamin, Schwartz, Olivier, Mouquet, Hugo, Duffy, Darragh, Di Santo, James P., Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Immunité Innée - Innate Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP), Immunologie humorale - Humoral Immunology, Datactix, Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Hôpital Cochin [AP-HP], Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Epidémiologie et modélisation de la résistance aux antimicrobiens - Epidemiology and modelling of bacterial escape to antimicrobials (EMAE), This study was supported by grants from the Institut Pasteur (CoVarImm) and from the Agence National de la Recherche (ANR-flash COVID-19, to D.D. and J.P.D.), and by the Laboratoire d’Excellence ‘Milieu Intérieur’ (grant no. ANR-10-LABX-69-01) and the Fonds IMMUNOV, for Innovation in Immunopathology. N.S. is a recipient of the Pasteur-Roux-Cantarini Fellowship., We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting Luminex and Simoa analysis. We thank L. Motreff and L. Ma (Biomics Platform supported by France Génomique, ANR-10-INBS-09-09), IBISA and the Illumina COVID-19 Projects’ offer for microbial sequencing. We thank the Bioinformatics and Biostatistics HUB, Institut Pasteur for the assistance with the 16S rRNA-sequencing data analysis. We acknowledge all health-care workers involved in the diagnosis and treatment of patients in Cochin Hospital, especially C. Azoulay, L. Beaudeau, E. Canoui, P. Cohen, A. Contejean, B. Dunogué, D. Journois, P. Legendre, J. Marey and A. Régent., ANR-20-COVI-0053,CoVarImm,Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence(2020), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), BONDET, Vincent, Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence - - CoVarImm2020 - ANR-20-COVI-0053 - COVID-19 - VALID, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), and École Pratique des Hautes Études (EPHE)
Subjects: Adult, Male, Adolescent, viruses, [SDV]Life Sciences [q-bio], Adaptive immunity, Antibodies, Viral, Article, Cohort Studies, Young Adult, Nasopharynx, Humans, Immunity, Mucosal, Aged, Bacteria, SARS-CoV-2, Microbiota, COVID-19, Middle Aged, Viral Load, Gastrointestinal Microbiome, Immunity, Humoral, [SDV] Life Sciences [q-bio], Viral infection, Acute Disease, Spike Glycoprotein, Coronavirus, Cytokines, Mucosal immunology, Female, Interferons
Abstract: Coordinated local mucosal and systemic immune responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection either protect against coronavirus disease 2019 (COVID-19) pathologies or fail, leading to severe clinical outcomes. To understand this process, we performed an integrated analysis of SARS-CoV-2 spike-specific antibodies, cytokines, viral load and bacterial communities in paired nasopharyngeal swabs and plasma samples from a cohort of clinically distinct patients with COVID-19 during acute infection. Plasma viral load was associated with systemic inflammatory cytokines that were elevated in severe COVID-19, and also with spike-specific neutralizing antibodies. By contrast, nasopharyngeal viral load correlated with SARS-CoV-2 humoral responses but inversely with interferon responses, the latter associating with protective microbial communities. Potential pathogenic microorganisms, often implicated in secondary respiratory infections, were associated with mucosal inflammation and elevated in severe COVID-19. Our results demonstrate distinct tissue compartmentalization of SARS-CoV-2 immune responses and highlight a role for the nasopharyngeal microbiome in regulating local and systemic immunity that determines COVID-19 clinical outcomes., Mucosal surfaces of the respiratory tract are the first sites of entry and defense against SARS-CoV-2. Di Santo and colleagues perform paired analysis of the nasopharyngeal and systemic immune responses of SARS-CoV-2-infected patients and demonstrate distinct compartmentalization of immunity and shifts in the microbiome.
Published: 2021

9. Effective Anti–SARS-CoV-2 Immune Response in Patients With Clonal Mast Cell Disorders

Author: Julien Rossignol, Amani Ouedrani, Cristina Bulai Livideanu, Stéphane Barete, Louis Terriou, David Launay, Richard Lemal, Celine Greco, Laurent Frenzel, Cecile Meni, Christine Bodemere-Skandalis, Laura Polivka, Anne-Florence Collange, Hassiba Hachichi, Sonia Bouzourine, Djazira Nait Messaoud, Mathilde Negretto, Laurence Vendrame, Marguerite Jambou, Marie Gousseff, Stéphane Durupt, Jean-Christophe Lega, Jean-Marc Durand, Caroline Gaudy, Gandhi Damaj, Marie-Pierre Gourin, Mohamed Hamidou, Laurence Bouillet, Edwige Le Mouel, Alexandre Maria, Patricia Zunic, Quentin Cabrera, Denis Vincent, Christian Lavigne, Etienne Riviere, Clement Gourguechon, Marie Courbebaisse, David Lebeaux, Béatrice Parfait, Gérard Friedlander, Anne Brignier, Ludovic Lhermitte, Thierry Jo Molina, Julie Bruneau, Julie Agopian, Patrice Dubreuil, Dana Ranta, Alexandre Mania, Michel Arock, Isabelle Staropoli, Olivier Tournilhac, Olivier Lortholary, Olivier Schwartz, Lucienne Chatenoud, Olivier Hermine, Centre de référence des mastocytoses (CEREMAST), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Mastocytoses de Toulouse (CEREMAST), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne (UCA), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The authors would like to thank Fondation Université de Paris, AXA research fund, Fondation Hôpitaux de Paris-Hôpitaux de France, Mécénat du GH APHP. CUP, Fondation pour la Recherche en Physiologie and DMU BioPhyGen for the funding of the COVID-HOP study., ANR-20-COV1-0001,APCOD,Les cellules présentatrices d'antigènes dans la maladie de COVID-19 à résolution monocellulaire(2020), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), CHU Toulouse [Toulouse], Virus et Immunité - Virus and immunity, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: PBMC, peripheral blood mononuclear cell, BMI, body mass index, T cells, B-cells, CEREMAST, Centre de Référence des Mastocytoses, CM, cutaneous mastocytosis, MMAS, monoclonal mast cell activation syndrome, PHA, phytohemagglutinin, PMSI, Programme de médicalisation des systèmes d'information, Antibodies, Viral, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, Antiviral Agents, WHO, World Health Organization, MIS, mastocytosis in the skin, HEK, human embryonic kidney, Humans, Immunology and Allergy, IFN, interferon, Mast Cells, APHP, Assistance Publique - Hôpitaux de Paris (Paris Public Hospital Group), B cells, SARS-CoV-2, T-cells, Immunity, COVID-19, ISM, indolent systemic mastocytosis, Clonal mast cell activation syndrome, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MCAS, mast cell activation syndrome, Original Article, Mast cell activation dis- orders, SSM, smoldering systemic mastocytosis, NK, natural killer, Mastocytosis, COVID-19, coronavirus disease 19, Mast cell activation disorders, cMCAD, clonal mast cell activation disorder
Abstract: International audience; BackgroundMast cells are key players in innate immunity and the TH2 adaptive immune response. The latter counterbalances the TH1 response, which is critical for antiviral immunity. Clonal mast cell activation disorders (cMCADs, such as mastocytosis and clonal mast cell activation syndrome) are characterized by abnormal mast cell accumulation and/or activation. No data on the antiviral immune response in patients with MCADs have been published.ObjectiveTo study a comprehensive range of outcomes in patients with cMCAD with PCR- or serologically confirmed coronavirus disease 2019 and to characterize the specific anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune response in this setting.MethodsClinical follow-up and outcome data were collected prospectively over a 12-month period by members of the French Centre de Référence des Mastocytoses rare disease network. Anti–SARS-CoV-2–specific T-cell activity was measured with an ELISA, and humoral responses were evaluated by assaying circulating levels of specific IgG, IgA, and neutralizing antibodies.ResultsOverall, 32 patients with cMCAD were evaluated. None required noninvasive or mechanical ventilation. Two patients were admitted to hospital for oxygen and steroid therapy. The SARS-CoV-2–specific immune response was characterized in 21 of the 32 patients. Most had high counts of circulating SARS-CoV-2–specific, IFN-γ–producing T cells and high titers of neutralizing antispike IgGs. The patients frequently showed spontaneous T-cell IFN-γ production in the absence of stimulation; this production was correlated with basal circulating tryptase levels (a marker of the mast cell burden).ConclusionsPatients with cMCADs might not be at risk of severe coronavirus disease 2019, perhaps due to their spontaneous production of IFN-γ.
Published: 2022

10. Fusogenicity and neutralization sensitivity of the SARS-CoV-2 Delta sublineage AY.4.2

Author: Nell Saunders, Delphine Planas, William H. Bolland, Christophe Rodriguez, Slim Fourati, Julian Buchrieser, Cyril Planchais, Matthieu Prot, Isabelle Staropoli, Florence Guivel-Benhassine, Françoise Porrot, David Veyer, Hélène Péré, Nicolas Robillard, Madelina Saliba, Artem Baidaliuk, Aymeric Seve, Laurent Hocqueloux, Thierry Prazuck, Felix A. Rey, Hugo Mouquet, Etienne Simon-Lorière, Timothée Bruel, Jean-Michel Pawlotsky, Olivier Schwartz, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre Hospitalier Régional d'Orléans (CHRO), Virologie Structurale - Structural Virology, Work in OS lab is funded by Institut Pasteur, Fondation pour la Recherche Médicale (FRM), Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR. Work in UPBI is funded by grant ANR-10-INSB-04-01 and Région Ile-de-France program DIM1-Health. NS is supported by the French Ministry of Higher Education, Research and Innovation. DP is supported by the Vaccine Research Institute. HM lab is funded by the Institut Pasteur, the Milieu Intérieur Program (ANR-10-LABX-69-01), the INSERM, REACTing, EU (RECOVER) and Fondation de France (#00106077) grants. ESL lab is funded by Institut Pasteur and the French Government's Investissement d'Avenir programme, Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant n°ANR-10-LABX-62-IBEID)., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute (VRI), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE)
Subjects: Vaccines, MESH: Humans, SARS-CoV-2, COVID-19, MESH: Spike Glycoprotein, Coronavirus, General Medicine, Antibodies, Monoclonal, Humanized, Antibodies, Viral, General Biochemistry, Genetics and Molecular Biology, Neutralization, Viral Envelope Proteins, Delta, MESH: Antibodies, Monoclonal, Humanized, AY.4.2, MESH: Viral Envelope Proteins, Spike Glycoprotein, Coronavirus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Fusogenicity, Humans, MESH: COVID-19, MESH: SARS-CoV-2, MESH: Antibodies, Viral
Abstract: SARS-CoV-2 lineages are continuously evolving. As of December 2021, the AY.4.2 Delta sub-lineage represented 20 % of sequenced strains in the UK and had been detected in dozens of countries. It has since then been supplanted by Omicron. The AY.4.2 spike displays three additional mutations (T95I, Y145H and A222V) in the N-terminal domain when compared to the original Delta variant (B.1.617.2) and remains poorly characterized.We compared the Delta and the AY.4.2 spikes, by assessing their binding to antibodies and ACE2 and their fusogenicity. We studied the sensitivity of an authentic AY.4.2 viral isolate to neutralizing antibodies.The AY.4.2 spike exhibited similar binding to all the antibodies and sera tested, and similar fusogenicity and binding to ACE2 than the ancestral Delta spike. The AY.4.2 virus was slightly less sensitive than Delta to neutralization by a panel of monoclonal antibodies; noticeably, the anti-RBD Imdevimab showed incomplete neutralization. Sensitivity of AY.4.2 to sera from vaccinated individuals was reduced by 1.3 to 3-fold, when compared to Delta.Our results suggest that mutations in the NTD remotely impair the efficacy of anti-RBD antibodies. The spread of AY.4.2 was not due to major changes in spike fusogenicity or ACE2 binding, but more likely to a partially reduced neutralization sensitivity.The work was funded by Institut Pasteur, Fondation pour la Recherche Médicale, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute, Labex IBEID, ANR/FRM Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR.
Published: 2022

11. Asymptomatic and symptomatic SARS-CoV-2 infections elicit polyfunctional antibodies

Author: Stéphane Pelleau, François Anna, Michael T. White, Pierre Charneau, Arnaud Fontanet, Timothée Bruel, Hugo Mouquet, Bruno Hoen, Yoann Madec, Jérémy Dufloo, Yves Levy, Ludivine Grzelak, Isabelle Staropoli, Marie-Noëlle Ungeheuer, Laura Tondeur, Rémy Robinot, Julian Buchrieser, Aurélie Wiedemann, Cyril Planchais, Olivier Schwartz, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris]-TheraVectys, Malaria : parasites et hôtes - Malaria : parasites and hosts, Institut Pasteur [Paris], Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Direction de la recherche médicale de l'Institut Pasteur, Conservatoire National des Arts et Métiers [CNAM] (CNAM), This work was supported by the Urgence COVID-19 Fundraising Campaign of Institut Pasteur. O.S. is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), the 'TIMTAMDEN' project (a collaboration of Inserm, Institut Pasteur, and IRD, ANR-14-CE14-0029), the ANR 'CHIKV-Viro-Immuno' project (ANR-14-CE14-0015-01), and the Gilead HIV cure program. J.D. and L.G. are supported by the French Ministry of Higher Education, Research and Innovation. H.M. is funded by the Institut Pasteur, the Milieu Intérieur Program (ANR-10-LABX-69-01), Inserm, and REACTing and EU RECOVER grants. C.P. is supported by a fellowship from the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS)., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Institut Pasteur [Paris] (IP)-TheraVectys, Institut Pasteur [Paris] (IP), Vaccine Research Institute [Créteil, France] (VRI), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)
Subjects: Male, Medicine (General), [SDV]Life Sciences [q-bio], Cell, Antibodies, Viral, Severity of Illness Index, Epitope, Immunoglobulin G, Neutralization, Antigen-Antibody Reactions, Epitopes, 0302 clinical medicine, antibody, Medicine, complement, Antibody-dependent cell-mediated cytotoxicity, 0303 health sciences, biology, Middle Aged, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, Spike Glycoprotein, Coronavirus, Female, medicine.symptom, Antibody, ADCC, Adult, Adolescent, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Asymptomatic, General Biochemistry, Genetics and Molecular Biology, Article, Virus, Young Adult, 03 medical and health sciences, R5-920, Neutralization Tests, Humans, asymptomatic, 030304 developmental biology, SARS-CoV-2, business.industry, Antibody-Dependent Cell Cytotoxicity, COVID-19, Complement System Proteins, Asymptomatic Diseases, Immunology, biology.protein, business, 030217 neurology & neurosurgery
Abstract: A large proportion of SARS-CoV-2 infected individuals remains asymptomatic. Little is known about the extent and quality of their antiviral humoral response. Here, we analyze antibody functions in 52 asymptomatic infected individuals, 119 mild and 21 hospitalized COVID-19 patients. We measured anti-Spike IgG, IgA and IgM levels with the S-Flow assay and map IgG-targeted epitopes by Luminex. We also evaluated neutralization, complement deposition and Antibody-Dependent Cellular Cytotoxicity (ADCC) using replication-competent SARS-CoV-2 or reporter cell systems. We show that COVID-19 sera mediate complement deposition and kill infected cells by ADCC. Sera from asymptomatic individuals neutralize the virus, activate ADCC and trigger complement deposition. Antibody levels and functions are lower in asymptomatic individuals than in symptomatic cases. Antibody functions are correlated, regardless of disease severity. Longitudinal samplings show that antibody functions follow similar kinetics of induction and contraction. Overall, asymptomatic SARS-CoV-2 infection elicits polyfunctional antibodies neutralizing the virus and targeting infected cells., Graphical Abstract, Dufloo et al. show that SARS-CoV-2 infection elicits antibodies that neutralize the virus, activate the complement system and kill infected cells by ADCC. These polyfunctional antibodies are slightly more abundant in symptomatic COVID-19 patients than in asymptomatic individuals and correlate with disease severity.
Published: 2020

12. SARS-CoV-2 infection in primary schools in northern France: A retrospective cohort study in an area of high transmission

Author: Yoann Madec, Pierre Charneau, Bruno Hoen, François Anna, Isabelle Cailleau, Marie-Noëlle Ungeheuer, Caroline Demeret, Lucie Kuhmel, Ludivine Grzelak, Laura Tondeur, Arnaud Fontanet, Olivier Schwartz, Rebecca Grant, Timothée Bruel, Isabelle Staropoli, Charlotte Renaudat, Sandrine Fernandes Pellerin, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Direction de la recherche médicale de l'Institut Pasteur, Institut Pasteur [Paris], Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Centre Médical de l'Institut Pasteur (CMIP), Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris]-TheraVectys, Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), The study was funded by Institut Pasteur, and several laboratories participating in the study receive funding from the Labex IBEID (ANR-10-LABX-62-IBEID), REACTing and the INCEPTION project (PIA/ANR-16-CONV-0005) for studies focusing on emerging viruses. OS lab is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro- Immuno' ANR-14-CE14-0015-01 and the Gilead HIV cure program. LG is supported by the French Ministry of Higher Education, Research and Innovation., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), Centre Médical de l'Institut Pasteur, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-TheraVectys, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: business.industry, Transmission (medicine), [SDV]Life Sciences [q-bio], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), education, Attack rate, School setting, Retrospective cohort study, Familial clustering, Asymptomatic, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, High transmission, Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030212 general & internal medicine, medicine.symptom, business, Demography
Abstract: BackgroundThe extent of SARS-CoV-2 transmission among pupils in primary schools and their families is unknown.MethodsBetween 28-30 April 2020, a retrospective cohort study was conducted among pupils, their parents and relatives, and staff of primary schools exposed to SARS-CoV-2 in February and March 2020 in a city north of Paris, France. Participants completed a questionnaire that covered sociodemographic information and history of recent symptoms. A blood sample was tested for the presence of anti-SARS-CoV-2 antibodies using a flow-cytometry-based assay.ResultsThe infection attack rate (IAR) was 45/510 (8.8%), 3/42 (7.1%), 1/28 (3.6%), 76/641 (11.9%) and 14/119 (11.8%) among primary school pupils, teachers, non-teaching staff, parents, and relatives, respectively (P = 0.29). Prior to school closure on February 14, three SARS-CoV-2 infected pupils attended three separate schools with no secondary cases in the following 14 days among pupils, teachers and non-teaching staff of the same schools. Familial clustering of cases was documented by the high proportion of antibodies among parents and relatives of infected pupils (36/59 = 61.0% and 4/9 = 44.4%, respectively). In children, disease manifestations were mild, and 24/58 (41.4%) of infected children were asymptomatic.InterpretationIn young children, SARS-CoV-2 infection was largely mild or asymptomatic and there was no evidence of onwards transmission from children in the school setting.
Published: 2020

13. Remodeling of the Core Leads HIV-1 Preintegration Complex into the Nucleus of Human Lymphocytes

Author: Florian Mueller, Blandine Monel, Pierre Charneau, Viviana Scoca, Stella Frabetti, Anastasia D. Gazi, Olivier Schwartz, Francesca Di Nunzio, Jacomine Krijnse-Locker, Guillermo Blanco-Rodriguez, Virologie moléculaire et Vaccinologie, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Ecole Doctorale Frontiere de l’Innovation en Recherche et Education (ED 474 FIRE), Université de Paris (UP)-Université Paris sciences et lettres (PSL), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris], Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Imagerie et Modélisation - Imaging and Modeling, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), This work was funded by the ANRS (Agence Nationale de Recherche sur le SIDA) grant ECTZ4469, the Sidaction/FRM grant n.11291, the Pasteur Institute., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Cité (UPCité)-Université Paris sciences et lettres (PSL), Institut Pasteur [Paris] (IP), Virus et Immunité - Virus and immunity (CNRS-UMR3569), and ANR-16-CE92-0008,membrane dynamics,Rupture et réparation membranaire : stratégies d'assemblage virale(2016)
Subjects: CD4-Positive T-Lymphocytes, Immunoelectron microscopy, Virus Integration, Immunology, Active Transport, Cell Nucleus, HIV Infections, integration, HIV Integrase, Microbiology, Genome, Pre-integration complex, nuclear import/export, 03 medical and health sciences, chemistry.chemical_compound, Virology, medicine, Humans, Nuclear pore, 030304 developmental biology, Cell Nucleus, 0303 health sciences, biology, human immunodeficiency virus, Chemistry, 030302 biochemistry & molecular biology, %22">HIV-Infektion , viral replication, Reverse transcriptase, 3. Good health, Cell biology, Integrase, Virus-Cell Interactions, medicine.anatomical_structure, HEK293 Cells, Viral replication, Cytoplasm, Insect Science, Multiprotein Complexes, biology.protein, HIV-1, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Nucleus, DNA, HeLa Cells
Abstract: How the reverse-transcribed genome reaches the host nucleus remains a main open question related to the infectious cycle of HIV-1. The HIV-1 core has a size of ∼100 nm, largely exceeding that of the NPC channel (∼39 nm). Thus, a rearrangement of the viral CA protein organization is required to achieve an effective nuclear translocation. The mechanism of this process remains undefined due to the lack of a technology capable of visualizing potential CA subcomplexes in association with the viral DNA in the nucleus of HIV-1-infected cells. By the means of state-of-the-art technologies (HIV-1 ANCHOR system combined with CLEM), our study shows that remodeled viral complexes retain multiple CA proteins but not an intact core or only a single CA monomer. These viral CA complexes associated with the retrotranscribed DNA can be observed inside the nucleus, and they represent a potential PIC. Thus, our study shed light on critical early steps characterizing HIV-1 infection, thereby revealing novel, therapeutically exploitable points of intervention. Furthermore, we developed and provided a powerful tool enabling direct, specific, and high-resolution visualization of intracellular and intranuclear HIV-1 subviral structures., Retroviral replication proceeds through obligate integration of the viral DNA into the host genome. In particular, for the HIV-1 genome to enter the nucleus, it must be led through the nuclear pore complex (NPC). During the HIV-1 cytoplasmic journey, the viral core acts as a shell to protect the viral genetic material from antiviral sensors and ensure an adequate environment for reverse transcription. However, the relatively narrow size of the nuclear pore channel requires that the HIV-1 core is reshaped into a structure that fits the pore. On the other hand, the organization of the viral CA proteins that remain associated with the preintegration complex (PIC) during and after nuclear translocation is still enigmatic. In this study, we analyzed the progressive organizational changes of viral CA proteins within the cytoplasm and the nucleus by immunogold labeling. Furthermore, we set up a novel technology, HIV-1 ANCHOR, which enables the specific detection of the retrotranscribed DNA by fluorescence microscopy, thereby offering the opportunity to uncover the architecture of the potential HIV-1 PIC. Thus, we combined the immunoelectron microscopy and ANCHOR technologies to reveal the presence of DNA- and CA-positive complexes by correlated light and electron microscopy (CLEM). During and after nuclear translocation, HIV-1 appears as a complex of viral DNA decorated by multiple viral CA proteins remodeled in a pearl necklace-like shape. Thus, we could describe how CA proteins are reshaped around the viral DNA to permit the entrance of the HIV-1 in the nucleus. This particular CA protein complex composed of the integrase and the retrotranscribed DNA leads the HIV-1 genome inside the host nucleus. Our findings contribute to the understanding of the early steps of HIV-1 infection and provide new insights into the organization of HIV-1 CA proteins during and after viral nuclear entry. Of note, we are now able to visualize the viral DNA in viral complexes, opening up new perspectives for future studies on virus’s fate in the cell nucleus. IMPORTANCE How the reverse-transcribed genome reaches the host nucleus remains a main open question related to the infectious cycle of HIV-1. The HIV-1 core has a size of ∼100 nm, largely exceeding that of the NPC channel (∼39 nm). Thus, a rearrangement of the viral CA protein organization is required to achieve an effective nuclear translocation. The mechanism of this process remains undefined due to the lack of a technology capable of visualizing potential CA subcomplexes in association with the viral DNA in the nucleus of HIV-1-infected cells. By the means of state-of-the-art technologies (HIV-1 ANCHOR system combined with CLEM), our study shows that remodeled viral complexes retain multiple CA proteins but not an intact core or only a single CA monomer. These viral CA complexes associated with the retrotranscribed DNA can be observed inside the nucleus, and they represent a potential PIC. Thus, our study shed light on critical early steps characterizing HIV-1 infection, thereby revealing novel, therapeutically exploitable points of intervention. Furthermore, we developed and provided a powerful tool enabling direct, specific, and high-resolution visualization of intracellular and intranuclear HIV-1 subviral structures.
Published: 2020

14. STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses

Author: Isabelle K. Vila, Hanane Chamma, Alizée Steer, Mathilde Saccas, Clara Taffoni, Evgenia Turtoi, Line S. Reinert, Saqib Hussain, Johanna Marines, Lei Jin, Xavier Bonnefont, Mathieu Hubert, Olivier Schwartz, Soren R. Paludan, Gaetan Van Simaeys, Gilles Doumont, Bijan Sobhian, Dimitrios Vlachakis, Andrei Turtoi, Nadine Laguette, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Aarhus University [Aarhus], Albany Medical College, Institut de Génomique Fonctionnelle (IGF), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Aarhus University Hospital, Center for Microscopy and Molecular Imaging (IBMM - CMMI), Université libre de Bruxelles (ULB), Agricultural University of Athens, Biomedical Research Foundation of the Academy of Athens (BRFAA), National and Kapodistrian University of Athens (NKUA), We acknowledge the SIRIC Montpellier Cancer grant (INCa_Inserm_DGOS_12553), Metamus-RAM and iExplore-RAM animal facilities, the Laboratoire de Mesures Physiques of the University of Montpellier for access to the MS instruments, the MRI imaging facility, member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency (ANR-10-INBS-04, 'Investments for the future'), and Ross Tomaino from the Taplin Mass Spectrometry Facility of Harvard Medical School for MS analysis. We thank T. Emilien, A. Sedda, C. de Maeseneire, N. Passon, and C. Van Heymbeek for their contribution. We thank the Cyclotron team from the Erasme Hospital, Brussels, Belgium, for the FDG provision. Work in N.L.’s laboratory is supported by the European Research Council (ERC-Stg CrIC: 637763, ERC-PoC DIM-CrIC: 893772), la Ligue pour la Recherche contre le Cancer, and the Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS: ECTZ117448). H.C. is supported by a PhD fellowship from la Ligue pour la Recherche contre le Cancer. C.T. is supported by the Merck Sharp and Dohme Avenir (MSD-Avenir – GnoSTic) program and an ANRS fellowship (ECTZ119088). J.M. is supported by a Conventions Industrielles de Formation par la Recherche (CIFRE) fellowship from the Agence Nationale de Recherche Technologie (ANRT). A.S. is supported by the ERC-PoC DIM-CrIC (893772). I.K.V. is supported by the ERC-Stg CrIC (637763) and the Fondation pour la Recherche Médicale (ARF20170938586). Work in S.R.P.’s laboratory is supported by the European Research Council (ERC-AdG ENVISION, 786602), the Novo Nordisk Foundation (NNF18OC0030274), and the Lundbeck Foundation (R198-2015-171 and R268-2016-3927). Work in A.T.’s laboratory is supported by a SIRIC Montpellier Cancer grant (INCa_Inserm_DGOS_12553), the Fondation de France (grant no. 00078461), and a LabEx MabImprove Starting Grant. X.B. is supported by ANR GH-gen (ANR-18-CE14-0017). The Center for Microscopy and Molecular Imaging (CMMI) is supported by the European Regional Development Fund (ERDF), the Walloon Region, the Fondation ULB, the Fonds Erasme, and Association Vinçotte Nuclear (AVN). G.D. is supported by the European Regional Development Fund (ERDF) and the Walloon Region. Work in O.S.’s lab is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, and IDISCOVR, Fondation pour la Recherche Médicale. Schematic representations were created with https://biorender.com, We thank M. Benkirane, G. Cavalli, J. Déjardin, and B. de Massy for discussions and comments. We thank C. Goujon and B. Bonaventure for CRISPR/Cas9 gRNA sequences., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used(2010), ANR-18-CE14-0017,GH-Gen,Origine et fonction du generateur hypophysaire de pulses d'hormone de croissance(2018), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-20-COVI-0062,proteoCOVID,Protéomique clinique de la protéine SARS-CoV-2 Spike pour optimiser sa détection et le développement de tests sérologiques(2020), European Project: 637763,H2020,ERC-2014-STG,CrIC(2015), European Project: 893772,DIM-CrIC, European Project: 786602,ENVISION, Virus et Immunité - Virus and immunity, Guerineau, Nathalie C., Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Laboratoires d'excellence - Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used - - MAbImprove2010 - ANR-10-LABX-0053 - LABX - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Origine et fonction du generateur hypophysaire de pulses d'hormone de croissance - - GH-Gen2018 - ANR-18-CE14-0017 - AAPG2018 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Protéomique clinique de la protéine SARS-CoV-2 Spike pour optimiser sa détection et le développement de tests sérologiques - - proteoCOVID2020 - ANR-20-COVI-0062 - COVID-19 - VALID, Molecular basis of the cross-talk between chronic inflammation and cancer - CrIC - - H20202015-04-01 - 2020-03-31 - 637763 - VALID, Decreasing Pancreatic Adenocarcinoma-related Inflammation using small molecule inhibitors of STING - DIM-CrIC - 893772 - INCOMING, Novel mechanisms of early defense against virus infections - ENVISION - 786602 - INCOMING, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), AZELEAD, 377 Rue du Professeur Blayac, 34080 Montpellier, France, Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Fatty Acid Desaturases, Physiology, [SDV]Life Sciences [q-bio], nucleic acid immunity, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, cytosolic DNA, Article, 03 medical and health sciences, 0302 clinical medicine, delta-6 Desaturase, Humans, FADS2, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, 030304 developmental biology, Inflammation, Metabolic Syndrome, interferon responses, 0303 health sciences, Cell Biology, Lipid Metabolism, eye diseases, 3. Good health, [SDV] Life Sciences [q-bio], Fatty Acids, Unsaturated/metabolism, inflammation, 030220 oncology & carcinogenesis, Fatty Acids, Unsaturated, metabolism, Fatty Acid Desaturases/genetics, STING, cGAS, polyunsaturated fatty acids
Abstract: Summary Concerted alteration of immune and metabolic homeostasis underlies several inflammation-related pathologies, ranging from metabolic syndrome to infectious diseases. Here, we explored the coordination of nucleic acid-dependent inflammatory responses and metabolic homeostasis. We reveal that the STING (stimulator of interferon genes) protein regulates metabolic homeostasis through inhibition of the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in polyunsaturated fatty acid (PUFA) desaturation. STING ablation and agonist-mediated degradation increased FADS2-associated desaturase activity and led to accumulation of PUFA derivatives that drive thermogenesis. STING agonists directly activated FADS2-dependent desaturation, promoting metabolic alterations. PUFAs in turn inhibited STING, thereby regulating antiviral responses and contributing to resolving STING-associated inflammation. Thus, we have unveiled a negative regulatory feedback loop between STING and FADS2 that fine-tunes inflammatory responses. Our results highlight the role of metabolic alterations in human pathologies associated with aberrant STING activation and STING-targeting therapies., Graphical abstract, Highlights • STING inhibits FADS2-dependent desaturation of PUFAs and LC-PUFAs • STING activation leads to upregulation of FADS2-associated desaturase activity • STING agonists activate FADS2-dependent PUFA and LC-PUFA desaturation • PUFAs inhibit STING-dependent inflammatory responses, The stimulator of interferon genes (STING) is a central regulator of nucleic acid-associated inflammatory responses. Here, Vila et al. discover that STING regulates polyunsaturated fatty acid (PUFA) metabolism, and in turn, PUFAs inhibit STING-dependent inflammation. This cross-regulation is central to the maintenance of metabolic homeostasis.
Published: 2022

15. Proliferative memory SAMHD1low CD4+ T cells harbour high levels of HIV-1 with compartmentalized viral populations

Author: Constance Delaugerre, Antoine Chaillon, Yves Levy, Olivier Schwartz, Joudy Alameddine, Davey M. Smith, Jean-Daniel Lelièvre, Maud Salmona, José-Luiz Lopez Zaragoza, Nabila Seddiki, Nicolas Ruffin, Lylia Hani, Marie-Laure Nere, Physiopathologie et immunothérapies dans l’infection VIH [Créteil] (Inserm U955 Équipe 16), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Vaccine Research Institute (VRI), Department of Medicine [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie clinique et maladies infectieuses [Créteil], Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This study was supported by the Investissement d’Avenir program managed by the ANR under reference ANR-10-LABX-77 and by the Agence Nationale pour la Recherche sur le SIDA et les hepatites virales (ANRS), the Vaccine Research Institute (VRI)., Bodescot, Myriam, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Medicine [Univ California San Diego] (MED - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute [Créteil, France] (VRI), and Virus et Immunité - Virus and immunity (CNRS-UMR3569)
Subjects: CD4-Positive T-Lymphocytes, Male, RNA viruses, Physiology, CCR4, HIV Infections, C-C chemokine receptor type 6, CXCR3, Pathology and Laboratory Medicine, Memory T cells, chemistry.chemical_compound, White Blood Cells, Cognition, Learning and Memory, Immunodeficiency Viruses, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Animal Cells, Medicine and Health Sciences, Biology (General), Data Management, Staining, 0303 health sciences, T Cells, 030302 biochemistry & molecular biology, Cell Staining, Phylogenetic Analysis, Middle Aged, Phenotype, 3. Good health, Viral Persistence and Latency, Body Fluids, Phylogenetics, Blood, Anti-Retroviral Agents, Medical Microbiology, Viral Pathogens, Viruses, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Lymph, Pathogens, Cellular Types, Anatomy, Research Article, Adult, Computer and Information Sciences, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, Immune Cells, Immunology, Biology, Research and Analysis Methods, Microbiology, Virus, SAM Domain and HD Domain-Containing Protein 1, 03 medical and health sciences, Memory, Virology, Retroviruses, Genetics, Humans, Evolutionary Systematics, Molecular Biology, Microbial Pathogens, 030304 developmental biology, Aged, Taxonomy, Evolutionary Biology, Blood Cells, Lentivirus, Organisms, Biology and Life Sciences, HIV, Cell Biology, RC581-607, Molecular biology, chemistry, Specimen Preparation and Treatment, HIV-1, Cognitive Science, Parasitology, Immunologic diseases. Allergy, Immunologic Memory, DNA, SAMHD1, Neuroscience
Abstract: We previously reported the presence of memory CD4+ T cells that express low levels of SAMHD1 (SAMHD1low) in peripheral blood and lymph nodes from both HIV-1 infected and uninfected individuals. These cells are enriched in Th17 and Tfh subsets, two populations known to be preferentially targeted by HIV-1. Here we investigated whether SAMHD1low CD4+ T-cells harbour replication-competent virus and compartimentalized HIV-1 genomes. We sorted memory CD4+CD45RO+SAMHD1low, CD4+CD45RO+SAMHD1+ and naive CD4+CD45RO-SAMHD1+ cells from HIV-1-infected patients on anti-retroviral therapy (c-ART) and performed HIV-1 DNA quantification, ultra-deep-sequencing of partial env (C2/V3) sequences and phenotypic characterization of the cells. We show that SAMHD1low cells include novel Th17 CCR6+ subsets that lack CXCR3 and CCR4 (CCR6+DN). There is a decrease of the % of Th17 in SAMHD1low compartment in infected compared to uninfected individuals (41% vs 55%, p, Author summary In our previous results we reported that memory CD4+ T cells expressing low levels of SAMHD1 (SAMHD1low) are present in peripheral blood and lymph nodes from HIV-1 infected and uninfected individuals. These cells were enriched in Th17 and Tfh, two populations targeted by HIV-1. Here we used purified memory CD4+CD45RO+SAMHD1low, CD4+CD45RO+SAMHD1+ and naive CD4+CD45RO-SAMHD1+ cells from HIV-1-infected and treated patients to perform cell-associated HIV-1 DNA quantification, p24-producing cells detection, ultra-deep-sequencing of partial env (C2/V3) HIV-1 DNA and further phenotypic characterization. Our results demonstrate that (i) Th17 and CCR6+DN-expressing transcriptional signature of early Th17, two major populations that are susceptible to HIV-1 infection, are present in SAMHD1low cells, and while the former decreased significantly in c-ART HIV-1 infected compared to uninfected individuals, the latter significantly increased; (ii) memory SAMHD1low cells from c-ART patients carry high levels of HIV-1 DNA compared to SAMHD1+ cells, and these levels positively and significantly correlated with Ki67 expression; (iii) memory SAMHD1low cells from patients harbour p24-producing cells; (iv) phylogenetic analyses revealed well-segregated HIV-1 DNA populations with significant compartmentalization between SAMHD1low and SAMHD1+ cells and limited viral exchange. Our data demonstrate that memory SAMHD1low cells contribute to HIV-1 persistence.
Published: 2018

16. Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection

Author: Beatrice Jacquelin, Alice Lepelley, Pierre Lebon, Steven E. Bosinger, Simon P. Jochems, Lise Chauveau, Mickaël J.-Y. Ploquin, Gaël Petitjean, Olivier Schwartz, Anne-Sophie Liovat, Michaela Müller-Trutwin, Nicolas Huot, Françoise Barré-Sinoussi, Emily K. Cartwright, Guido Silvestri, HIV, Inflammation et persistance, Institut Pasteur [Paris], Université Paris Diderot - Paris 7 (UPD7), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Régulation des Infections Rétrovirales, Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center [Lawrenceville, GA], Emory University [Atlanta, GA]-Emory University [Atlanta, GA], Non-Human Primate Genomics Core, Laboratoire de Virologie, Hôpital Saint-Vincent de Paul-Université Paris Descartes - Paris 5 (UPD5), This work was supported by Fondation AREVA, the French National Agency for Research on AIDS and Viral Hepatitis (ANRS), Sidaction, Fondation TOTAL (to F.B.-S.), the French Ministry of Higher Education and Research, and Institut Pasteur., Virus et Immunité, Institut Pasteur [Paris] - Université Paris Diderot - Paris 7 (UPD7) - Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Yerkes National Primate Research Center, Hôpital Saint-Vincent de Paul - Université Paris Descartes - Paris 5 (UPD5), HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: Receptors, CCR5, viruses, Immunology, Heterologous, Inflammation, macromolecular substances, Plasmacytoid dendritic cell, medicine.disease_cause, Microbiology, Macaque, Cercocebus atys, 03 medical and health sciences, Immune system, Interferon, Virology, biology.animal, Chlorocebus aethiops, medicine, Animals, 030304 developmental biology, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, biology, 030306 microbiology, virus diseases, hemic and immune systems, Dendritic Cells, Virus Internalization, Simian immunodeficiency virus, 3. Good health, Insect Science, CD4 Antigens, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Pseudotyping, Pathogenesis and Immunity, Simian Immunodeficiency Virus, medicine.symptom, medicine.drug
Abstract: Human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques (MAC) lead to chronic inflammation and AIDS. Natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM), are protected against SIV-induced chronic inflammation and AIDS. Here, we report that AGM plasmacytoid dendritic cells (pDC) express extremely low levels of CD4, unlike MAC and human pDC. Despite this, AGM pDC efficiently sensed SIVagm, but not heterologous HIV/SIV isolates, indicating a virus-host adaptation. Moreover, both AGM and SM pDC were found to be, in contrast to MAC pDC, predominantly negative for CCR5. Despite such limited CD4 and CCR5 expression, lymphoid tissue pDC were infected to a degree similar to that seen with CD4 + T cells in both MAC and AGM. Altogether, our finding of efficient pDC infection by SIV in vivo identifies pDC as a potential viral reservoir in lymphoid tissues. We discovered low expression of CD4 on AGM pDC, which did not preclude efficient sensing of host-adapted viruses. Therefore, pDC infection and efficient sensing are not prerequisites for chronic inflammation. The high level of pDC infection by SIVagm suggests that if CCR5 paucity on immune cells is important for nonpathogenesis of natural hosts, it is possibly not due to its role as a coreceptor. IMPORTANCE The ability of certain key immune cell subsets to resist infection might contribute to the asymptomatic nature of simian immunodeficiency virus (SIV) infection in its natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM). This relative resistance to infection has been correlated with reduced expression of CD4 and/or CCR5. We show that plasmacytoid dendritic cells (pDC) of natural hosts display reduced CD4 and/or CCR5 expression, unlike macaque pDC. Surprisingly, this did not protect AGM pDC, as infection levels were similar to those found in MAC pDC. Furthermore, we show that AGM pDC did not consistently produce type I interferon (IFN-I) upon heterologous SIVmac/HIV type 1 (HIV-1) encounter, while they sensed autologous SIVagm isolates. Pseudotyping SIVmac/HIV-1 overcame this deficiency, suggesting that reduced uptake of heterologous viral strains underlays this lack of sensing. The distinct IFN-I responses depending on host species and HIV/SIV isolates reveal the host/virus species specificity of pDC sensing.
Published: 2015

17. Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation

Author: Tévy Suzy Tep, Wendy Bakeman, Gordon J. Freeman, Yuwei Zhang, Quentin Eichbaum, Olivier Schwartz, Sandrina DaFonseca, Mohamed El-Far, Annie Gosselin, Elias K. Haddad, Rebeka Bordi, Elias A. Said, Nicolas Chomont, Petronela Ancuta, Rafick Pierre Sekaly, Jean-Pierre Routy, Julien van Grevenynghe, Department of Microbiology, Infectiology and Immunology, Université de Montréal, Centre de recherche, CHU Montréal, McGill University Health Center [Montreal] (MUHC), Vaccine and Gene Therapy Institute Florida (VGTI), Vanderbilt University [Nashville], Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Dana-Farber Cancer Institute [Boston], Case Western Reserve University [Cleveland], M. E., E. A. S. and J. V. G. are funded by the Canadian Institutes of Health Research. J-P. R. holds the Louis Lowenstein Chair in Haematology & Oncology at McGill University. This study was supported by funds from the US National Institutes of Health (NIH U19 AI096109-03 and IDPIDA028871-01), Canadian Institutes of Health Research (103230), Canadian Institutes of Health Research Canadian HIV Trials Network (CTN 257) and Fonds de la Recherche Québec-Santé: Réseau SIDA/Maladies infectieuses., Virus et Immunité - Virus and immunity (CNRS-UMR3569), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, CD4-Positive T-Lymphocytes, Male, [SDV]Life Sciences [q-bio], T cell, chemical and pharmacologic phenomena, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, Virology, medicine, Humans, Cytotoxic T cell, CTLA-4 Antigen, nef Gene Products, Human Immunodeficiency Virus, IL-2 receptor, Antigen-presenting cell, Animal - Retroviruses, Immune Evasion, 030304 developmental biology, Interleukin 3, 0303 health sciences, CD40, biology, Animal, ZAP70, virus diseases, hemic and immune systems, 3. Good health, medicine.anatomical_structure, Gene Expression Regulation, Host-Pathogen Interactions, HIV-1, biology.protein, Female, T-Lymphocytes, Cytotoxic, 030215 immunology
Abstract: International audience; CTLA-4 is a negative regulator of T-cell receptor-mediated CD4(+) T-cell activation and function. Upregulation of CTLA-4 during human immunodeficiency virus type 1 (HIV-1) infection on activated T cells, particularly on HIV-specific CD4(+) T cells, correlates with immune dysfunction and disease progression. As HIV-1 infects and replicates in activated CD4(+) T cells, we investigated mechanisms by which HIV-1 modulates CTLA-4 expression to establish productive viral infection in these cells. Here, we demonstrate that HIV-1 infection in activated CD4(+) T cells was followed by Nef-mediated downregulation of CTLA-4. This was associated with a decreased T-cell activation threshold and significant resistance to CTLA-4 triggering. In line with these in vitro results, quantification of pro-viral HIV DNA from treatment-naive HIV-infected subjects demonstrated a preferential infection of memory CD4(+)CTLA-4(+) T cells, thus identifying CTLA-4 as a biomarker for HIV-infected cells in vivo. As transcriptionally active HIV-1 and Nef expression in vivo were previously shown to take place mainly in the CD3(+)CD4(-)CD8(-) [double-negative (DN)] cells, we further quantified HIV DNA in the CTLA-4(+) and CTLA-4(-) subpopulations of these cells. Our results showed that DN T cells lacking CTLA-4 expression were enriched in HIV DNA compared with DN CTLA-4(+) cells. Together, these results suggested that HIV-1 preferential infection of CD4(+)CTLA-4(+) T cells in vivo was followed by Nef-mediated concomitant downregulation of both CD4 and CTLA-4 upon transition to productive infection. This also highlights the propensity of HIV-1 to evade restriction of the key negative immune regulator CTLA-4 on cell activation and viral replication, and therefore contributes to the overall HIV-1 pathogenesis.
Published: 2015

18. A human immune system mouse model with robust lymph node development

Author: Hugo Mouquet, Grégory Jouvion, Helene Strick-Marchand, Ai Ing Lim, Nicolas Serafini, Zacarias Garcia, Philippe Bousso, Yan Li, Daniela Finke, Olivier Schwartz, Timothée Bruel, Ayrin Kök, Franck Bourgade, Guillemette Masse-Ranson, Thierry Hieu, Antoine Toubert, Mathilde Dusséaux, James P. Di Santo, Immunité Innée - Innate Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamiques des Réponses immunes - Dynamics of Immune Responses, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Réponse humorale aux pathogènes, Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris]-Université de Paris (UP), Animalerie centrale (Plate-forme), Institut Pasteur [Paris], Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Developmental Immunology, University of Basel (Unibas), This work was supported by the Agence Nationale de la Recherche (ANR) programme RPIB (Im_HIS to J.P.D.), the Laboratoire d’Excellence REVIVE (grant ANR-10-LABX-73 to Y.L. and J.P.D.), the Laboratoire d’Excellence Vaccine Research Institute (grant ANR-10-LABX-77 to T.B. and O.S.), the Laboratoire d’Excellence Milieu Intérieur (grant ANR-10-LABX-69 to H.M.), the Laboratoire d’Excellence IBEID (grant ANR-10-LABX-62 to O.S.), the Agence Nationale de Recherche sur le SIDA et les hepatitis (grant 15465 to O.S.), the European Commission Seventh Framework Programme no. 305578 (PathCO, to J.P.D.), the European Research Council (grant ERC-2013-StG 337146 to A.K. and T.H., grant ERC-2017-AvG 771167 to P.B.), Gilead Sciences (grant 00397 to G.M.-R. and J.P.D.), the Institut Pasteur (Core grant to J.P.D., G5 Program to H.M.), and INSERM (Core grant to J.P.D.)., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 305578,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,PATHCO(2012), European Project: 337146,EC:FP7:ERC,ERC-2013-StG,HUMANTIVIRUSES(2014), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute [Créteil, France] (VRI), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), and Institut Pasteur [Paris]-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Male, T-Lymphocytes, MESH: Lymph Nodes, HIV Infections, Biochemistry, MESH: Mice, Knockout, MESH: HIV-1, Mice, MESH: Animals, Lymph node, Mice, Knockout, MESH: Cytokines, B-Lymphocytes, Mice, Inbred BALB C, MESH: Virus Latency, MESH: HIV Infections, 3. Good health, Virus Latency, medicine.anatomical_structure, Lymphatic system, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, MESH: Immunoglobulin Class Switching, Cytokines, Female, Lymph, Biotechnology, Interleukin Receptor Common gamma Subunit, MESH: Mice, Transgenic, Transgene, MESH: Mice, Inbred BALB C, Mice, Transgenic, Biology, MESH: Models, Immunological, 03 medical and health sciences, Immune system, Thymic Stromal Lymphopoietin, Immunity, MESH: Mice, Inbred C57BL, MESH: B-Lymphocytes, medicine, Animals, Humans, Secondary lymphoid tissue, Molecular Biology, MESH: Mice, MESH: Humans, MESH: Interleukin Receptor Common gamma Subunit, Models, Immunological, Cell Biology, Immunoglobulin Class Switching, MESH: Male, Mice, Inbred C57BL, 030104 developmental biology, MESH: T-Lymphocytes, Immunoglobulin class switching, Immunology, HIV-1, Lymph Nodes, MESH: Female
Abstract: International audience; Lymph nodes (LNs) facilitate the cellular interactions that orchestrate immune responses. Human immune system (HIS) mice are powerful tools for interrogation of human immunity but lack secondary lymphoid tissue (SLT) as a result of a deficiency in Il2rg-dependent lymphoid tissue inducer cells. To restore LN development, we induced expression of thymic-stromal-cell-derived lymphopoietin (TSLP) in a Balb/c Rag2-/-Il2rg-/-SirpaNOD (BRGS) HIS mouse model. The resulting BRGST HIS mice developed a full array of LNs with compartmentalized human B and T cells. Compared with BRGS HIS mice, BRGST HIS mice have a larger thymus, more mature B cells, and abundant IL-21-producing follicular helper T (TFH) cells, and show enhanced antigen-specific responses. Using BRGST HIS mice, we demonstrated that LN TFH cells are targets of acute HIV infection and represent a reservoir for latent HIV. In summary, BRGST HIS mice reflect the effects of SLT development on human immune responses and provide a model for visualization and interrogation of regulators of immunity.
Published: 2017

19. Complement contributes to antibody-mediated protection against repeated SHIV challenge

Author: Benjamin S. Goldberg, David A. Spencer, Shilpi Pandey, Tracy Ordonez, Philip Barnette, Yun Yu, Lina Gao, Jérémy Dufloo, Timothée Bruel, Olivier Schwartz, Margaret E. Ackerman, Ann J. Hessell, Dartmouth College [Hanover], Oregon Health and Science University [Portland] (OHSU), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and This work was supported by the following grants: R01 AI129801, P51 OD011092, R01 AI131975, and U42 OD023038-03.
Subjects: Multidisciplinary, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy
Abstract: International audience; The first clinical efficacy trials of a broadly neutralizing antibody (bNAb) resulted in less benefit than expected and suggested that improvements are needed to prevent HIV infection. While considerable effort has focused on optimizing neutralization breadth and potency, it remains unclear whether augmenting the effector functions elicited by broadly neutralizing antibodies (bNAbs) may also improve their clinical potential. Among these effector functions, complement-mediated activities, which can culminate in the lysis of virions or infected cells, have been the least well studied. Here, functionally modified variants of the second-generation bNAb 10-1074 with ablated and enhanced complement activation profiles were used to examine the role of complement-associated effector functions. When administered prophylactically against simian-HIV challenge in rhesus macaques, more bNAb was required to prevent plasma viremia when complement activity was eliminated. Conversely, less bNAb was required to protect animals from plasma viremia when complement activity was enhanced. These results suggest that complement-mediated effector functions contribute to in vivo antiviral activity, and that their engineering may contribute to the further improvements in the efficacy of antibody-mediated prevention strategies.
Published: 2023

20. Dual inhibitory effects of APOBEC family proteins on retrotransposition of mammalian endogenous retroviruses

Author: Olivier Schwartz, Thierry Heidmann, Cécile Esnault, Jean K. Millet, Institut Gustave Roussy (IGR), Rétrovirus endogènes et éléments rétroides des eucaryotes supérieurs (REERES (UMR 8122)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported by the CNRS, by grants from the Ligue Nationale contre le Cancer (to T.H., Equipe Labellise´e) and from ANRS, Sidaction and Institut Pasteur (O.S.). Funding to pay the Open Access publication charges for this article was provided by CNRS, Virus et Immunité - Virus and immunity (CNRS-UMR3569), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio], viruses, Endogenous retrovirus, Retrotransposon, APOBEC-3G Deaminase, Nucleoside Deaminases, Biology, Polymerase Chain Reaction, Article, Cytosine Deaminase, Mice, 03 medical and health sciences, Cytidine Deaminase, Complementary DNA, Chlorocebus aethiops, Genetics, Animals, Humans, APOBEC3G, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Endogenous Retroviruses, 030302 biochemistry & molecular biology, Cytosine deaminase, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cytidine deaminase, Repressor Proteins, RNA editing, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA Editing, HeLa Cells
Abstract: International audience; We demonstrated previously that the cytosine deaminase APOBEC3G inhibits retrotransposition of two active murine endogenous retroviruses, namely intracisternal A-particles (IAP) and MusD, in an ex vivo assay where retrotransposition was monitored by selection of neo-marked elements. Sequencing of the transposed copies further disclosed extensive editing, resulting in a high load of G-to-A mutations. Here, we asked whether this G-to-A editing was associated with an impact of APOBEC3G on viral cDNA yields. To this end, we used a specially designed quantitative PCR method to selectively measure the copy number of transposed retroelements, in the absence of G418 selection. We show that human APOBEC3G severely reduces the number of MusD and IAP transposed cDNA copies, with no effect on the level of the intermediate RNA transcripts. The magnitude of the decrease closely parallels that observed when transposed copies are assayed by selection of G418-resistant cells. Moreover, sequencing of transposed elements recovered by PCR without prior selection of the cells reveals high-level editing. Using this direct method with a series of cytosine deaminases, we further demonstrate a similar dual effect of African green monkey APOBE3G, human APOBEC3F and murine APOBEC3 on MusD retrotransposition, with a distinct extent and site specificity for each editing activity. Altogether the data demonstrate that cytosine deaminases have a protective effect against endogenous retroviruses both by reducing viral cDNA levels and by introducing mutations in the transposed copies, thus inactivating them for subsequent rounds of retrotransposition. This dual, two-step effect likely participates in the efficient defense of the cell genome against invading endogenous retroelements.
Published: 2006

21. The SAMHD1 knockout mouse model: in vivo veritas?

Author: Ferdinand Roesch, Olivier Schwartz, Université Sorbonne Paris Cité (USPC), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity (CNRS-UMR3569), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio], Mutant, Inflammation, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Retrovirus, medicine, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Autoimmune disease, 0303 health sciences, General Immunology and Microbiology, biology, General Neuroscience, biology.organism_classification, medicine.disease, Virology, Reverse transcriptase, 3. Good health, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Knockout mouse, medicine.symptom, 030217 neurology & neurosurgery, Intracellular, SAMHD1
Abstract: EMBO J 32 18, 2454–2462 doi:10.1038/emboj.2013.163; published online July192013 SAMHD1, a dNTP hydrolase mutated in the autoimmune encephalopathy Aicardi-Goutieres syndrome, restricts HIV replication in non-dividing human cells by reducing intracellular deoxyribonucleotide pools. New work in The EMBO Journal unexpectedly finds neither autoimmune disease nor increased murine retrovirus infection in SAMHD1 knockout mice, but improved replication of a mutant HIV with increased sensitivity to low dNTP levels. Thus, while the new mouse model partially recapitulates known features of human SAMHD1, it represents a unique tool to study the role of dNTP regulation during inflammation, viral infection and other pathologies.
Published: 2013

22. Erratum: Corrigendum: CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses

Author: Christine Lacabaratz, Yves Levy, Christina Psomas, José-Luis López-Zaragoza, Benjamin Descours, Raoul Raffel, Monsef Benkirane, Jean-Daniel Lelièvre, Timothée Bruel, Gaël Petitjean, Jacques Reynes, Olivier Schwartz, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute, Université Paris-Est, Faculté de Médecine, INSERM U955, and Assistance Publique-Hôpitaux de Paris, Groupe Henri-Mondor Albert-Chenevier, Service d'Immunologie Clinique, Créteil, France, Inserm, U955, Equipe 16, Créteil, France, AP-HP, Hôpital Henri-Mondor Albert-Chenevier, Service d'Immunologie Clinique et Maladies Infectieuses 94000 Créteil, France, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Virus et Immunité - Virus and immunity (CNRS-UMR3569), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Cd4 t cell, [SDV]Life Sciences [q-bio], Human immunodeficiency virus (HIV), Biology, medicine.disease_cause, Virology, 03 medical and health sciences, 030104 developmental biology, Replication (statistics), medicine, ComputingMilieux_MISCELLANEOUS
Abstract: Nature 543, 564–567 (2017); doi:10.1038/nature21710 In the Acknowledgements section, the European FP7 contract number was incorrect in two places; it should be 305762. The original Letter has been corrected online.
Published: 2017

23. Type I interferon response and vascular alteration in chilblain‐like lesions during the COVID‐19 outbreak*

Author: Jérôme Hadjadj, Bruno Charbit, Djaouida Bengoufa, A. Philippe, Laura Barnabei, Olivier Schwartz, Coralie L. Guerin, Léa Jaume, Hervé Bachelez, Darragh Duffy, David M. Smadja, Jean-David Bouaziz, Nicolas Gendron, A. Calugareanu, B. Joly, Sonia Meynier, Martine Bagot, Saint-Louis Core, Frédéric Rieux-Laucat, Jérôme LeGoff, H. Le Buanec, Marisa Battistella, S. Maylin, Nader Yatim, C. Delaugerre, V. Siguret, Richard Chocron, Charles Cassius, L. Frumholtz, Ludivine Grzelak, Nikaïa Smith, Université de Paris, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut Curie [Paris], Hôpital Lariboisière-Fernand-Widal [APHP], Recherche clinique appliquée à l'hématologie (URP_3518), Université Paris Cité (UPCité), Genetic skin diseases : from disease mechanism to therapies (Equipe Inserm U1163), Fondation Alain Carpentier - (Centre Médical International) [Paris] (FAC - CMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), The study was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and by a government grant managed by the Agence National de la Recherche as part of the ‘Investment for the Future’ programme (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010), grants from the Agence National de la Recherche (ANR-flash Covid19 ‘AIROCovid’ to F.R.L.) and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). J.H. was a recipient of an INSERM ‘poste d’acceuil’ programme, and an Institut Imagine MD-PhD fellowship programme supported by the Fondation Bettencourt Schueller. L.B. was a recipient of an Imagine Institute PhD international programme supported by the Fondation Bettencourt Schueller. S. Meynier was a recipient of an INSERM and Institut Imagine postdoctoral programme supported by the Fondation pour la Recherche Médicale (FRM no. SPF20170938825)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), and ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018)
Subjects: 0303 health sciences, business.industry, Angiogenesis, [SDV]Life Sciences [q-bio], Dermatology, Gene signature, medicine.disease, Endothelial progenitor cell, Pathophysiology, 3. Good health, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Immune system, immune system diseases, hemic and lymphatic diseases, Immunology, Medicine, Endothelial dysfunction, business, Chilblains, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Anti-neutrophil cytoplasmic antibody
Abstract: International audience; BackgroundThe outbreak of chilblain-like lesions (CLL) during the COVID-19 pandemic has been reported extensively, potentially related to SARS-CoV-2 infection, yet its underlying pathophysiology is unclear.ObjectivesTo study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold-induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus.MethodsThis observational study was conducted during 9–16 April 2020 at Saint-Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID-19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included.ResultsHistological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic–natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL.ConclusionsOur findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestations.
Published: 2021

24. Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2

Author: Veronica V. Rezelj, Audrey Fischer, Francesca Moretti, Romel Rosales, Olivier Schwartz, Jiankun Lyu, Francois Pognan, Andrew C. Kruse, Kris M. White, Marco Vignuzzi, Heiko Schadt, Ziyang Zhang, Henry R. O’Donnell, Michael Schotsaert, Kevan M. Shokat, Tia A. Tummino, Adolfo García-Sastre, Nevan J. Krogan, Jean-Rene Galarneau, Raveen Rathnasinghe, Blandine Monel, Benoit Fischer, Briana L. McGovern, Assaf Alon, Matthew J. O’Meara, Thomas Vallet, Brian K. Shoichet, Sonia Jangra, Laszlo Urban, University of California [San Francisco] (UC San Francisco), University of California (UC), Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Novartis Institutes for BioMedical Research (NIBR), University of Michigan [Ann Arbor], University of Michigan System, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Harvard Medical School [Boston] (HMS), This work was supported by grants from the Defense Advanced Research Projects Agency (HR0011-19-2-0020 to B.K.S., N.J.K., A.G.-S., and K.M.S.), NIGMS R35GM122481 (to B.K.S.), National Institutes of Health (P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, P01AI063302, and R01AI122747 to N.J.K.), Excellence in Research Award (ERA) from the Laboratory for Genomics Research (LGR) (to N.J.K.), a collaboration between UCSF, UCB, and GSK (no. 133122P to N.J.K.), a Fast Grant for COVID-19 from the Emergent Ventures program at the Mercatus Center of George Mason University (to N.J.K.), funding from the Roddenberry Foundation (to N.J.K.), funding from F. Hoffmann–La Roche and Vir Biotechnology (to N.J.K.), gifts from QCRG philanthropic donors (to N.J.K.), funding from Institut Pasteur (to O.S. and M.V.), Urgence COVID-19 Fundraising Campaign of Institut Pasteur (to O.S. and M.V.), Labex IBEID (ANR-10-LABX-62-IBEID to O.S. and M.V.), ANR/FRM Flash Covid PROTEO-SARS-CoV-2 (to O.S.), IDISCOVR (to O.S.), National Institutes of Health (R01GM119185 to A.C.K.), partly supported by the Center for Research for Influenza Pathogenesis, a Center of Excellence for Influenza Research and Surveillance supported by the National Institute of Allergy and Infectious Diseases (contract no. HHSN272201400008C to A.G.-S.), a supplement to NIAID grant U19AI135972 and to DoD grant W81XWH-20-1-0270 (to A.G.-S.), a Fast Grant from the Mercatus Center (to A.G.-S.), the generous support of the JPB Foundation and the Open Philanthropy Project [research grant 2020-215611 (5384) to A.G.-S.], and anonymous donors (to A.G.-S.). Z.Z. is a Damon Runyon fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2281-17)., We gratefully acknowledge the Région Ile-de-France (program DIM1Health) for the use of the Institut Pasteur imaging facility. We thank N. Aulner for assistance with image requisition and A. Danckaert for assistance with image analysis at Institut Pasteur, Paris. We thank R. Albrecht for support with the BSL3 facility and procedures at the Icahn School of Medicine at Mount Sinai, New York. We thank C. Hayden for the work with the transmission electron microscopy at Novartis. We thank T. R. O’Meara for reading the manuscript. We thank K. Obernier, M. Bouhaddou, and J. M. Fabius for contributions to the overall COVID-19 effort at QCRG., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020)
Subjects: Drug, General Science & Technology, media_common.quotation_subject, Microbial Sensitivity Tests, Pharmacology, Lipidoses, Virus Replication, Amiodarone, Antiviral Agents, Article, Dose-Response Relationship, Mice, Surface-Active Agents, Cations, Chlorocebus aethiops, Animals, Humans, Medicine, Lung, Vero Cells, Phospholipids, Repurposing, media_common, Phospholipidosis, Multidisciplinary, Dose-Response Relationship, Drug, SARS-CoV-2, Drug discovery, business.industry, Drug Repositioning, COVID-19, Hydroxychloroquine, Molecular Pharmacology, COVID-19 Drug Treatment, Drug repositioning, Infectious Diseases, Good Health and Well Being, 5.1 Pharmaceuticals, A549 Cells, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Development of treatments and therapeutic interventions, business, medicine.drug
Abstract: International audience; Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs we tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs and does not reflect specific target-based activities—rather, it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.
Published: 2021

25. Complications de la grossesse et protéines transmembranaires induites par l’interféron (IFITM) : équilibre entre immunité antivirale et développement placentaire

Author: Julian Buchrieser, Olivier Schwartz, Virus et Immunité - Virus and immunity (CNRS-UMR3569), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Placenta, Inflammation, Antiviral Agents, IFITM, Cell–cell fusion, Antiviral immunity, Syncytiotrophoblast, Pregnancy, Interferon, medicine, Animals, Humans, Gene, business.industry, Interférons, General Medicine, medicine.disease, Placentation, Transmembrane protein, Pregnancy Complications, IFITMs, Syncytiotrophoblaste, medicine.anatomical_structure, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Immunology, Female, Interferons, medicine.symptom, business, Fusion cellule–cellule, medicine.drug
Abstract: International audience; Pregnancy complications occur frequently and are particularly prevalent during the first trimester. They are caused by a multitude of factors, including karyotypic, genetic or environmental conditions, congenital infections and inflammation. The molecular mechanisms leading to placental complications under inflammatory conditions remain unclear. In this review, we discuss how uncontrolled inflammation, triggered by viral infections or other diseases can lead to placental complications. We first highlight the importance of syncytins, ancestral retroviral genes co-opted by mammals including humans, millions of years ago for the process of placenta formation. We then focus on recent advances elucidating how interferon-induced transmembrane (IFITM) proteins, antiviral proteins rendering cells refractory to viral infections, interfere with placental development.; Certaines grossesses s’accompagnent de complications et sont dites pathologiques, elles sont particulièrement prévalentes lors du premier trimestre. Celles-ci peuvent être causées par une multitude de facteurs, comme les anormalités caryotypiques, des facteurs génétiques et environnementaux, des infections congénitales et une sur-inflammation. Dans cette revue, nous examinons comment une inflammation incontrôlée, déclenchée par des infections virales ou d’autres maladies inflammatoires, peut entraîner des complications placentaires. Dans un premier temps, nous mettrons en évidence l’importance des syncytines, protéines d’enveloppe rétrovirales capturées par les mammifères, dont l’homme, dans la formation du placenta. Dans un deuxième temps, nous nous concentrons sur la manière dont des protéines cellulaires appelées « IFITM » (interferon-induced transmembrane proteins), qui sont des protéines antivirales rendant les cellules réfractaires aux infections virales, interfèrent avec un mécanisme clé du développement placentaire.
Published: 2021

26. IRF8 regulates efficacy of therapeutic anti-CD20 monoclonal antibodies

Author: Ludivine Grzelak, Ferdinand Roesch, Amaury Vaysse, Anne Biton, Rachel Legendre, Françoise Porrot, Pierre‐Henri Commère, Cyril Planchais, Hugo Mouquet, Marco Vignuzzi, Timothée Bruel, Olivier Schwartz, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris] (IP), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale (FRM, IDISCOVR European Health Emergency Preparedness and Response Authority (HERA), French Ministry of Higher Education, Research and Innovation, ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), and ANR-21-CO14-0007,CoronaMito,Conséquences de l'infection par le SRAS-CoV-2 sur la fonction mitochondriale(2021)
Subjects: Immunology, Antineoplastic Agents, anti-CD20 monoclonal antibodies, Antigens, CD20, IRF8, DLBCL, Interferon Regulatory Factors, Immunology and Allergy, [SDV.IMM]Life Sciences [q-bio]/Immunology, Humans, RNA, CD20 protein, Rituximab, CRISPR/Cas9
Abstract: International audience; Anti-CD20 monoclonal antibodies such as Rituximab, Ofatumumab, and Obinutuzumab are widely used to treat lymphomas and autoimmune diseases. They act by depleting B cells, mainly through Fc-dependent effectors functions. Some patients develop resistance to treatment but the underlying mechanisms are poorly understood. Here, we performed a genome-wide CRISPR/Cas9 screen to identify genes regulating the efficacy of anti-CD20 antibodies. We used as a model the killing of RAJI B cells by Rituximab through complement-dependent-cytotoxicity (CDC). As expected, the screen identified MS4A1, encoding CD20, the target of Rituximab. Among other identified genes, the role of Interferon Regulatory Factor 8 (IRF8) was validated in two B-cell lines. IRF8 KO also decreased the efficacy of antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) induced by anti-CD20 antibodies. We further show that IRF8 is necessary for efficient CD20 transcription. Levels of IRF8 and CD20 RNA or proteins correlated in normal B cells and in hundreds of malignant B cells. Therefore, IRF8 regulates CD20 expression and controls the depleting capacity of anti-CD20 antibodies. Our results bring novel insights into the pathways underlying resistance to CD20-targeting immunotherapies.
Published: 2022

27. Structural insights of a highly potent pan-neutralizing SARS-CoV-2 human monoclonal antibody

Author: Lorena Donnici, Rino Rappuoli, Ian A. Wilson, Matteo Conti, Hugo Mouquet, Hejun Liu, Raffaele De Francesco, Claudia Sala, Ida Paciello, Gabriel Ozorowski, Timothée Bruel, Giulia Piccini, Cyril Planchais, Jonathan L. Torres, Olivier Schwartz, Jeffrey Copps, Piero Pileri, Noemi Manganaro, Elisa Pantano, Emanuele Montomoli, Delphine Planas, Andrew B. Ward, Emanuele Andreano, The Scripps Research Institute [La Jolla, San Diego], Fondazione Toscana Gabriele Monasterio, Istituto Nazionale Genetica Molecolare [Milano] (INGM), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Università degli Studi di Siena = University of Siena (UNISI), Università degli Studi di Milano = University of Milan (UNIMI), This work was funded by Toscana Life Sciences, through the European Research Council advanced Grant agreement number 787552 (vAMRes), the European Union’s Horizon 2020 research and innovation program under Grant agreement no. 653316, and the Italian Ministry of Health COVID-2020-12371817 project, under collaborative agreements with The Scripps Research Institute. Work in the O.S. lab is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, and IDISCOVR. This work was also funded by the Bill & Melinda Gates Foundation (OPP1170236/INV-004923)., We thank B. Anderson and H. Turner for microscope assistance, C. Bowman for computational assistance, and G.K. Hedestam and M. Corcoran for scientific discussion regarding human antibody germline genes. We thank Dr. Piet Maes from NRC UZ/KU Leuven (Leuven, Belgium) for kindly providing the Omicron live., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), and European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015)
Subjects: 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), medicine.drug_class, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Cell, Antibody Affinity, cryoelectron microscopy, Alpha (ethology), Biology, Monoclonal antibody, Antibodies, Viral, variants of concern, MESH: Antibodies, Monoclonal, MESH: Antibodies, Neutralizing, MESH: Antibody Affinity, Neutralization Tests, medicine, Potency, Humans, MESH: COVID-19, MESH: SARS-CoV-2, MESH: Humans, Multidisciplinary, SARS-CoV-2, monoclonal therapy, MESH: Neutralization Tests, Antibodies, Monoclonal, COVID-19, neutralizing antibody, Virology, Antibodies, Neutralizing, medicine.anatomical_structure, Monoclonal, MESH: Antibodies, Viral
Abstract: As the coronavirus disease 2019 (COVID-19) pandemic continues, there is a strong need for highly potent monoclonal antibodies (mAbs) that are resistant against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) variants of concern (VoCs). Here, we evaluate the potency of a previously described mAb J08 against these variants using cell-based assays and delve into the molecular details of the binding interaction using cryo-EM. We show that mAb J08 has low nanomolar affinity against VoCs, binds high on the receptor binding domain (RBD) ridge and is therefore unaffected by most mutations, and can bind in the RBD-up and -down conformations. These findings further validate the phase II/III human clinical trial underway using mAb J08 as a monoclonal therapy.One Sentence SummaryPotent neutralizing monoclonal antibody J08 binds SARS-CoV-2 spike independent of known escape mutations.
Published: 2022

28. Duration of BA.5 neutralization in sera and nasal swabs from SARS-CoV-2 vaccinated individuals, with or without omicron breakthrough infection

Author: Delphine Planas, Isabelle Staropoli, Françoise Porot, Florence Guivel-Benhassine, Lynda Handala, Mathieu Prot, William-Henry Bolland, Julien Puech, Hélène Péré, David Veyer, Aymeric Sève, null Etienne-Simon-Lorière, Timothée Bruel, Thierry Prazuck, Karl Stefic, Laurent Hocqueloux, Olivier Schwartz, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre Hospitalier Régional d'Orléans (CHRO), Work in O.S.'s laboratory is funded by the Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale (FRM), ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, ANR Coronamito, and IDISCOVR, Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant no. ANR-10-LABX-62-IBEID), HERA european funding and the NIH PICREID (grant no U01AI151758)., The authors thank A. Fontanet for critical reading of the manuscript, the patients who participated to this study, members of the Virus and Immunity Unit and other teams for discussion and help, N. Aulner and the staff at the UtechS Photonic BioImaging (UPBI) core facility (Institut Pasteur), a member of the France BioImaging network, for image acquisition and analysis, and F. Peira, V. Legros, and L. Courtellemont for their help with the cohorts., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020)
Subjects: variants, MESH: Humans, Breakthrough Infections, IgG, Omicron, SARS-CoV-2, MESH: Breakthrough Infections, [SDV]Life Sciences [q-bio], Translation to patients, COVID-19, General Medicine, neutralization, Antibodies, Neutralizing, MESH: Antibodies, Neutralizing, vaccine, mucosal immunity, MESH: COVID-19, Humans, breakthrough, MESH: SARS-CoV-2, MESH: BNT162 Vaccine, IgA, BNT162 Vaccine, BA.5
Abstract: Since early 2022, Omicron BA.1 has been eclipsed by BA.2, which was in turn outcompeted by BA.5, which displays enhanced antibody escape properties.Here, we evaluated the duration of the neutralizing antibody (Nab) response, up to 18 months after Pfizer BNT162b2 vaccination, in individuals with or without BA.1/BA.2 breakthrough infection. We measured neutralization of the ancestral D614G lineage, Delta, and Omicron BA.1, BA.2, and BA.5 variants in 300 sera and 35 nasal swabs from 27 individuals.Upon vaccination, serum Nab titers were decreased by 10-, 15-, and 25-fold for BA.1, BA.2, and BA.5, respectively, compared with D614G. We estimated that, after boosting, the duration of neutralization was markedly shortened from 11.5 months with D614G to 5.5 months with BA.5. After breakthrough, we observed a sharp increase of Nabs against Omicron subvariants, followed by a plateau and a slow decline after 5-6 months. In nasal swabs, infection, but not vaccination, triggered a strong immunoglobulin A (IgA) response and a detectable Omicron-neutralizing activity.BA.5 spread is partly due to abbreviated vaccine efficacy, particularly in individuals who were not infected with previous Omicron variants.Work in O.S.'s laboratory is funded by the Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale (FRM), ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, ANR Coronamito, and IDISCOVR, Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant no. ANR-10-LABX-62-IBEID), HERA european funding and the NIH PICREID (grant no U01AI151758).
Published: 2022

29. Characterising proteolysis during SARS-CoV-2 infection identifies viral cleavage sites and cellular targets with therapeutic potential

Author: Jeanne Chiaravalli, Marius Walter, Edward Emmott, Emma Sierecki, Stacy Gellenoncourt, Philip Brownridge, Arturas Grauslys, Andrew R. Jones, Fabrice Agou, Charles S. Craik, Marco Vignuzzi, Yann Gambin, Patrick A. Eyers, Lisa A. Chakrabarti, Eric Verdin, Leonard A. Daly, Bjoern Meyer, Dominic P. Bryne, Claire E. Eyers, Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Criblage chémogénomique et biologique (Plateforme) - Chemogenomic and Biological Screening Platform (PF-CCB), Institut Pasteur [Paris] (IP), Virus et Immunité - Virus and immunity (CNRS-UMR3569), University of Liverpool, Buck Institute for Research on Aging, University of California [San Francisco] (UC San Francisco), University of California (UC), University of New South Wales [Sydney] (UNSW), This work was supported by the Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant ANR-10-LABX-62-IBEID) to M.V. S.G. is the recipient of a MESR/Ecole Doctorale BioSPC ED562, Université de Paris fellowship. L.A.C. is supported by Institut Pasteur TASK FORCE SARS COV-2 (Tropicoro project), DIM ELICIT Region Ile-de-France, and ANRS. E.E. is supported by startup funding from the University of Liverpool, as well as a Wellcome Trust ISSF Interdisciplinary & Industry Award. E.E. is grateful for the support of GoFundMe donors for sponsoring SARS-CoV-2 research in his laboratory., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: Proteomics, MESH: Virus Internalization, viruses, medicine.medical_treatment, General Physics and Astronomy, Virus Replication, MESH: Dipeptides, MESH: RNA, Small Interfering, 2.2 Factors relating to the physical environment, MESH: COVID-19, MESH: Animals, MESH: Myosin-Light-Chain Kinase, RNA, Small Interfering, Aetiology, skin and connective tissue diseases, Lung, MESH: Protease Inhibitors, MESH: Viral Proteases, Multidisciplinary, medicine.diagnostic_test, Viral Proteases, MESH: Proteomics, Proteases, Dipeptides, src-Family Kinases, Infectious Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Infection, Biotechnology, Proto-oncogene tyrosine-protein kinase Src, MESH: Antiviral Agents, MESH: Mutation, Science, Proteolysis, MESH: Proteolysis, Context (language use), Biology, Small Interfering, Antiviral Agents, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Vaccine Related, Viral Proteins, Biodefense, medicine, Animals, Humans, Protease Inhibitors, MESH: SARS-CoV-2, Myosin-Light-Chain Kinase, MESH: Humans, Protease, SARS-CoV-2, Prevention, fungi, MESH: Virus Replication, COVID-19, MYLK, Pneumonia, General Chemistry, Virus Internalization, MESH: Viral Proteins, Virology, COVID-19 Drug Treatment, MESH: Cell Line, body regions, Emerging Infectious Diseases, Good Health and Well Being, MESH: src-Family Kinases, Viral replication, Mutation, RNA, Immunization
Abstract: SARS-CoV-2 is the causative agent behind the COVID-19 pandemic, responsible for over 170 million infections, and over 3.7 million deaths worldwide. Efforts to test, treat and vaccinate against this pathogen all benefit from an improved understanding of the basic biology of SARS-CoV-2. Both viral and cellular proteases play a crucial role in SARS-CoV-2 replication. Here, we study proteolytic cleavage of viral and cellular proteins in two cell line models of SARS-CoV-2 replication using mass spectrometry to identify protein neo-N-termini generated through protease activity. We identify previously unknown cleavage sites in multiple viral proteins, including major antigens S and N: the main targets for vaccine and antibody testing efforts. We discover significant increases in cellular cleavage events consistent with cleavage by SARS-CoV-2 main protease, and identify 14 potential high-confidence substrates of the main and papain-like proteases. We show that siRNA depletion of these cellular proteins inhibits SARS-CoV-2 replication, and that drugs targeting two of these proteins: the tyrosine kinase SRC and Ser/Thr kinase MYLK, show a dose-dependent reduction in SARS-CoV-2 titres. Overall, our study provides a powerful resource to understand proteolysis in the context of viral infection, and to inform the development of targeted strategies to inhibit SARS-CoV-2 and treat COVID-19., During SARS-CoV-2 replication, viral and cellular proteases play crucial roles and have been shown to be promising anti-viral targets. Here, Meyer et al. apply mass spectrometry to characterize the proteolytic cleavage profile of viral and cellular proteins in vitro.
Published: 2021

30. Gain-of-Function Research: Unknown Risks

Author: Félix A. Rey, Simon Wain-Hobson, Olivier Schwartz, Virologie Structurale - Structural Virology, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Rétrovirologie Moléculaire, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Virus et Immunité - Virus and immunity (CNRS-UMR3569)
Subjects: Manifesto, MESH: Pandemics, 0303 health sciences, MESH: Humans, Multidisciplinary, MESH: Influenza, Human, [SDV]Life Sciences [q-bio], MESH: Influenza A virus, Influenza a, Genealogy, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Gain of function, MESH: Influenza in Birds, MESH: Drug Resistance, Multiple, Viral, MESH: Animals, 030212 general & internal medicine, Psychology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: We were astonished by the recent letter by R. A. M. Fouchier et al. (“Gain-offunction experiments on H7N9,” 9 August, p. [612][1]; published online 7 August) and the simultaneous publication in Nature (1). We find it odd that an H7N9 influenza A research manifesto signed by a number of flu
Published: 2013

31. Virus, épidémies et réseaux de surveillance de la grippe

Author: Sylvie Behillil, Vincent Enouf, Sylvie van der Werf, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP), Virus et Immunité - Virus and immunity, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pharmacology, 0303 health sciences, grippe, pandémie, 030306 microbiology, pandemic, [SDV]Life Sciences [q-bio], education, epidemic, influenza virus, 3. Good health, 03 medical and health sciences, virus influenza, Pharmacology (medical), réseau de surveillance, influenza, épidémie, monitoring network, 030304 developmental biology
Abstract: International audience; Influenza is an acute contagious respiratory infection caused by influenza viruses, which are unique in their vast genetic variability. By the number of patients affected and the excess of mortality attributable to it, it represents a public health issue. The pandemic risk associated with zoonotic influenza is also a major concern. An active monitoring policy is in place at national and international levels.; La grippe est une infection respiratoire aiguë contagieuse due aux virus influenza, dont la particularité réside dans sa grande variabilité génétique. Par le nombre de patients atteints et l’excès de mortalité qui lui est attribuable, elle représente un enjeu de santé publique. Le risque pandémique associé à la grippe zoonotique constitue également une préoccupation majeure. Une politique de surveillance active est en place au niveau national et international.
Published: 2019

32. Accelerated thymopoiesis and improved T‐cell responses in HLA‐A2/‐DR2 transgenic BRGS‐based human immune system mice

Author: Sylvie Darche, Hergen Spits, James P. Di Santo, Helene Strick-Marchand, Silvia Lopez-Lastra, Yan Li, Guillemette Masse-Ranson, Olivier Schwartz, Maud Boussand, Mathilde Dusséaux, Yves Levy, Antoine Toubert, Timothée Bruel, Oriane Fiquet, Erwan Corcuff, Mireille Centlivre, Nicolas Legrand, Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'immunologie clinique et maladies infectieuses [Créteil], Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Supported by grants from the Institut Pasteur, INSERM, Gates Foundation (Grand Challenges in Global Health, J.P.D.), Agence Nationale de la Recherche (ANR) programme RPIB (Im_HIS, J.P.D.), the Laboratoire d'Excellence REVIVE (ANR‐10‐LABX‐73, J.P.D.), the Laboratoire d'Excellence Vaccine Research Institute (ANR‐10‐LABX‐77, Y.L.), the Laboratoire d'Excellence Milieu Intérieur (ANR‐10‐LABX‐69, H.M.), the Laboratoire d'Excellence IBEID (ANR‐10‐LABX‐62, O.S.), the Agence Nationale de Recherche sur le SIDA et les hepatites virales (ANRS 15465, O.S.), the European Commission Seventh Framework Programme n°305578 (PathCO, J.P.D.), and Gilead Sciences (00397, O.S. and J.P.D.)., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), European Project: 305578,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,PATHCO(2012), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute (VRI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Experimental Immunology, AGEM - Digestive immunity, and AII - Inflammatory diseases
Subjects: MESH: Cell Differentiation, MESH: Mice, Transgenic, T-Lymphocytes, Transgene, T cell, Immunology, MESH: Mice, Inbred BALB C, Mice, Transgenic, Human leukocyte antigen, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, Humanized mice, MESH: B-Lymphocytes, MESH: HLA-A2 Antigen, HLA-A2 Antigen, medicine, Animals, Humans, Immunology and Allergy, MESH: Animals, HLA-DR2 Antigen, MESH: Mice, 030304 developmental biology, B-Lymphocytes, Mice, Inbred BALB C, 0303 health sciences, MESH: Humans, Lymphopoiesis, Cell Differentiation, MESH: Lymphopoiesis, Animal models, 3. Good health, Cell biology, Disease Models, Animal, MESH: HLA-DR2 Antigen, Lymphocyte development, MESH: T-Lymphocytes, medicine.anatomical_structure, Lymphatic system, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, MESH: Disease Models, Animal, Stem cell, CD8, 030215 immunology
Abstract: International audience; Human immune system (HIS) mouse models provide a robust in vivo platform to study human immunity. Nevertheless, the signals that guide human lymphocyte differentiation in HIS mice remain poorly understood. Here, we have developed a novel Balb/c Rag2-/- Il2rg-/- SirpaNOD (BRGS) HIS mouse model expressing human HLA-A2 and -DR2 transgenes (BRGSA2DR2). When comparing BRGS and BRGSA2DR2 HIS mice engrafted with human CD34+ stem cells, a more rapid emergence of T cells in the circulation of hosts bearing human HLA was shown, which may reflect a more efficient human T-cell development in the mouse thymus. Development of CD4+ and CD8+ T cells was accelerated in BRGSA2DR2 HIS mice and generated more balanced B and T-cell compartments in peripheral lymphoid organs. Both B- and T-cell function appeared enhanced in the presence of human HLA transgenes with higher levels of class switched Ig, increased percentages of polyfunctional T cells and clear evidence for antigen-specific T-cell responses following immunization. Taken together, the presence of human HLA class I and II molecules can improve multiple aspects of human B- and T-cell homeostasis and function in the BRGS-based HIS mouse model.
Published: 2019

33. Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen

Author: Alice Mac Kain, Ghizlane Maarifi, Sophie-Marie Aicher, Nathalie Arhel, Artem Baidaliuk, Sandie Munier, Flora Donati, Thomas Vallet, Quang Dinh Tran, Alexandra Hardy, Maxime Chazal, Françoise Porrot, Molly OhAinle, Jared Carlson-Stevermer, Jennifer Oki, Kevin Holden, Gert Zimmer, Etienne Simon-Lorière, Timothée Bruel, Olivier Schwartz, Sylvie van der Werf, Nolwenn Jouvenet, Sébastien Nisole, Marco Vignuzzi, Ferdinand Roesch, Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Signalisation antivirale - Virus sensing and signaling, Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Synthego [Redwood City, CA], Universität Bern [Bern] (UNIBE), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This work was funded by the Institut Pasteur Coronavirus Task Force, CNRS (UMR 3569), the Labex IBEID (ANR-10-LABX-62-IBEID), the Occitanie region and by the ANR (ANR-20-COVI-000, projects IDISCOVR to M.V. and Alpha-COV to S.N.). A.M.K. is supported by a grant of the French Ministry of Higher Education, Research and Innovation. G.M. is supported by a grant from the Agence nationale de recherches sur le sida et les hépatites virales (ANRS). S.M.A. is supported by the Pasteur-Paris University (PPU) International PhD Program., We thank the Cytometry Platform, Center for Technological Resources and Research, Institut Pasteur, for cell sorting experiments., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0068,DisCoVer,Histoire naturelle du SARS-CoV2 : Emergence et Réservoir(2020), and ANR-20-COVI-0099,Alpha-COV,Mise en œuvre d'un test rapide et fiable pour le criblage haut-débit de molécules antivirales actives contre le SARS-CoV-2(2020)
Subjects: Proteasome Endopeptidase Complex, Multidisciplinary, 630 Agriculture, SARS-CoV-2, [SDV]Life Sciences [q-bio], viruses, fungi, General Physics and Astronomy, virus diseases, COVID-19, General Chemistry, General Biochemistry, Genetics and Molecular Biology, body regions, Humans, Interferons, CRISPR-Cas Systems, skin and connective tissue diseases, Co-Repressor Proteins, Molecular Chaperones
Abstract: Interferon restricts SARS-CoV-2 replication in cell culture, but only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identify DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 and SARS-CoV replication in human cells. Basal expression of DAXX is sufficient to limit the replication of SARS-CoV-2, and DAXX over-expression further restricts infection. DAXX restricts an early, post-entry step of the SARS-CoV-2 life cycle. DAXX-mediated restriction of SARS-CoV-2 is independent of the SUMOylation pathway but dependent on its D/E domain, also necessary for its protein-folding activity. SARS-CoV-2 infection triggers the re-localization of DAXX to cytoplasmic sites and promotes its degradation. Mechanistically, this process is mediated by the viral papain-like protease (PLpro) and the proteasome. Together, these results demonstrate that DAXX restricts SARS-CoV-2, which in turn has evolved a mechanism to counteract its action.
Published: 2021

34. Low CCR5 expression protects HIV-specific CD4+ T cells of elite controllers from viral entry

Author: Mathieu Claireaux, Rémy Robinot, Jérôme Kervevan, Mandar Patgaonkar, Isabelle Staropoli, Anne Brelot, Alexandre Nouël, Stacy Gellenoncourt, Xian Tang, Mélanie Héry, Stevenn Volant, Emeline Perthame, Véronique Avettand-Fenoël, Julian Buchrieser, Thomas Cokelaer, Christiane Bouchier, Laurence Ma, Faroudy Boufassa, Samia Hendou, Valentina Libri, Milena Hasan, David Zucman, Pierre de Truchis, Olivier Schwartz, Olivier Lambotte, Lisa A. Chakrabarti, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Laboratoire de Microbiologie Clinique [AP-HP Hôpital Necker-Enfants Malades], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biomics (plateforme technologique), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Hôpital Foch [Suresnes], Hôpital Raymond Poincaré [AP-HP], Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris-Sud - Paris 11 (UP11), This work was supported by grants to L.A.C. from ANRS (17218 and 19206), Institut Pasteur (PasteurInnov TETRHIS), and ANR (14 CE 16002901). The Biomics Platform is a member of the 'France Génomique' consortium (ANR10-INBS-09-08). M.C. was the recipient of a Sidaction fellowship, R.R. of a Pasteur Carnot MS and a Sidaction fellowships, M.P. of an ANRS fellowship, and S.G. of a MESR/Université de Paris fellowship., We are grateful to patients who participated in the study. We thank the investigators of the ANRS CO21 CODEX cohort and Camille Lecuroux for help with recruitment of controller patients, Morgane Marcou and Katia Bourdic for help with recruitment of treated patients, Bernard Lagane for the gift of plamids, and Sophie Novault from the Pasteur CB UTechS for advice on cell sorting. MHC class II tetramer reagents were provided by the NIH Tetramer Core facility at Emory University. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: HIV-1 PTE Gag peptide set (Cat # 11554)., ANR-14-CE16-0029,PD1VAX,Une nouvelle stratégie de vaccination par vecteur ADN PD1 pour mimer les réponses spécifiques de Gag trouvées chez les contrôleurs spontanés du VIH(2014), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
Subjects: CD4-Positive T-Lymphocytes, Viral membrane fusion, MESH: Mutation, Receptors, CXCR3, Receptors, CCR5, Science, MESH: Virus Internalization, viruses, General Physics and Astronomy, Down-Regulation, Gene Products, gag, HIV Infections, MESH: Receptors, CCR5, MESH: Down-Regulation, General Biochemistry, Genetics and Molecular Biology, Article, MESH: Receptors, CXCR3, MESH: HIV-1, MESH: Elite Controllers, Humans, MESH: Humans, Multidisciplinary, Retrovirus, Histocompatibility Antigens Class II, MESH: CD4-Positive T-Lymphocytes, virus diseases, MESH: HIV Infections, General Chemistry, Virus Internalization, MESH: Chemokines, MESH: Gene Expression Regulation, Gene Expression Regulation, MESH: Gene Products, gag, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Mutation, MESH: Histocompatibility Antigens Class II, HIV-1, Chemokines, Elite Controllers
Abstract: HIV elite controllers maintain a population of CD4 + T cells endowed with high avidity for Gag antigens and potent effector functions. How these HIV-specific cells avoid infection and depletion upon encounter with the virus remains incompletely understood. Ex vivo characterization of single Gag-specific CD4 + T cells reveals an advanced Th1 differentiation pattern in controllers, except for the CCR5 marker, which is downregulated compared to specific cells of treated patients. Accordingly, controller specific CD4 + T cells show decreased susceptibility to CCR5-dependent HIV entry. Two controllers carried biallelic mutations impairing CCR5 surface expression, indicating that in rare cases CCR5 downregulation can have a direct genetic cause. Increased expression of β-chemokine ligands upon high-avidity antigen/TCR interactions contributes to autocrine CCR5 downregulation in controllers without CCR5 mutations. These findings suggest that genetic and functional regulation of the primary HIV coreceptor CCR5 play a key role in promoting natural HIV control., Here, Claireaux et al. show that people who naturally control HIV infection express lower levels of the viral co-receptor CCR5 in specific CD4+ T cells, and that this results from mutations or receptor internalization by CD4+ T cell-produced chemokines.
Published: 2019

35. The Phosphatidylserine and Phosphatidylethanolamine Receptor CD300a Binds Dengue Virus and Enhances Infection

Author: Manuel Perera-Lecoin, Ali Amara, Ophélie Dejarnac, Rasika Ramdasi, Laurent Meertens, Jiro Kitaura, Xavier Carnec, Mohamed Lamine Hafirassou, Olivier Schwartz, Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Medical Science [tokyo], The University of Tokyo (UTokyo), Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], This study was supported by grants from the Fondation pour la Recherche Médicale and the French National Research Agency (ANR, ANR-14-CE14-0029) to A.A. This study is also supported by a public grant overseen by the ANR as part of the Investissements d'Avenir program (ANR-10-IHUB-0002). X.C., M.P.-L., and O.D. are supported by fellowships from the Fondation pour la Recherche Médicale, Total Oil and Gas Venezuela, and the Instituto Venezolano de Investigaciones Cientificas and the Ministère de la Recherche, respectively, ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], viruses, media_common.quotation_subject, Immunology, Phosphatidylserines, Dengue virus, Biology, Endocytosis, medicine.disease_cause, Microbiology, Virus, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Antigens, CD, Viral entry, Virology, medicine, Humans, Chikungunya, Receptors, Immunologic, Internalization, media_common, Macrophages, Phosphatidylethanolamines, Membrane Proteins, virus diseases, Phosphatidylserine, Dengue Virus, Virus Internalization, biochemical phenomena, metabolism, and nutrition, Virus-Cell Interactions, 3. Good health, 030104 developmental biology, chemistry, Insect Science, Host-Pathogen Interactions, Receptors, Virus, Viral disease, Chikungunya virus, West Nile virus, Protein Binding, 030215 immunology
Abstract: Dengue virus (DENV) is the etiological agent of the major human arboviral disease. We previously demonstrated that the TIM and TAM families of phosphatidylserine (PtdSer) receptors involved in the phagocytosis of apoptotic cells mediate DENV entry into target cells. We show here that human CD300a, a recently identified phospholipid receptor, also binds directly DENV particles and enhances viral entry. CD300a facilitates infection of the four DENV serotypes, as well as of other mosquito-borne viruses such as West Nile virus and Chikungunya virus. CD300a acts as an attachment factor that enhances DENV internalization through clathrin-mediated endocytosis. CD300a recognizes predominantly phosphatidylethanolamine (PtdEth) and to a lesser extent PtdSer associated with viral particles. Mutation of residues in the IgV domain critical for phospholipid binding abrogate CD300a-mediated enhancement of DENV infection. Finally, we show that CD300a is expressed at the surface of primary macrophages and anti-CD300a polyclonal antibodies partially inhibited DENV infection of these cells. Overall, these data indicate that CD300a is a novel DENV binding receptor that recognizes PtdEth and PtdSer present on virions and enhance infection. IMPORTANCE Dengue disease, caused by dengue virus (DENV), has emerged as the most important mosquito-borne viral disease of humans and is a major global health concern. The molecular bases of DENV-host cell interactions during virus entry are poorly understood, hampering the discovery of new targets for antiviral intervention. We recently discovered that the TIM and TAM proteins, two receptor families involved in the phosphatidylserine (PtdSer)-dependent phagocytic removal of apoptotic cells, interact with DENV particles-associated PtdSer through a mechanism that mimics the recognition of apoptotic cells and mediate DENV infection. In this study, we show that CD300a, a novel identified phospholipid receptor, mediates DENV infection. CD300a-dependent DENV infection relies on the direct recognition of phosphatidylethanolamine and to a lesser extent PtdSer associated with viral particles. This study provides novel insights into the mechanisms that mediate DENV entry and reinforce the concept that DENV uses an apoptotic mimicry strategy for viral entry.
Published: 2016

36. HIV-1 Envelope Recognition by Polyreactive and Cross-Reactive Intestinal B Cells

Author: Thierry Prazuck, Hedda Wardemann, Alexia Kanyavuz, Olivier Schwartz, Tim Rollenske, Valérie Lorin, Laurent Lefrou, Hugo Mouquet, Jordan D. Dimitrov, Ayrin Kök, Timothée Bruel, Florence Guivel-Benhassine, Laurent Hocqueloux, Cyril Planchais, Thierry Hieu, Julie Prigent, Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Centre Hospitalier Régional d'Orléans (CHRO), Work in the O.S. lab is funded by the Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), the Labex IBEID (ANR-10-IHUB-0002), the 'TIMTAMDEN' ANR-14-CE14-0029, the 'CHIKV-Viro-Immuno' ANR-14-CE14-0015-01, and the Gilead HIV Cure program. H.M. received core grants from the G5 Institut Pasteur program, the Milieu Intérieur program (ANR-10-LABX-69-01), and INSERM. This work was funded by the European Research Council (ERC)-Seventh Framework Program (ERC-2013-StG 337146). C.P., A.K., and T.H. were supported by the ERC-2013-StG 337146 program and J.P. by an ANRS postdoctoral fellowship. J.D.D. was supported by an ERC starting grant (ERC-2015-StG 678905)., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), European Project: 337146,EC:FP7:ERC,ERC-2013-StG,HUMANTIVIRUSES(2014), European Project: 678905,H2020-EU.1.1., ERC-StG-2015,CoBABATI(2016), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional d'Orléans (CHR), ANR-10-LABX-0077/10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR: 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, medicine.drug_class, Cross Reactions, Gp41, medicine.disease_cause, Monoclonal antibody, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Viral envelope, medicine, Humans, lcsh:QH301-705.5, B cell, Antibody-dependent cell-mediated cytotoxicity, B-Lymphocytes, biology, Chemistry, virus diseases, Molecular biology, 3. Good health, Intestines, Molecular mimicry, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Humoral immunity, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, HIV-1, Antibody, 030217 neurology & neurosurgery
Abstract: Summary: Mucosal immune responses to HIV-1 involve the recognition of the viral envelope glycoprotein (gp)160 by tissue-resident B cells and subsequent secretion of antibodies. To characterize the B cells “sensing” HIV-1 in the gut of infected individuals, we probed monoclonal antibodies produced from single intestinal B cells binding to recombinant gp140 trimers. A large fraction of mucosal B cell antibodies were polyreactive and showed only low affinity to HIV-1 envelope glycoproteins, particularly the gp41 moiety. A few high-affinity gp140 antibodies were isolated but lacked neutralizing, potent ADCC, and transcytosis-blocking capacities. Instead, they displayed cross-reactivity with defined self-antigens. Specifically, intestinal HIV-1 gp41 antibodies targeting the heptad repeat 2 region (HR2) cluster II cross-reacted with the p38α mitogen-activated protein kinase 14 (MAPK14). Hence, physiologic polyreactivity of intestinal B cells and molecular mimicry-based self-reactivity of HIV-1 antibodies are two independent phenomena, possibly diverting and/or impairing mucosal humoral immunity to HIV-1. : Antibodies produced in mucosa after sexual transmission of HIV-1 could affect viral propagation. Planchais et al. show that intestinal B cells from HIV-1-infected individuals that recognize the HIV-1 envelope (Env) proteins are mainly low affinity and polyreactive and that rare, high-affinity antibodies to HIV-1 Env lack potent antiviral capacities and cross-react with self-antigens. Keywords: HIV-1, antibodies, B cells, mucosa, polyreactivity, cross-reactivity, MAPK14, intestine
Published: 2018

37. SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells

Author: Arnaud Moris, Françoise Porrot, Julia G. Prado, Timothée Bruel, Sylvain Cardinaud, Diana Ayinde, Olivier Schwartz, Virus et Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche sur le Vaccin (VRI), PRES Université Paris-Est-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), IrsiCaixa (Institut de Recerca de la Sida), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), D.A. was supported by a postdoctoral fellowship from ANRS and the FP7 HIT Hidden HIV program. The work was supported by grants from the ANRS, SIDACTION, AREVA Foundation, the Labex IBEID program, the FP7 program, HIT Hidden HIV (Health-F3-2012-305762), and Institut Pasteur, as well as by the Vaccine Research Institute, Investissements d'Avenir program (ANR-10-LABX-77).We thank the Programme EVA Centre for AIDS Reagents and the NIH AIDS Reagent Program for the gifts of reagents., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), European Project: 305762,HEALTH,FP7-HEALTH-2012-INNOVATION-1,HIT HIDDEN HIV(2012), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'Immunologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: HIV Antigens, [SDV]Life Sciences [q-bio], Immunology, Antigen presentation, Cellular Response to Infection, MESH: Monomeric GTP-Binding Proteins, CD8-Positive T-Lymphocytes, Major histocompatibility complex, Microbiology, SAM Domain and HD Domain-Containing Protein 1, 03 medical and health sciences, 0302 clinical medicine, Antigen, Viral entry, Virology, Humans, Cytotoxic T cell, Cells, Cultured, Monomeric GTP-Binding Proteins, 030304 developmental biology, Antigen Presentation, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, MESH: Humans, biology, MESH: Antigen Presentation, Dendritic Cells, MESH: HIV Antigens/immunology, 3. Good health, CTL, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: CD8-Positive T-Lymphocytes/immunology, MESH: T-Lymphocytes, Cytotoxic/immunology, Insect Science, HIV-1, Pseudotyping, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: HIV-1/immunology, T-Lymphocytes, Cytotoxic, MESH: Cells, Cultured, MESH: Dendritic Cells/immunology, 030215 immunology, SAMHD1
Abstract: Monocyte-derived dendritic cells (MDDC) stimulate CD8 + cytotoxic T lymphocytes (CTL) by presenting endogenous and exogenous viral peptides via major histocompatibility complex class I (MHC-I) molecules. MDDC are poorly susceptible to HIV-1, in part due to the presence of SAMHD1, a cellular enzyme that depletes intracellular deoxynucleoside triphosphates (dNTPs) and degrades viral RNA. Vpx, an HIV-2/SIVsm protein absent from HIV-1, antagonizes SAMHD1 by inducing its degradation. The impact of SAMHD1 on the adaptive cellular immune response remains poorly characterized. Here, we asked whether SAMHD1 modulates MHC-I-restricted HIV-1 antigen presentation. Untreated MDDC or MDDC pretreated with Vpx were exposed to HIV-1, and antigen presentation was examined by monitoring the activation of an HIV-1 Gag-specific CTL clone. SAMHD1 depletion strongly enhanced productive infection of MDDC as well as endogenous HIV-1 antigen presentation. Time-lapse microscopy analysis demonstrated that in the absence of SAMHD1, the CTL rapidly killed infected MDDC. We also report that various transmitted/founder (T/F) HIV-1 strains poorly infected MDDC and, as a consequence, did not stimulate CTL. Vesicular stomatitis virus glycoprotein (VSV-G) pseudotyping of T/F alleviated a block in viral entry and induced antigen presentation only in the absence of SAMHD1. Furthermore, by using another CTL clone that mostly recognizes incoming HIV-1 antigens, we demonstrate that SAMHD1 does not influence exogenous viral antigen presentation. Altogether, our results demonstrate that the antiviral activity of SAMHD1 impacts antigen presentation by DC, highlighting the link that exists between restriction factors and adaptive immune responses. IMPORTANCE Upon viral infection, DC may present antigens derived from incoming viral material in the absence of productive infection of DC or from newly synthesized viral proteins. In the case of HIV, productive infection of DC is blocked at an early postentry step. This is due to the presence of SAMHD1, a cellular enzyme that depletes intracellular levels of dNTPs and inhibits viral reverse transcription. We show that the depletion of SAMHD1 in DCs strongly stimulates the presentation of viral antigens derived from newly produced viral proteins, leading to the activation of HIV-1-specific cytotoxic T lymphocytes (CTL). We further show in real time that the enhanced activation of CTL leads to killing of infected DCs. Our results indicate that the antiviral activity of SAMHD1 not only impacts HIV replication but also impacts antigen presentation by DC. They highlight the link that exists between restriction factors and adaptive immune responses.
Published: 2015

38. Broadly neutralizing antibodies that inhibit HIV-1 cell to cell transmission

Author: Olivier Schwartz, Florian Klein, Caroline Eden, Réjane Rua, Michel C. Nussenzweig, Joshua A. Horwitz, Marine Malbec, Johannes F. Scheid, Ari Halper-Stromberg, Françoise Porrot, Hugo Mouquet, Virus et Immunité, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Cellule Pasteur UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris], Laboratory of Molecular Immunology, Rockefeller University [New York], Réponse humorale aux pathogènes, Howard Hughes Medical Institute (HHMI), O. Schwartz was supported by grants from the Agence Nationale de Recherchesur le Sida, Sidaction, AREVA Foundation, the Vaccine Research Institute, the LabexIBEID program, the FP7 program HIT Hidden HIV (Health-F3-2012-305762), andInstitut Pasteur. M. Malbec was supported by fellowships from Sidaction, Fonds dedotation Pierre Bergé, and Fondation pour la Recherche Médicale. H. Mouquet wassupported by the Milieu Intérieur program (ANR-10-LABX-69-01). M.C. Nussenzweigwas supported by grants from the Bill and Melinda Gates Foundation (Collaborationfor AIDS Vaccine Discovery grant 38619s) and the Center for HIV/AIDS VaccineImmunology and Immunogen Discovery grant AI 100663-01, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)
Subjects: CD4-Positive T-Lymphocytes, Time Factors, viruses, HIV Infections, MESH: Microscopy, Fluorescence, HIV Antibodies, V3 loop, MESH: Antibodies, Neutralizing, Cell to cell transmission, Immunology and Allergy, MESH: Inhibitory Concentration 50, 0303 health sciences, MESH: Dendritic Cells, MESH: HIV, Transmission (medicine), virus diseases, MESH: CD4-Positive T-Lymphocytes, MESH: HIV Infections, 3. Good health, MESH: HEK293 Cells, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Virion, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, Glycan, Immunology, Biology, MESH: Coculture Techniques, Inhibitory Concentration 50, 03 medical and health sciences, Humans, Potency, 030304 developmental biology, MESH: Humans, MESH: HIV Antibodies, 030306 microbiology, MESH: Time Factors, HEK 293 cells, Virion, Brief Definitive Report, HIV, Dendritic Cells, Antibodies, Neutralizing, Virology, Coculture Techniques, HEK293 Cells, Microscopy, Fluorescence, Cell culture, MESH: HeLa Cells, biology.protein, HeLa Cells
Abstract: A subset of broadly neutralizing anti-HIV antibodies inhibits cell to cell transmission of the virus., The neutralizing activity of anti–HIV-1 antibodies is typically measured in assays where cell-free virions enter reporter cell lines. However, HIV-1 cell to cell transmission is a major mechanism of viral spread, and the effect of the recently described broadly neutralizing antibodies (bNAbs) on this mode of transmission remains unknown. Here we identify a subset of bNAbs that inhibit both cell-free and cell-mediated infection in primary CD4+ lymphocytes. These antibodies target either the CD4-binding site (NIH45-46 and 3BNC60) or the glycan/V3 loop (10-1074 and PGT121) on HIV-1 gp120 and act at low concentrations by inhibiting multiple steps of viral cell to cell transmission. These antibodies accumulate at virological synapses and impair the clustering and fusion of infected and target cells and the transfer of viral material to uninfected T cells. In addition, they block viral cell to cell transmission to plasmacytoid DCs and thereby interfere with type-I IFN production. Thus, only a subset of bNAbs can efficiently prevent HIV-1 cell to cell transmission, and this property should be considered an important characteristic defining antibody potency for therapeutic or prophylactic antiviral strategies.
Published: 2013

39. Broadly neutralizing antibodies suppress post-transcytosis HIV-1 infectivity

Author: Michael S. Seaman, Valérie Lorin, Marine Malbec, Caroline Eden, Olivier Schwartz, Hugo Mouquet, Timothée Bruel, Françoise Porrot, Réponse humorale aux pathogènes, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Molecular Immunology, Rockefeller University [New York], Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Immunoglobulin A, Primates, HIV Antigens, Immunology, HIV Infections, Cross Reactions, HIV Antibodies, Epithelium, Neutralization, Immunoglobulin G, 03 medical and health sciences, 0302 clinical medicine, Immunology and Allergy, Animals, Humans, Cells, Cultured, Infectivity, AIDS Vaccines, biology, Virulence, Virion, Epithelial Cells, Virology, Antibodies, Neutralizing, Immune complex, 3. Good health, 030104 developmental biology, Transcytosis, Mucosal immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, HIV-1, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunotherapy, Antibody, 030215 immunology
Abstract: International audience; Broadly neutralizing antibodies (bNAbs) offer promising opportunities for preventing HIV-1 infection in humans. Immunoprophylaxis with potent bNAbs efficiently protects non-human primates from mucosal transmission even after repeated challenges. However, the precise mechanisms of bNAb-mediated viral inhibition in mucosal tissues are currently unknown. Here, we show that immunoglobulin (Ig)G and IgA bNAbs do not interfere with the endocytic transport of HIV-1 across epithelial cells, a process referred to as transcytosis. Instead, both viruses and antibodies are translocated to the basal pole of epithelial cells, possibly in the form of an immune complex. Importantly, as opposed to free virions, viral particles bound by bNAbs are no longer infectious after transepithelial transit. Post-transcytosis neutralization activity of bNAbs displays comparable inhibitory concentrations as those measured in classical neutralization assays. Thus, bNAbs do not block the transport of incoming HIV-1 viruses across the mucosal epithelium but rather neutralize the transcytosed virions, highlighting their efficient prophylactic and protective activity in vivo.
Published: 2016

40. Transcytosis of HTLV-1 across a tight human epithelial barrier and infection of subepithelial dendritic cells

Author: Florence Guivel-Benhassine, Nina-Francesca Gnädig, Antoine Gessain, Simona Ozden, Olivier Schwartz, Patricia Jeannin, Sandra Martin-Latil, Pierre-Emmanuel Ceccaldi, Marion Desdouits, Adeline Mallet, Marie-Christine Prévost, Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Microscopie Ultrastructurale (Plate-forme), Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, This work and S.M.-L. were supported by French Agence Nationnale de la Recherche. M.D. is recipient of a fellowship from the French Ministry of Education and Research. Part of the microscopy was performed at the Dynamic Imaging Platform, Imagopole, Pasteur Institute, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Sexual transmission, T-Lymphocytes, [SDV]Life Sciences [q-bio], viruses, Immunology, Cell, Biology, Biochemistry, Tight Junctions, 03 medical and health sciences, 0302 clinical medicine, Microscopy, Electron, Transmission, immune system diseases, hemic and lymphatic diseases, Tropical spastic paraparesis, medicine, Humans, 030304 developmental biology, Human T-lymphotropic virus 1, 0303 health sciences, Transmission (medicine), Virion, virus diseases, Epithelial Cells, Dendritic Cells, Cell Biology, Hematology, medicine.disease, HTLV-I Infections, Virology, Coculture Techniques, Epithelium, 3. Good health, Lymphoma, Leukemia, Enterocytes, HEK293 Cells, medicine.anatomical_structure, Transcytosis, 030220 oncology & carcinogenesis, Caco-2 Cells, HT29 Cells
Abstract: Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma and HTLV-1–associated myelopathy/tropical spastic paraparesis. In addition to blood transfusion and sexual transmission, HTLV-1 is transmitted mainly through prolonged breastfeeding, and such infection represents a major risk for the development of adult T-cell leukemia/lymphoma. Although HTLV-1–infected lymphocytes can be retrieved from maternal milk, the mechanisms of HTLV-1 transmission through the digestive tract remain unknown. In the present study, we assessed HTLV-1 transport across the epithelial barrier using an in vitro model. Our results show that the integrity of the epithelial barrier was maintained during coculture with HTLV-1–infected lymphocytes, because neither morphological nor functional alterations of the cell monolayer were observed. Enterocytes were not susceptible to HTLV-1 infection, but free infectious HTLV-1 virions could cross the epithelial barrier via a transcytosis mechanism. Such virions were able to infect productively human dendritic cells located beneath the epithelial barrier. Our data indicate that HTLV-1 crosses the tight epithelial barrier without disruption or infection of the epithelium to further infect target cells such as dendritic cells. The present study provides the first data pertaining to the mode of HTLV-1 transport across a tight epithelial barrier, as can occur during mother-to-child HTLV-1 transmission during breastfeeding.
Published: 2012

41. Innate Sensing of Foamy Viruses by Human Hematopoietic Cells

Author: Réjane Rua, Alice Lepelley, Antoine Gessain, Olivier Schwartz, Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This study was supported by grants from the Agence Nationale de Recherche sur le SIDA (ANRS), the Agence Nationale de Recherche (ANR), SIDACTION, the CNRS, AREVA, and the Institut Pasteur. We thank the Centre d'Immunologie Humaine at the Institut Pasteur for support, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio], Immunology, Microbiology, Virus, Cell Line, 03 medical and health sciences, Interferon, Virology, medicine, Animals, Humans, Spumavirus, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Innate immune system, biology, 030306 microbiology, Dendritic Cells, TLR7, biology.organism_classification, Immunity, Innate, Virus-Cell Interactions, 3. Good health, Toll-Like Receptor 7, Viral replication, Cell culture, Insect Science, Interferon Type I, Leukocytes, Mononuclear, Interferon type I, Retroviridae Infections, medicine.drug
Abstract: Foamy viruses (FV) are nonpathogenic retroviruses that have cospeciated with primates for millions of years. FV can be transmitted through severe bites from monkeys to humans. Viral loads remain generally low in infected humans, and no secondary transmission has been reported. Very little is known about the ability of FV to trigger an innate immune response in human cells. A few previous reports suggested that FV do not induce type I interferon (IFN) in nonhematopoietic cells. Here, we examined how human hematopoietic cells sense FV particles and FV-infected cells. We show that peripheral blood mononuclear cells (PBMCs), plasmacytoid dendritic cells (pDCs), and the pDC-like cell line Gen2.2 detect FV, produce high levels of type I IFN, and express the IFN-stimulated gene MxA. Fewer than 20 FV-infected cells are sufficient to trigger an IFN response. Both prototypic and primary viruses stimulated IFN release. Donor cells expressing a replication-defective virus, carrying a mutated reverse transcriptase, induced IFN production by target cells as potently as wild-type virus. In contrast, an FV strain with env deleted, which does not produce viral particles, was inactive. IFN production was blocked by an inhibitor of endosomal acidification (bafilomycin A1) and by an endosomal Toll-like receptor (TLR) antagonist (A151). Silencing experiments in Gen2.2 further demonstrated that TLR7 is involved in FV recognition. Therefore, FV are potent inducers of type I IFN by pDCs and by PBMCs. This previously underestimated activation of the innate immune response may be involved in the control of viral replication in humans.
Published: 2012

42. Les anticorps anti-VIH-1 et la transmission virale de cellule à cellule

Author: Hugo Mouquet, Olivier Schwartz, Marine Malbec, Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Réponse humorale aux pathogènes, Institut Pasteur [Paris], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, business.industry, [SDV]Life Sciences [q-bio], 030220 oncology & carcinogenesis, Medicine, General Medicine, business, ComputingMilieux_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, 030304 developmental biology
Abstract: International audience
Published: 2014

43. Role of Gag in HIV Resistance to Protease Inhibitors

Author: François Clavel, Fabrizio Mammano, Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Mammano, Fabrizio
Subjects: [SDV]Life Sciences [q-bio], viruses, medicine.medical_treatment, lcsh:QR1-502, Human immunodeficiency virus (HIV), Review, Biology, Cleavage (embryo), medicine.disease_cause, lcsh:Microbiology, resistance, 03 medical and health sciences, Virology, medicine, Hiv resistance, 030304 developmental biology, Gag, chemistry.chemical_classification, Infectivity, 0303 health sciences, Protease, 030306 microbiology, protease, mutations, 3. Good health, [SDV] Life Sciences [q-bio], NS2-3 protease, Infectious Diseases, Enzyme, chemistry, Viral protease, HIV-1
Abstract: International audience; Cleavage of Gag and Gag-Pol precursors by the viral protease is an essential step in the replication cycle of HIV. Protease inhibitors, which compete with natural cleavage sites, strongly impair viral infectivity and have proven to be highly valuable in the treatment of HIV-infected subjects. However, as with all other antiretroviral drugs, the clinical benefit of protease inhibitors can be compromised by resistance. One key feature of HIV resistance to protease inhibitors is that the mutations that promote resistance are not only located in the protease itself, but also in some of its natural substrates. The best documented resistance-associated substrate mutations are located in, or near, the cleavage sites in the NC/SP2/p6 region of Gag. These mutations improve interactions between the substrate and the mutated enzyme and correspondingly increase cleavage. Initially described as compensatory mutations able to partially correct the loss of viral fitness that results from protease mutations, changes in Gag are now recognized as being directly involved in resistance. Besides NC/SP2/p6 mutations, polymorphisms in other regions of Gag have been found to exert various effects on viral fitness and or resistance, but their importance deserves further evaluation.
Published: 2010

44. Human Immunodeficiency Virus-1 Inhibition of Immunoamphisomes in Dendritic Cells Impairs Early Innate and Adaptive Immune Responses

Author: Eduardo Garcia, Romaine Stalder, Vincent Piguet, Sylvain Cardinaud, Arnaud Moris, Fabien Blanchet, Florence Leuba, Martin Lehmann, Olivier Schwartz, Vojo Deretic, Christina Dinkins, Damjan S. Nikolic, Li Wu, Departments of Dermatology and Venereology, Microbiology and Molecular Medicine, University Hospital and Medical School of Geneva, Virus et Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Immunité et Infection, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), The University of New Mexico [Albuquerque], Center for Retrovirus Research, Ohio State University [Columbus] (OSU), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: MICROBIO, Immunology, Antigen presentation, chemical and pharmacologic phenomena, Biology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Downregulation and upregulation, Immunity, Immunology and Allergy, MOLIMMUNO, 030304 developmental biology, Phagosome, 0303 health sciences, Autophagy, virus diseases, hemic and immune systems, Acquired immune system, 3. Good health, Cell biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, 030220 oncology & carcinogenesis, CELLBIO, Signal transduction
Abstract: International audience; Dendritic cells (DCs) in mucosal surfaces are early targets for human immunodeficiency virus-1 (HIV-1). DCs mount rapid and robust immune responses upon pathogen encounter. However, immune response in the early events of HIV-1 transmission appears limited, suggesting that HIV-1 evade early immune control by DCs. We report that HIV-1 induces a rapid shutdown of autophagy and immunoamphisomes in DCs. HIV-1 envelope activated the mammalian target of rapamycin pathway in DCs, leading to autophagy exhaustion. HIV-1-induced inhibition of autophagy in DC increased cell-associated HIV-1 and transfer of HIV-1 infection to CD4(+) T cells. HIV-1-mediated downregulation of autophagy in DCs impaired innate and adaptive immune responses. Immunoamphisomes in DCs engulf incoming pathogens and appear to amplify pathogen degradation as well as Toll-like receptor responses and antigen presentation. The findings that HIV-1 downregulates autophagy and impedes immune functions of DCs represent a pathogenesis mechanism that can be pharmacologically countered with therapeutic and prophylactic implications.
Published: 2010

45. TIP47 is Required for the Production of Infectious HIV-1 Particles from Primary Macrophages

Author: Katy Janvier, Anne Hosmalin, Guillaume Hoeffel, Clarisse Berlioz-Torrent, Sandra López-Vergès, Hélène Bauby, Fabrizio Mammano, Delphine Delcroix-Genête, BMC, Ed., Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche Antivirale, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] - Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UM3 (UMR 8104 / U1016)), and Université Paris Diderot - Paris 7 (UPD7) - Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: viruses, Viral pathogenesis, Human immunodeficiency virus (HIV), Vesicular Transport Proteins, Pregnancy Proteins, Matrix (biology), medicine.disease_cause, gag Gene Products, Human Immunodeficiency Virus, Biochemistry, MESH: HIV-1, Protein structure, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Structural Biology, MESH: RNA, Small Interfering, RNA, Small Interfering, ComputingMilieux_MISCELLANEOUS, Infectivity, MESH: Pregnancy Proteins, 0303 health sciences, Mutation, 030302 biochemistry & molecular biology, Intracellular Signaling Peptides and Proteins, env Gene Products, Human Immunodeficiency Virus, virus diseases, MESH: gag Gene Products, Human Immunodeficiency Virus, 3. Good health, Cell biology, DNA-Binding Proteins, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, lcsh:Immunologic diseases. Allergy, MESH: Virus Assembly, MESH: Mutation, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunoprecipitation, Morphogenesis, Biology, Perilipin-3, 03 medical and health sciences, Virology, MESH: Intracellular Signaling Peptides and Proteins, Genetics, medicine, Compartment (development), Humans, Gene silencing, Molecular Biology, 030304 developmental biology, MESH: Humans, 030306 microbiology, MESH: Immunoprecipitation, Macrophages, Virus Assembly, MESH: Macrophages, Colocalization, Cell Biology, MESH: Hela Cells, Poster Presentation, biology.protein, HIV-1, MESH: env Gene Products, Human Immunodeficiency Virus, lcsh:RC581-607, MESH: DNA-Binding Proteins, HeLa Cells
Abstract: Macrophages are, along with T CD4+lymphocytes, the major targets of HIV-1 infection and play a key role in viral pathogenesis as a significant reservoir. Identification of the cellular cofactors involved in the production of infectious HIV-1 from macrophages is thus crucial. Nevertheless molecular mechanisms allowing the production of infectious particles from macrophages are not entirely deciphered. In this study, we investigated the role of the cellular cofactor TIP47 in HIV-1 morphogenesis in primary macrophages. Our data show that TIP47 is essential for HIV-1 infectivity and propagation. Mutations in HIV-1 Gag or Envelope (Env) proteins, which abolish interaction with TIP47, impair HIV-1 propagation and infectivity preventing colocalization of Gag and Env, and thereby inhibiting Env incorporation into virions. Whereas disruption of Gag-TIP47 interaction increases slightly Gag particles production, impaired Env-TIP47 binding reduces Gag particles release and, strikingly, induces their retention in the viral assembly compartments. Thus, as in T lymphocytes, TIP47 is critical for the efficient release of infectious HIV-1 particles from the assembly compartment of primary macrophages, making TIP47 a new potential therapeutic target for limiting HIV-1 infectivity and spreading. This work is funded by ANRS, SIDACTION, ANR-07-JCJC-0102 programs and is part of the activities of the HIV-ACE research network (HEALTH-F3-2008-201095) supported by a grant of the European Commission, within the Priority 1 ''Health'' work programme of the 7th Framework Programme of the EU.
Published: 2010

46. Partial Inhibition of Human Immunodeficiency Virus Replication by Type I Interferons: Impact of Cell-to-Cell Viral Transfer

Author: Olivier Schwartz, Marion Sourisseau, Virginie Perrin, Daniela Vendrame, Fabrizio Mammano, Virus et Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), FP7 contract 201412, and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: MESH: Interferon Type I, CD4-Positive T-Lymphocytes, T-Lymphocytes, viruses, medicine.medical_treatment, Cell, HIV Core Protein p24, HIV Infections, Virus Replication, MESH: HIV-1, Jurkat Cells, Interferon, MESH: Jurkat Cells, Cells, Cultured, 0303 health sciences, MESH: HIV Core Protein p24, biology, MESH: CD4-Positive T-Lymphocytes, virus diseases, MESH: HIV Infections, 3. Good health, Cytokine, medicine.anatomical_structure, Interferon Type I, Lentivirus, MESH: Cells, Cultured, medicine.drug, Immunology, Microbiology, Virus, Cell Line, 03 medical and health sciences, Immune system, Immunity, Virology, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, 030304 developmental biology, MESH: Humans, 030306 microbiology, MESH: Virus Replication, biology.organism_classification, MESH: Cell Line, MESH: T-Lymphocytes, Viral replication, Insect Science, HIV-1, Pathogenesis and Immunity
Abstract: Type I interferons (IFN) inhibit several steps of the human immunodeficiency virus type 1 (HIV) replication cycle. Some HIV proteins, like Vif and Vpu, directly counteract IFN-induced restriction factors. Other mechanisms are expected to modulate the extent of IFN inhibition. Here, we studied the impact of IFN on various aspects of HIV replication in primary T lymphocytes. We confirm the potent effect of IFN on Gag p24 production in supernatants. Interestingly, IFN had a more limited effect on HIV spread, measured as the appearance of Gag-expressing cells. Primary isolates displayed similar differences in the inhibition of p24 release and virus spread. Virus emergence was the consequence of suboptimal inhibition of HIV replication and was not due to the selection of resistant variants. Cell-to-cell HIV transfer, a potent means of virus replication, was less sensitive to IFN than infection by cell-free virions. These results suggest that IFN are less active in cell cultures than initially thought. They help explain the incomplete protection by naturally secreted IFN during HIV infection and the unsatisfactory outcome of IFN treatment in HIV-infected patients.
Published: 2009

47. Human Dendritic Cell-Specific Intercellular Adhesion Molecule-Grabbing Nonintegrin (CD209) Is a Receptor forYersinia pestisThat Promotes Phagocytosis by Dendritic Cells

Author: Silvia Bulgheresi, Ramaswamy Kalyanasundaram, Tie Chen, Mikael Skurnik, B. Joseph Hinnebusch, John D. Klena, Shusheng Zhang, Olivier Schwartz, Pei Zhang, Johnny J. He, Department of Biomedical Sciences, College of Medicine, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Bacteriology and Immunology [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Faculty of Life Sciences, University of Vienna [Vienna], Department of Microbiology and Immunology, Indiana University School of Medicine, Indiana University System-Indiana University System, School of Biological Sciences, University of Canterbury [Christchurch], Laboratory of Zoonotic Pathogens, National Institutes of Health, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Lipopolysaccharides, MESH: Macrophages, Alveolar, Yersinia pestis, Phagocytosis, Immunology, MESH: Yersinia pestis, Receptors, Cell Surface, Models, Biological, Microbiology, Cell Line, 03 medical and health sciences, Macrophages, Alveolar, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Lectins, C-Type, MESH: Phagocytosis, Receptor, Cells, Cultured, MESH: Receptors, Cell Surface, 030304 developmental biology, 0303 health sciences, MESH: Humans, Cellular Microbiology: Pathogen-Host Cell Molecular Interactions, MESH: Dendritic Cells, biology, 030306 microbiology, Cell adhesion molecule, MESH: Models, Biological, Dendritic Cells, Dendritic cell, biology.organism_classification, Intercellular adhesion molecule, Enterobacteriaceae, MESH: Cell Line, 3. Good health, Infectious Diseases, Cell culture, MESH: Cell Adhesion Molecules, Parasitology, MESH: Lipopolysaccharides, Cell Adhesion Molecules, MESH: Lectins, C-Type, MESH: Cells, Cultured
Abstract: Yersinia pestisis the etiologic agent of bubonic and pneumonic plagues. It is speculated thatY. pestishijacks antigen-presenting cells (APCs), such as dendritic cells (DCs) and alveolar macrophages, in order to be delivered to lymph nodes. However, how APCs initially capture the bacterium remains uncharacterized. It is well known that HIV-1 uses human DC-specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN) (CD209) receptor, expressed by APCs, to be captured and delivered to target cell, such as CD4+lymphocytes. Several gram-negative bacteria utilize their core lipopolysaccharides (LPS) as ligands to interact with the human DC-SIGN. Therefore, it is possible thatY. pestis, whose core LPS is naturally exposed, might exploit DC-SIGN to invade APCs. We demonstrate in this study thatY. pestisdirectly interacts with DC-SIGN and invades both DCs and alveolar macrophages. In contrast, when engineered to cover the core LPS,Y. pestisloses its ability to invade DCs, alveolar macrophages, and DC-SIGN-expressing transfectants. The interaction betweenY. pestisand human DCs can be reduced by a combination treatment with anti-CD209 and anti-CD207 antibodies. This study shows that human DC-SIGN is a receptor forY. pestisthat promotes phagocytosis by DCs in vitro.
Published: 2008

48. HIV-1 Buds and Accumulates in 'Nonacidic' Endosomes of Macrophages

Author: Philippe Benaroch, Olivier Schwartz, Mabel Jouve, Sarah Watson, Nathalie Sol-Foulon, Immunité et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Hydrogen-Ion Concentration, Cancer Research, MICROBIO, viruses, Endocytic cycle, Virus Replication, MESH: HIV-1, 0302 clinical medicine, Cells, Cultured, Adenosine Triphosphatases, 0303 health sciences, Transferrin, Hydrogen-Ion Concentration, Endocytosis, 3. Good health, Cell biology, MESH: Gene Products, gag, MESH: Endocytosis, MESH: Virion, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Transferrin, MESH: Cells, Cultured, Endosome, MESH: Biological Transport, Gene Products, gag, Endosomes, Biology, Microbiology, Virus, Viral Proteins, 03 medical and health sciences, Virology, Immunology and Microbiology(all), MESH: Adenosine Triphosphatases, Humans, Compartment (pharmacokinetics), Molecular Biology, 030304 developmental biology, MESH: Humans, Macrophages, MESH: Virus Replication, Virion, MESH: Macrophages, Biological Transport, MESH: Viral Proteins, Viral assembly compartment, Viral replication, MESH: Endosomes, HIV-1, Ultrastructure, CELLBIO, Parasitology, 030217 neurology & neurosurgery
Abstract: International audience; Macrophages represent viral reservoirs in HIV-1-infected patients and accumulate viral particles within an endosomal compartment where they remain infectious for long periods of time. To determine how HIV-1 survives in endocytic compartments that become highly acidic and proteolytic and to study the nature of these virus-containing compartments, we carried out an ultrastructural study on HIV-1-infected primary macrophages. The endosomal compartments contain newly formed virions rather than internalized ones. In contrast to endocytic compartments free of viral proteins within the same infected cells, the virus containing compartments do not acidify. The lack of acidification is associated with an inability to recruit the proton pump vacuolar ATPase into the viral assembly compartment. This may prevent its fusion with lysosomes, since acidification is required for the maturation of endosomes. Thus, HIV-1 has developed a strategy for survival within infected macrophages involving prevention of acidification within a devoted endocytic virus assembly compartment.
Published: 2007
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49. A novel pathway down-modulating T cell activation involves HPK-1–dependent recruitment of 14-3-3 proteins on SLP-76

Author: Julien Fourtane, Olivier Schwartz, Oreste Acuto, Florent Carrette, Mogjiborahman Salek, Britta Jungwirth, Nathalie Sol-Foulon, Benjamin Montagne, Vincenzo Di Bartolo, Frédérique Michel, Wolf D. Lehmann, Immunologie Moléculaire, Institut Pasteur [Paris] - Centre National de la Recherche Scientifique (CNRS), Central Spectroscopy German Cancer Research Center (DKFZ) (CENTRAL SPECTROSCOPY), German Cancer Research Center DKFZ, Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Central Spectroscopy, German Cancer Research Center, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the Institut Pasteur, the CNRS, the Association pour la Recherche sur le Cancer, the Ligue Contre le Cancer-Comité Ile-de-France, and the European Union (MUGEN Network of Excellence, contract no. LSGH-CT-2005-005203)., European Project: 39516,MUGEN, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: genetic structures, T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Down-Regulation, Protein Serine-Threonine Kinases, Biology, Lymphocyte Activation, Jurkat cells, Article, Phosphorylation cascade, Serine, Jurkat Cells, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Chlorocebus aethiops, Animals, Humans, Immunology and Allergy, Protein phosphorylation, Phosphorylation, Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, T-cell receptor, Tyrosine phosphorylation, Articles, Phosphoproteins, equipment and supplies, Molecular biology, eye diseases, Cell biology, 14-3-3 Proteins, chemistry, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, COS Cells, sense organs, Signal transduction, Protein Binding, Signal Transduction, 030215 immunology
Abstract: International audience; The SH2 domain-containing leukocyte protein of 76 kD (SLP-76) is a pivotal element of the signaling machinery controlling T cell receptor (TCR)-mediated activation. Here, we identify 14-3-3epsilon and zeta proteins as SLP-76 binding partners. This interaction was induced by TCR ligation and required phosphorylation of SLP-76 at serine 376. Ribonucleic acid interference and in vitro phosphorylation experiments showed that serine 376 is the target of the hematopoietic progenitor kinase 1 (HPK-1). Interestingly, either S376A mutation or HPK-1 knockdown resulted in increased TCR-induced tyrosine phosphorylation of SLP-76 and phospholipase C-gamma1. Moreover, an SLP-76-S376A mutant induced higher interleukin 2 gene transcription than wild-type SLP-76. These data reveal a novel negative feedback loop involving HPK-1-dependent serine phosphorylation of SLP-76 and 14-3-3 protein recruitment, which tunes T cell activation.
Published: 2007

50. Poor recognition of HIV-1 Nef protein by CD8 T cells from HIV-1-infected children: Impact of age

Author: Christine Rouzioux, Florence Buseyne, Daniel Scott-Algara, Marianne Burgard, Elizabeth Monchatre, Nassima Bellal, Stéphane Blanche, Yves Rivière, Béatrice Corre, Françoise Porrot, Régulation des Infections Rétrovirales, Institut Pasteur [Paris], Immunologie Moléculaire, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunopathologie Virale, Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Nef Protein, Anti-HIV Agents, viruses, Human immunodeficiency virus (HIV), HIV Infections, CD8-Positive T-Lymphocytes, Biology, medicine.disease_cause, Gene Products, nef, MESH: HIV-1, 03 medical and health sciences, 0302 clinical medicine, Virology, medicine, Humans, Cytotoxic T cell, nef Gene Products, Human Immunodeficiency Virus, HIV perinatal infection, MESH: Anti-HIV Agents, Children, Retrospective Studies, 030304 developmental biology, Dominance (genetics), MESH: Age Factors, 0303 health sciences, MESH: Humans, ELISPOT, MESH: Child, Preschool, Age Factors, Infant, HIV, virus diseases, MESH: Retrospective Studies, MESH: HIV Infections, MESH: CD8-Positive T-Lymphocytes, MESH: Infant, CTL, Elispot, Positive response, CD8 T cell, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Immunology, HIV-1, MESH: Gene Products, nef, Ex vivo, 030215 immunology
Abstract: International audience; Recognition of various HIV proteins by CD8 T cells from HIV-infected children was determined by two functional assays. First, using an Elispot assay, we show that 80% of patients recognized Gag, 77% recognized Pol, 61% recognized Env, 44% recognized Nef and 29% recognized Vif. Frequencies of Gag-, Pol-, and Env-specific IFN-gamma producing CD8 T cells were higher than frequencies of Nef and Vif-specific CD8 T cells. The poor recognition of Nef by ex vivo CD8 T cells was confirmed by CTL assays performed in HAART na? children: 25% of children had positive response against Nef versus 44, 63 and 62% for Env, Gag, and Pol, respectively. Memory Gag-specific CTL were positively correlated with age, whereas Nef-specific CTL were negatively correlated with age. The poor Nef-specific CD8 T cell response in HIV-infected children contrasts with dominance of Nef-specific responses in infected adults.
Published: 2006

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65 results on '"Virus et Immunité"'

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