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1. Methotrexate treatment hampers induction of vaccine-specific CD4 T cell responses in patients with IMID

Author

Sander W Tas, Joep Killestein, Joost Raaphorst, Taco W Kuijpers, Alexandre E Voskuyl, Gertjan Wolbink, Theo Rispens, Anneke J van der Kooi, Anja Ten Brinke, Karina de Leeuw, Abraham Rutgers, Juan J Garcia-Vallejo, Frederike J Bemelman, YK Onno Teng, Phyllis I Spuls, Mark Löwenberg, Jelle de Wit, Diane van der Woude, Marcel W Bekkenk, Luuk Wieske, Esther Brusse, Laura Boekel, Filip Eftimov, Eileen W Stalman, Maurice Steenhuis, Sofie Keijzer, Olvi Cristianawati, Koos P J van Dam, Adriaan G Volkers, Annelie H Musters, Nicoline F Post, Angela L Bosma, Marc L Hilhorst, Yosta Vegting, Bo Broens, Barbara Horváth, Annabel M Ruiter, Matthias H Busch, Dirk Jan Hijnen, Niels J M Verstegen, Pieter A van Doorn, Jan JGM Verschuuren, Laura Y L Kummer, Ruth R Hagen, Christine Kreher, Lisan H Kuijper, Mariël C Duurland, Veronique A L Konijn, Carolien E van de Sandt, Laura Fernández Blanco, Amélie Bos, Charlotte Menage, Tineke Jorritsma, Jet van den Dijssel, Rivka de Jongh, Tom Ashhurst, Marit J van Gils, Mathieu Claireaux, Sija Marieke van Ham, Renée CF van Allaart, Adája E Baars, George Elias, Cécile ACM van Els, H Stephan Goedee, Geert RAM D’Haens, Papay BP Jallah, Elham S Mirfazeli, Jim BD Keijser, Lotte van Ouwerkerk, Pieter van Paassen, Agner R Parra Sanchez, W Ludo van der Pol, Corine RG Schreurs, R Bart Takkenberg, and Koos AH Zwinderman

Subjects
Medicine
Abstract

Objectives Methotrexate (MTX) is one of the most commonly used medications to treat rheumatoid arthritis (RA). However, the effect of MTX treatment on cellular immune responses remains incompletely understood. This raises concerns about the vulnerability of these patients to emerging infections and following vaccination.Methods In the current study, we investigated the impact of MTX treatment in patients with immune-mediated inflammatory disease on B and CD4 T cell SARS-CoV-2 vaccination responses. Eighteen patients with RA and two patients with psoriatic arthritis on MTX monotherapy were included, as well as 10 patients with RA without immunosuppressive treatment, and 29 healthy controls. CD4 T and B cell responses were analysed 7 days and 3–6 months after two SARS-CoV-2 messenger RNA vaccinations. High-dimensional flow cytometry analysis was used to analyse fresh whole blood, an activation-induced marker assay to measure antigen-specific CD4 T cells, and spike probes to study antigen-specific B cells.Results Seven days following two SARS-CoV-2 vaccinations, total B and T cell counts were similar between MTX-treated patients and controls. In addition, spike-specific B cell frequencies were unaffected. Remarkably, the frequency of antigen-specific CD4 T cells was reduced in patients using MTX and correlated strongly with anti-RBD IgG antibodies. These results suggest that decreased CD4 T cell activity may result in slower vaccination antibody responses in MTX-treated patients.Conclusion Taken together, MTX treatment reduces vaccine-induced CD4 T cell activation, which correlates with lower antibody responses.Trial registration number NL8900.

Published
2024
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2. Primary SARS-CoV-2 variant of concern infections elicit broad antibody Fc-mediated effector functions and memory B cell responses.

Author

Karlijn van der Straten, Denise Guerra, Gius Kerster, Mathieu Claireaux, Marloes Grobben, Angela I Schriek, Anders Boyd, Jacqueline van Rijswijk, Khadija Tejjani, Dirk Eggink, Tim Beaumont, Steven W de Taeye, Godelieve J de Bree, Rogier W Sanders, and Marit J van Gils

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by human sera is a strong correlate of protection against symptomatic and severe Coronavirus Disease 2019 (COVID-19). The emergence of antigenically distinct SARS-CoV-2 variants of concern (VOCs) and the relatively rapid waning of serum antibody titers, however, raises questions about the sustainability of serum protection. In addition to serum neutralization, other antibody functionalities and the memory B cell (MBC) response are suggested to help maintaining this protection. In this study, we investigate the breadth of spike (S) protein-specific serum antibodies that mediate effector functions by interacting with Fc-gamma receptor IIa (FcγRIIa) and FcγRIIIa, and of the receptor binding domain (RBD)-specific MBCs, following a primary SARS-CoV-2 infection with the D614G, Alpha, Beta, Gamma, Delta, Omicron BA.1 or BA.2 variant. Irrespectively of the variant causing the infection, the breadth of S protein-specific serum antibodies that interact with FcγRIIa and FcγRIIIa and the RBD-specific MBC responses exceeded the breadth of serum neutralization, although the Alpha-induced B cell response seemed more strain-specific. Between VOC groups, both quantitative and qualitative differences in the immune responses were observed, suggesting differences in immunogenicity. Overall, this study contributes to the understanding of protective humoral and B cell responses in the light of emerging antigenically distinct VOCs, and highlights the need to study the immune system beyond serum neutralization to gain a better understanding of the protection against emerging variants.

Published
2024
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3. Systematic evaluation of B-cell clonal family inference approaches

Author

Daria Balashova, Barbera D. C. van Schaik, Maria Stratigopoulou, Jeroen E. J. Guikema, Tom G. Caniels, Mathieu Claireaux, Marit J. van Gils, Anne Musters, Dornatien C. Anang, Niek de Vries, Victor Greiff, and Antoine H. C. van Kampen

Subjects
B-cell receptor repertoire, B-cell clonal family partitioning, AIRR-seq data, AIRR-seq data simulation, B-cell shared clonal families, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract The reconstruction of clonal families (CFs) in B-cell receptor (BCR) repertoire analysis is a crucial step to understand the adaptive immune system and how it responds to antigens. The BCR repertoire of an individual is formed throughout life and is diverse due to several factors such as gene recombination and somatic hypermutation. The use of Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) using next generation sequencing enabled the generation of full BCR repertoires that also include rare CFs. The reconstruction of CFs from AIRR-seq data is challenging and several approaches have been developed to solve this problem. Currently, most methods use the heavy chain (HC) only, as it is more variable than the light chain (LC). CF reconstruction options include the definition of appropriate sequence similarity measures, the use of shared mutations among sequences, and the possibility of reconstruction without preliminary clustering based on V- and J-gene annotation. In this study, we aimed to systematically evaluate different approaches for CF reconstruction and to determine their impact on various outcome measures such as the number of CFs derived, the size of the CFs, and the accuracy of the reconstruction. The methods were compared to each other and to a method that groups sequences based on identical junction sequences and another method that only determines subclones. We found that after accounting for data set variability, in particular sequencing depth and mutation load, the reconstruction approach has an impact on part of the outcome measures, including the number of CFs. Simulations indicate that unique junctions and subclones should not be used as substitutes for CF and that more complex methods do not outperform simpler methods. Also, we conclude that different approaches differ in their ability to correctly reconstruct CFs when not considering the LC and to identify shared CFs. The results showed the effect of different approaches on the reconstruction of CFs and highlighted the importance of choosing an appropriate method.

Published
2024
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4. Broad SARS-CoV-2 neutralization by monoclonal and bispecific antibodies derived from a Gamma-infected individual

Author

Denise Guerra, Tim Beaumont, Laura Radić, Gius Kerster, Karlijn van der Straten, Meng Yuan, Jonathan L. Torres, Wen-Hsin Lee, Hejun Liu, Meliawati Poniman, Ilja Bontjer, Judith A. Burger, Mathieu Claireaux, Tom G. Caniels, Jonne L. Snitselaar, Tom P.L. Bijl, Sabine Kruijer, Gabriel Ozorowski, David Gideonse, Kwinten Sliepen, Andrew B. Ward, Dirk Eggink, Godelieve J. de Bree, Ian A. Wilson, Rogier W. Sanders, and Marit J. van Gils

Subjects
Immunology, Virology, Structural biology, Science
Abstract

Summary: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has remained a medical threat due to the evolution of multiple variants that acquire resistance to vaccines and prior infection. Therefore, it is imperative to discover monoclonal antibodies (mAbs) that neutralize a broad range of SARS-CoV-2 variants. A stabilized spike glycoprotein was used to enrich antigen-specific B cells from an individual with a primary Gamma variant infection. Five mAbs selected from those B cells showed considerable neutralizing potency against multiple variants, with COVA309-35 being the most potent against the autologous virus, as well as Omicron BA.1 and BA.2, and COVA309-22 having binding and neutralization activity against Omicron BA.4/5, BQ.1.1, and XBB.1. When combining the COVA309 mAbs as cocktails or bispecific antibodies, the breadth and potency were improved. In addition, the mechanism of cross-neutralization of the COVA309 mAbs was elucidated by structural analysis. Altogether these data indicate that a Gamma-infected individual can develop broadly neutralizing antibodies.

Published
2023
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5. A public antibody class recognizes an S2 epitope exposed on open conformations of SARS-CoV-2 spike

Author

Mathieu Claireaux, Tom G. Caniels, Marlon de Gast, Julianna Han, Denise Guerra, Gius Kerster, Barbera D. C. van Schaik, Aldo Jongejan, Angela I. Schriek, Marloes Grobben, Philip J. M. Brouwer, Karlijn van der Straten, Yoann Aldon, Joan Capella-Pujol, Jonne L. Snitselaar, Wouter Olijhoek, Aafke Aartse, Mitch Brinkkemper, Ilja Bontjer, Judith A. Burger, Meliawati Poniman, Tom P. L. Bijl, Jonathan L. Torres, Jeffrey Copps, Isabel Cuella Martin, Steven W. de Taeye, Godelieve J. de Bree, Andrew B. Ward, Kwinten Sliepen, Antoine H. C. van Kampen, Perry D. Moerland, Rogier W. Sanders, and Marit J. van Gils

Subjects
Science
Abstract

To fully understand the potential shortcomings of SARS-CoV-2 vaccination, it is necessary to delineate the properties of the antibodies elicited, during immunization, and also infection. Through investigation of the SARS-CoV-2 spike-reactive B cell repertoire, authors identify following infection, a subset of B cells enriched and almost exclusively target a non-neutralizing S2 epitope present in aberrant forms.

Published
2022
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6. 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, and Lisa A. Chakrabarti

Subjects
Science
Abstract

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
2022
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7. Primary antibody response after influenza virus infection is first dominated by low-mutated HA-stem antibodies followed by higher-mutated HA-head antibodies

Author

Aafke Aartse, Daniella Mortier, Petra Mooij, Sam Hofman, Marlies M. van Haaren, Martin Corcoran, Gunilla B. Karlsson Hedestam, Dirk Eggink, Mathieu Claireaux, Willy M. J. M. Bogers, Marit J. van Gils, and Gerrit Koopman

Subjects
influenza A virus, hemagglutinin, HA-stem, HA-head, primary response, antibody response, Immunologic diseases. Allergy, RC581-607
Abstract

Several studies have shown that the first encounter with influenza virus shapes the immune response to future infections or vaccinations. However, a detailed analysis of the primary antibody response is lacking as this is difficult to study in humans. It is therefore not known what the frequency and dynamics of the strain-specific hemagglutinin (HA) head- and stem-directed antibody responses are directly after primary influenza virus infection. Here, sera of twelve H1N1pdm2009 influenza virus-infected cynomolgus macaques were evaluated for HA-head and HA-stem domain antibody responses. We observed an early induction of HA-stem antibody responses, which was already decreased by day 56. In contrast, responses against the HA-head domain were low early after infection and increased at later timepoint. The HA-specific B cell repertoires in each animal showed diverse VH-gene usage with preferred VH-gene and JH-gene family usage for HA-head or HA-stem B cells but a highly diverse allelic variation within the VH-usage. HA-head B cells had shorter CDRH3s and higher VH-gene somatic hyper mutation levels relative to HA-stem B cells. In conclusion, our data suggest that HA-stem antibodies are the first to react to the infection while HA-head antibodies show a delayed response, but a greater propensity to enter the germinal center and undergo affinity maturation.

Published
2022
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8. Influenza A Virus Hemagglutinin Trimer, Head and Stem Proteins Identify and Quantify Different Hemagglutinin-Specific B Cell Subsets in Humans

Author

Aafke Aartse, Dirk Eggink, Mathieu Claireaux, Sarah van Leeuwen, Petra Mooij, Willy M. Bogers, Rogier W. Sanders, Gerrit Koopman, and Marit J. van Gils

Subjects
antibody responses, influenza A virus, hemagglutinin, trimer specific, head, stem, Medicine
Abstract

Antibody responses against the influenza A virus hemagglutinin (HA)-protein are studied intensively because they can protect against (re)infection. Previous studies have focused on antibodies targeting the head or stem domains, while other possible specificities are often not taken into account. To study such specificities, we developed a diverse set of HA-domain proteins based on an H1N1pdm2009-like influenza virus strain, including monomeric head and trimeric stem domain, as well as the full HA-trimer. These proteins were used to study the B cell and antibody responses in six healthy human donors. A large proportion of HA-trimer B cells bound exclusively to HA-trimer probe (54–77%), while only 8–18% and 9–23% were able to recognize the stem or head probe, respectively. Monoclonal antibodies (mAbs) were isolated and three of these mAbs, targeting the different domains, were characterized in-depth to confirm the binding profile observed in flow cytometry. The head-directed mAb, targeting an epitope distinct from known head-specific mAbs, showed relatively broad H1N1 neutralization and the stem-directed mAb was able to broadly neutralize diverse H1N1 viruses. Moreover, we identified a trimer-directed mAb that did not compete with known head or stem domain specific mAbs, suggesting that it targets an unknown epitope or conformation of influenza virus’ HA. These observations indicate that the described method can characterize the diverse antibody response to HA and might be able to identify HA-specific B cells and antibodies with previously unknown specificities that could be relevant for vaccine design.

Published
2021
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9. MHC Class II Tetramer Labeling of Human Primary CD4+ T Cells from HIV Infected Patients

Author

Moran Galperin, Daniela Benati, Mathieu Claireaux, Madhura Mukhopadhyay, and Lisa Chakrabarti

Subjects
Biology (General), QH301-705.5
Abstract

Major Histocompatibility Complex (MHC) tetramers have been used for two decades to detect, isolate and characterize T cells specific for various pathogens and tumor antigens. In the context of Human Immunodeficiency Virus (HIV) infection, antigen-specific CD8+ T cells have been extensively studied ex vivo, as they can be readily detected by HIV peptide-loaded MHC class I tetramers. In contrast, the detection of HIV-specific CD4+ T cells has proven more challenging, due to the intrinsically lower clonal expansion rates of CD4+ T cells, and to the preferential depletion of HIV-specific CD4+ T cells in the course of HIV infection.In the following protocol, we describe a simple method that facilitates the identification of CD4+ T cells specific for an HIV-1 capsid epitope using peptide-loaded MHC class II tetramers. Tetramer labeled CD4+ T cells can be analyzed for their cell surface phenotype and/or FACS-sorted for further downstream applications. A key point for successful detection of specific CD4+ T cells ex vivo is the choice of a peptide/MHC II combination that results in high-affinity T Cell Receptor (TCR) binding (Benati et al., 2016). A second key point for reliable detection of MHC II tetramer-positive cells is the systematic use of a control tetramer loaded with an irrelevant peptide, with the sample and control tubes being processed in identical conditions.

Published
2017
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10. Distinct dynamics of antigen-specific induction and differentiation of different CD11c + Tbet + B cell subsets

Author

Juulke Steuten, Amélie V. Bos, Lisan H. Kuijper, Mathieu Claireaux, Wouter Olijhoek, George Elias, Mariel C. Duurland, Tineke Jorritsma, Casper Marsman, Alberta G.A. Paul, Juan J. Garcia Vallejo, Marit J. van Gils, Luuk Wieske, Taco W. Kuijpers, Filip Eftimov, S. Marieke van Ham, Anja ten Brinke, Molecular cell biology and Immunology, AII - Cancer immunology, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, Pediatrics, Graduate School, Landsteiner Laboratory, Medical Microbiology and Infection Prevention, AII - Infectious diseases, AII - Inflammatory diseases, Neurology, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, ANS - Neuroinfection & -inflammation, and EURO-NMD

Subjects
SARS-CoV-2 vaccination, antibody-secreting cell differentiation, CD11c Tbet atypical B cell, Immunology, Immunology and Allergy, age-associated B cell, activated naive, double negative 2
Abstract

Background: CD11c +Tbet + B cells are enriched in autoimmunity and chronic infections and also expand on immune challenge in healthy individuals. CD11c +Tbet + B cells remain an enigmatic B-cell population because of their intrinsic heterogeneity. Objectives: We investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen-specific development and differentiation properties of 3 separate CD11c + B-cell subsets—age-associated B cells (ABCs), double-negative 2 (DN2) B cells, and activated naive B cells—and compared them to their canonical CD11c − counterparts. Methods: Dynamics of the response of the 3 CD11c + B-cell subsets were assessed at SARS-CoV-2 vaccination in healthy donors by spectral flow cytometry. Distinct CD11c + B-cell subsets were functionally characterized by optimized in vitro cultures. Results: In contrast to a durable expansion of antigen-specific CD11c − memory B cells over time, both ABCs and DN2 cells were strongly expanded shortly after second vaccination and subsequently contracted. Functional characterization of antibody-secreting cell differentiation dynamics revealed that CD11c +Tbet + B cells were primed for antibody-secreting cell differentiation compared to relevant canonical CD11c − counterparts. Conclusion: Overall, CD11c +Tbet + B cells encompass heterogeneous subpopulations, of which primarily ABCs as well as DN2 B cells respond early to immune challenge and display a pre–antibody-secreting cell phenotype.

Published
2023

11. Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

Author

Philip J.M. Brouwer, Aleksandar Antanasijevic, Adam J. Ronk, Helena Müller-Kräuter, Yasunori Watanabe, Mathieu Claireaux, Hailee R. Perrett, Tom P.L. Bijl, Marloes Grobben, Jeffrey C. Umotoy, Angela I. Schriek, Judith A. Burger, Khadija Tejjani, Nicole M. Lloyd, Thijs H. Steijaert, Marlies M. van Haaren, Kwinten Sliepen, Steven W. de Taeye, Marit J. van Gils, Max Crispin, Thomas Strecker, Alexander Bukreyev, Andrew B. Ward, Rogier W. Sanders, Medical Microbiology and Infection Prevention, AII - Infectious diseases, Graduate School, and Experimental Immunology

Subjects
Virology, antibody, vaccine, cryo-EM, Parasitology, nanoparticles, Lassa virus, Microbiology, challenge study
Abstract

The Lassa virus is endemic in parts of West Africa, and it causes hemorrhagic fever with high mortality. The development of a recombinant protein vaccine has been hampered by the instability of soluble Lassa virus glycoprotein complex (GPC) trimers, which disassemble into monomeric subunits after expression. Here, we use two-component protein nanoparticles consisting of trimeric and pentameric subunits to stabilize GPC in a trimeric conformation. These GPC nanoparticles present twenty prefusion GPC trimers on the surface of an icosahedral particle. Cryo-EM studies of GPC nanoparticles demonstrated a well-ordered structure and yielded a high-resolution structure of an unliganded GPC. These nanoparticles induced potent humoral immune responses in rabbits and protective immunity against the lethal Lassa virus challenge in guinea pigs. Additionally, we isolated a neutralizing antibody that mapped to the putative receptor-binding site, revealing a previously undefined site of vulnerability. Collectively, these findings offer potential approaches to vaccine and therapeutic design for the Lassa virus.

Published
2022

12. Broad SARS-CoV-2 Neutralization by Monoclonal and Bispecific Antibodies Derived from a Gamma-infected Individual

Author

Denise Guerra, Tim Beaumont, Laura Radić, Gius Kerster, Karlijn van der Straten, Meng Yuan, Jonathan L. Torres, Wen-Hsin Lee, Hejun Liu, Meliawati Poniman, Ilja Bontjer, Judith A. Burger, Mathieu Claireaux, Tom G. Caniels, Jonne L. Snitselaar, Tom P. L. Bijl, Sabine Kruijer, Gabriel Ozorowski, David Gideonse, Kwinten Sliepen, Andrew B. Ward, Dirk Eggink, Godelieve J. de Bree, Ian A. Wilson, Rogier W. Sanders, and Marit J. van Gils

Subjects
Article
Abstract

The worldwide pandemic caused by SARS-CoV-2 has remained a human medical threat due to the continued evolution of multiple variants that acquire resistance to vaccines and prior infection. Therefore, it is imperative to discover monoclonal antibodies (mAbs) that neutralize a broad range of SARS-CoV-2 variants for therapeutic and prophylactic use. A stabilized autologous SARS-CoV-2 spike glycoprotein was used to enrich antigen-specific B cells from an individual with a primary Gamma variant infection. Five mAbs selected from those B cells showed considerable neutralizing potency against multiple variants of concern, with COVA309-35 being the most potent against the autologous virus, as well as against Omicron BA.1 and BA.2. When combining the COVA309 mAbs as cocktails or bispecific antibody formats, the breadth and potency was significantly improved against all tested variants. In addition, the mechanism of cross-neutralization of the COVA309 mAbs was elucidated by structural analysis. Altogether these data indicate that a Gamma-infected individual can develop broadly neutralizing antibodies.

Published
2022

13. Lassa virus glycoprotein nanoparticles elicit a neutralizing antibody that defines a new site of vulnerability

Author

Philip J.M. Brouwer, Aleksandar Antanasijevic, Adam J. Ronk, Helena Müller-Kräuter, Yasunori Watanabe, Mathieu Claireaux, Nicole M. Lloyd, Tom. P. L. Bijl, Hailee R. Perrett, Thijs Steijaert, Judith A. Burger, Marlies M. van Haaren, Kwinten Sliepen, Marit J. van Gils, Max Crispin, Thomas Strecker, Alexander Bukreyev, Andrew B. Ward, and Rogier W. Sanders

Subjects
viruses
Abstract

Lassa virus is endemic in large parts of West Africa and causes a hemorrhagic fever. Recent years have seen several serious outbreaks of Lassa fever with high mortality rates. A vaccine to curtail infection is urgently needed. The development of a recombinant protein vaccine has been hampered by the instability of soluble Lassa virus glycoprotein complex (GPC) trimers, which disassemble into monomeric subunits after expression. Here we use two-component protein nanoparticles to stabilize GPC in a trimeric conformation and present twenty prefusion GPC trimers on the surface of an icosahedral nanoparticle. Cryo-EM studies of assembled GPC nanoparticles demonstrated a well-ordered structure and yielded a high-resolution structure of an unliganded GPC. These nanoparticles induced potent humoral immune responses in rabbits and protective immunity against a lethal Lassa virus challenge in guinea pigs. We isolated a neutralizing antibody which was mapped to the putative receptor-binding site, revealing a novel site of vulnerability on GPC.

Published
2022

14. A public antibody class recognizes a novel S2 epitope exposed on open conformations of SARS-CoV-2 spike

Author

Mathieu Claireaux, Tom G Caniels, Marlon de Gast, Julianna Han, Denise Guerra, Gius Kerster, Barbera DC van Schaik, Aldo Jongejan, Angela I. Schriek, Marloes Grobben, Philip JM Brouwer, Karlijn van der Straten, Yoann Aldon, Joan Capella-Pujol, Jonne L Snitselaar, Wouter Olijhoek, Aafke Aartse, Mitch Brinkkemper, Ilja Bontjer, Judith A Burger, Meliawati Poniman, Tom PL Bijl, Jonathan L Torres, Jeffrey Copps, Isabel Cuella Martin, Steven W de Taeye, Godelieve J de Bree, Andrew B Ward, Kwinten Sliepen, Antoine HC van Kampen, Perry D Moerland, Rogier W Sanders, and Marit J van Gils

Abstract

Delineating the origins and properties of antibodies elicited by SARS-CoV-2 infection and vaccination is critical for understanding their benefits and potential shortcomings. Therefore, we investigated the SARS-CoV-2 spike (S)-reactive B cell repertoire in unexposed individuals by flow cytometry and single-cell sequencing. We found that ∼82% of SARS-CoV-2 S-reactive B cells show a naive phenotype, which represents an unusually high fraction of total human naive B cells (∼0.1%). Approximately 10% of these naive S-reactive B cells shared an IGHV1-69/IGKV3-11 B cell receptor pairing, an enrichment of 18-fold compared to the complete naive repertoire. A proportion of memory B cells, comprising switched (∼0.05%) and unswitched B cells (∼0.04%), was also reactive with S and some of these cells were reactive with ADAMTS13, which is associated with thrombotic thrombocytopenia. Following SARS-CoV-2 infection, we report an average 37-fold enrichment of IGHV1-69/IGKV3-11 B cell receptor pairing in the S-reactive memory B cells compared to the unselected memory repertoire. This class of B cells targets a previously undefined non-neutralizing epitope on the S2 subunit that becomes exposed on S proteins used in approved vaccines when they transition away from the native pre-fusion state because of instability. These findings can help guide the improvement of SARS-CoV-2 vaccines.

Published
2021

15. Influenza a virus hemagglutinin trimer, head and stem proteins identify and quantify different hemagglutinin-specific b cell subsets in humans

Author

Marit J. van Gils, Mathieu Claireaux, Willy M. J. M. Bogers, Rogier W. Sanders, Sarah van Leeuwen, Petra Mooij, Aafke Aartse, Gerrit Koopman, Dirk Eggink, Medical Microbiology and Infection Prevention, and AII - Infectious diseases

Subjects
0301 basic medicine, medicine.drug_class, Immunology, Hemagglutinin (influenza), Stem, medicine.disease_cause, Monoclonal antibody, Article, Neutralization, Epitope, Virus, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, Influenza A virus, medicine, Pharmacology (medical), Hemagglutinin, B cell, Pharmacology, biology, Virology, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, Trimer specific, biology.protein, Medicine, Antibody responses, Antibody, Head, 030217 neurology & neurosurgery
Abstract

Antibody responses against the influenza A virus hemagglutinin (HA)-protein are studied intensively because they can protect against (re)infection. Previous studies have focused on antibodies targeting the head or stem domains, while other possible specificities are often not taken into account. To study such specificities, we developed a diverse set of HA-domain proteins based on an H1N1pdm2009-like influenza virus strain, including monomeric head and trimeric stem domain, as well as the full HA-trimer. These proteins were used to study the B cell and antibody responses in six healthy human donors. A large proportion of HA-trimer B cells bound exclusively to HA-trimer probe (54–77%), while only 8–18% and 9–23% were able to recognize the stem or head probe, respectively. Monoclonal antibodies (mAbs) were isolated and three of these mAbs, targeting the different domains, were characterized in-depth to confirm the binding profile observed in flow cytometry. The head-directed mAb, targeting an epitope distinct from known head-specific mAbs, showed relatively broad H1N1 neutralization and the stem-directed mAb was able to broadly neutralize diverse H1N1 viruses. Moreover, we identified a trimer-directed mAb that did not compete with known head or stem domain specific mAbs, suggesting that it targets an unknown epitope or conformation of influenza virus’ HA. These observations indicate that the described method can characterize the diverse antibody response to HA and might be able to identify HA-specific B cells and antibodies with previously unknown specificities that could be relevant for vaccine design.

Published
2021

16. Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection

Author

Anna Z Mykytyn, Max Crispin, Mathieu Claireaux, Karlijn van der Straten, Tom G. Caniels, Rashmi Ravichandran, Raphael Ho Tsong Fang, Kwinten Sliepen, Nisreen M.A. Okba, Mitch Brinkkemper, Nidhal Kahlaoui, Marlon de Gast, Rogier W. Sanders, Ilja Bontjer, Hannah L. Turner, Romain Marlin, Jelle van Schooten, Sylvie van der Werf, Meliawati Poniman, Godelieve J. de Bree, Yoann Aldon, Julien Lemaitre, Thibaut Naninck, Yasunori Watanabe, Roger Le Grand, Eric Ginoux, Ségolène Diry, Pauline Maisonnasse, Julien Villaudy, Edith E. Schermer, Julia M. Giezen, Vanessa Contreras, Bart L. Haagmans, Catherine Chapon, Gius Kerster, Philip J. M. Brouwer, Cynthia A. van der Linden, Yme U. van der Velden, Judith A. Burger, Andrew B. Ward, Virginie Chesnais, Mariëlle J. van Breemen, Marit J. van Gils, Marloes Grobben, Nathalie Dereuddre-Bosquet, Neil P. King, Joel D. Allen, Department of Medical Microbiology and Infection Prevention [Amsterdam], University of Amsterdam [Amsterdam] (UvA), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Life and Soft, University of Southampton, University of Oxford, The Scripps Research Institute [La Jolla, San Diego], Imperial College London, Amsterdam UMC - Amsterdam University Medical Center, Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Washington [Seattle], AIMM Therapeutics [Amsterdam, the Netherlands], 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)-Université Paris Cité (UPCité), This work was supported by a Netherlands Organisation for Scientific Research (NWO) Vici grant (to R.W.S.), the Bill & Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery (CAVD) grants OPP1111923, OPP1132237, and INV-002022 (to R.W.S. and/or N.P.K.), INV-008352/OPP1153692 and OPP1196345/INV-008813 (to M.C.), and OPP1170236 (to A.B.W.), the Fondation Dormeur, Vaduz (R.W.S. and to M.J.v.G.) and Health-Holland PPS-allowance LSHM20040 (to M.J.v.G.), the University of Southampton Coronavirus Response Fund (M.C.), and the Netherlands Organisation for Health Research and Development ZONMW (B.L.H). M.J.v.G. is a recipient of an AMC Fellowship from Amsterdam UMC and a COVID-19 grant from the Amsterdam Institute for Infection and Immunity. R.W.S. and M.J.v.G. are recipients of support from the University of Amsterdam Proof of Concept fund (contract 200421) as managed by Innovation Exchange Amsterdam (IXA). The Infectious Disease Models and Innovative Therapies (IDMIT) research infrastructure is supported by the Programme Investissements d’Avenir, managed by the National Research Agency (ANR) under reference ANR-11-INBS-0008. The Fondation Bettencourt Schueller and the Region Ile-de-France contributed to the implementation of IDMIT’s facilities and imaging technologies. The non-human primate study received financial support from REACTing, the ANR (AM-CoV-Path), and the European Infrastructure TRANSVAC2 (730964)., ANR-11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), ANR-20-COVI-0021,AM-Cov-Path,Pathogénèse de l'infection SARS-Cov-2 dans un modèle de primates non humains : un modèle pour les traitements et la prévention(2020), European Project: 730964, H2020, RIA,H2020-INFRAIA-2016-1,TRANSVAC2(2017), Graduate School, AII - Infectious diseases, Medical Microbiology and Infection Prevention, Experimental Immunology, Infectious diseases, APH - Aging & Later Life, APH - Global Health, and Virology

Subjects
T-Lymphocytes, viruses, [SDV]Life Sciences [q-bio], Disease, Public administration, Mice, 0302 clinical medicine, vaccine, Pandemic, antibodies, Spike (database), Neutralizing antibody, 0303 health sciences, B-Lymphocytes, Mice, Inbred BALB C, biology, Transmission (medicine), Viral Load, protection, Models, Animal, Spike Glycoprotein, Coronavirus, Christian ministry, Rabbits, Antibody, Viral load, Healthcare system, COVID-19 Vaccines, Coronavirus disease 2019 (COVID-19), macaques, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Acquired immunodeficiency syndrome (AIDS), Immunity, Political science, medicine, Animals, 030304 developmental biology, B cells, SARS-CoV-2, Conflict of interest, Spike Protein, COVID-19, medicine.disease, Antibodies, Neutralizing, Virology, immunity, Macaca fascicularis, Immunization, Infectious disease (medical specialty), biology.protein, nanoparticles, 030217 neurology & neurosurgery
Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication in the upper and lower airways. These nanoparticles are a promising vaccine candidate to curtail the SARS-CoV-2 pandemic., Graphical Abstract, Brouwer et al. present preclinical evidence in support of a COVID-19 vaccine candidate, designed as a self-assembling two-component protein nanoparticle displaying multiple copies of the SARS-CoV-2 spike protein, which induces strong neutralizing antibody responses and protects from high-dose SARS-CoV-2 challenge.

Published
2021

17. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability

Author

Gestur Vidarsson, Mathieu Claireaux, Ilja Bontjer, Marlies M. van Haaren, Alex van der Kooi, Philip J. M. Brouwer, Jelle van Schooten, Niels van der Velde, Ronald Derking, Karlijn van der Straten, Denise Guerra, Gius Kerster, Andrew B. Ward, Jonathan L. Torres, W. Joost Wiersinga, Neeltje A. Kootstra, Sandhya Bangaru, Tom P. L. Bijl, Aafke Aartse, Edith E. Schermer, Judith A. Burger, Kirsten D. Verheul, Bart L. Haagmans, Mariëlle J. van Breemen, Tom G. Caniels, Marit J. van Gils, Yoann Aldon, Nisreen M.A. Okba, Godelieve J. de Bree, Kwinten Sliepen, Jonne L. Snitselaar, Rogier W. Sanders, Arthur E. H. Bentlage, Virology, AII - Infectious diseases, Graduate School, Medical Microbiology and Infection Prevention, APH - Aging & Later Life, Experimental Immunology, Infectious diseases, Center of Experimental and Molecular Medicine, AII - Inflammatory diseases, AII - Cancer immunology, Landsteiner Laboratory, and APH - Global Health

Subjects
Male, 0301 basic medicine, Vulnerability, Antibody Affinity, Antibodies, Viral, medicine.disease_cause, Epitope, Epitopes, 0302 clinical medicine, Immunophenotyping, skin and connective tissue diseases, Antigens, Viral, Research Articles, Coronavirus, Multidisciplinary, biology, Antibodies, Monoclonal, Microbio, Middle Aged, 030220 oncology & carcinogenesis, Spike Glycoprotein, Coronavirus, Receptors, Virus, Female, Antibody, Coronavirus Infections, Research Article, Adult, Coronavirus disease 2019 (COVID-19), medicine.drug_class, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, Pneumonia, Viral, Protein domain, B-Lymphocyte Subsets, Somatic hypermutation, Monoclonal antibody, Betacoronavirus, 03 medical and health sciences, Protein Domains, Antigen, Cell Line, Tumor, medicine, Humans, Protein Interaction Domains and Motifs, Pandemics, Aged, SARS-CoV-2, R-Articles, Spike Protein, COVID-19, Antibodies, Neutralizing, Virology, 030104 developmental biology, biology.protein, Immunologic Memory, Broadly Neutralizing Antibodies, Receptors, Coronavirus
Abstract

Sites of vulnerability in SARS-CoV-2 Antibodies that neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could be an important tool in treating coronavirus disease 2019 (COVID-19). Brouwer et al. isolated 403 monoclonal antibodies from three convalescent COVID-19 patients. They show that the patients had strong immune responses against the viral spike protein, a complex that binds to receptors on the host cell. A subset of antibodies was able to neutralize the virus. Competition and electron microscopy studies showed that these antibodies target diverse epitopes on the spike, with the two most potent targeting the domain that binds the host receptor. Science , this issue p. 643

Published
2020
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18. 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

20. MHC Class II Tetramer Labeling of Human Primary CD4(+) T Cells from HIV Infected Patients

Author

Madhura Mukhopadhyay, Mathieu Claireaux, Daniela Benati, Lisa A. Chakrabarti, and Moran Galperin

Subjects
MHC class II, biology, Chemistry, Strategy and Management, Mechanical Engineering, T-cell receptor, Metals and Alloys, Major histocompatibility complex, Molecular biology, Industrial and Manufacturing Engineering, Epitope, Antigen, MHC class I, biology.protein, Methods Article, Ex vivo, CD8
Abstract

Major Histocompatibility Complex (MHC) tetramers have been used for two decades to detect, isolate and characterize T cells specific for various pathogens and tumor antigens. In the context of Human Immunodeficiency Virus (HIV) infection, antigen-specific CD8(+) T cells have been extensively studied ex vivo, as they can be readily detected by HIV peptide-loaded MHC class I tetramers. In contrast, the detection of HIV-specific CD4(+) T cells has proven more challenging, due to the intrinsically lower clonal expansion rates of CD4(+) T cells, and to the preferential depletion of HIV-specific CD4(+) T cells in the course of HIV infection. In the following protocol, we describe a simple method that facilitates the identification of CD4(+) T cells specific for an HIV-1 capsid epitope using peptide-loaded MHC class II tetramers. Tetramer labeled CD4(+) T cells can be analyzed for their cell surface phenotype and/or FACS-sorted for further downstream applications. A key point for successful detection of specific CD4(+) T cells ex vivo is the choice of a peptide/MHC II combination that results in high-affinity T Cell Receptor (TCR) binding ( Benati et al., 2016 ). A second key point for reliable detection of MHC II tetramer-positive cells is the systematic use of a control tetramer loaded with an irrelevant peptide, with the sample and control tubes being processed in identical conditions.

Published
2017

21. Public T cell receptors confer high-avidity CD4 responses to HIV controllers

Author

Pierre de Truchis, Mathieu Claireaux, Alexandre Nouël, Lisa A. Chakrabarti, Moran Galperin, Samia Hendou, Daniela Benati, Pierre Lechat, Brigitte Lemercier, Annick Lim, Fernando Arenzana-Seisdedos, Olivier Lambotte, Jean-François Delfraissy, Kristy-Anne Campbell, Jamie Rossjohn, Stephanie Gras, Faroudy Boufassa, Madhura Mukhopadhyay, Pathogénie Virale - Viral Pathogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University [Clayton], Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris] (IP), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institute of Infection and Immunity, Cardiff University, This work was supported by ANRS, Sidaction, the Pasteur Institute, the Australian Research Council (ARC), and the National Health and Medical Research Council of Australia (NHMRC). L.A. Chakrabarti is supported by grants grants from ANRS (EP36-8) and Agence Nationale de la Recherche (ANR PD1VAX), S. Gras is supported by an ARC Future Fellowship (FF120100416), and J. Rossjohn by an NHMRC Australia Fellowship (AF50). D. Benati was the recipient of postdoctoral fellowships from ANRS, the Fondation pour la Recher- che Médicale, and the Institut Servier. M. Galperin is the recipient of an ANRS doctoral fellowship. M. Mukhopadhyay is a scholar in the Pasteur - Paris University (PPU) International PhD program., 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), Pathogénie Virale, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Pham, Cécile, and Appel à projets générique - Une nouvelle stratégie de vaccination par vecteur ADN PD1 pour mimer les réponses spécifiques de Gag trouvées chez les contrôleurs spontanés du VIH - - PD1VAX2014 - ANR-14-CE16-0029 - Appel à projets générique - VALID

Subjects
0301 basic medicine, Adult, CD4-Positive T-Lymphocytes, Adoptive cell transfer, CD4 antigen, Receptors, Antigen, T-Cell, chemical and pharmacologic phenomena, HIV Infections, Biology, gag Gene Products, Human Immunodeficiency Virus, Epitope, HIV Long-Term Survivors, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Immune system, L Cells, Antigen, Antiretroviral Therapy, Highly Active, Animals, Humans, HLA-DR Antigen, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Immunity, Cellular, T-cell receptor, HIV, Adoptive Transfer, CD4 Antigens, Genes, T-Cell Receptor alpha, Genes, T-Cell Receptor beta, HLA-DR Antigens, L Cells (Cell Line), Middle Aged, HIV-1, Medicine (all), hemic and immune systems, General Medicine, Virology, 3. Good health, 030104 developmental biology, chemistry, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, CD8, 030215 immunology, Research Article
Abstract

International audience; The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes. The most prevalent public clonotypes generated TCRs with affinities at the higher end of values reported for naturally occurring TCRs. The high-affinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for the expression of these TCRs in HIV controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctionality, thus recapitulating key features of the controller CD4 response. Transfer of a high-affinity Gag293-specific TCR also redirected CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. Together, these findings indicate that TCR clonotypes with superior functions are associated with HIV control. Amplification or transfer of such clonotypes may contribute to immunotherapeutic approaches aiming at a functional HIV cure.

Published
2016

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