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5. Structural Basis for Broad HIV-1 Neutralization by the MPER-Specific Human Broadly Neutralizing Antibody LN01

Author

Pinto, Dora, Fenwick, Craig, Caillat, Christophe, Silacci, Chiara, Guseva, Serafima, Dehez, François, Chipot, Christophe, Barbieri, Sonia, Minola, Andrea, Jarrossay, David, Tomaras, Georgia D., Shen, Xiaoying, Riva, Agostino, Tarkowski, Maciej, Schwartz, Olivier, Bruel, Timothée, Dufloo, Jérémy, Seaman, Michael S., Montefiori, David C., Lanzavecchia, Antonio, Corti, Davide, Pantaleo, Giuseppe, and Weissenhorn, Winfried

Published
2019
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7. An Inducible ESCRT-III Inhibition Tool to Control HIV-1 Budding

Author

Wang, Haiyan, primary, Gallet, Benoit, additional, Moriscot, Christine, additional, Pezet, Mylène, additional, Chatellard, Christine, additional, Kleman, Jean-Philippe, additional, Göttlinger, Heinrich, additional, Weissenhorn, Winfried, additional, and Boscheron, Cécile, additional

Published
2023
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12. Intravacuolar Membranes Regulate CD8 T Cell Recognition of Membrane-Bound Toxoplasma gondii Protective Antigen

Author

Lopez, Jodie, Bittame, Amina, Massera, Céline, Vasseur, Virginie, Effantin, Grégory, Valat, Anne, Buaillon, Célia, Allart, Sophie, Fox, Barbara A., Rommereim, Leah M., Bzik, David J., Schoehn, Guy, Weissenhorn, Winfried, Dubremetz, Jean-François, Gagnon, Jean, Mercier, Corinne, Cesbron-Delauw, Marie-France, and Blanchard, Nicolas

Published
2015
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13. Structure of hiv-1 gp41 with its membrane anchors targeted by neutralizing antibodies

Author

European Commission, Agence Nationale de la Recherche (France), Université Grenoble Alpes, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Eusko Jaurlaritza, Ministerio de Economía y Competitividad (España), Caillat, Christophe [0000-0003-2959-1871], Friedrich, Nikolas [0000-0003-0694-657X], Trkola, Alexandra [0000-0003-1013-876X], Chipot, Christophe J. [0000-0002-9122-1698], Weissenhorn, Winfried [0000-0001-5532-4959], Caillat, Christophe, Guilligay, Delphine, Torralba, Johana, Friedrich, Nikolas, Nieva, José Luis, Trkola, Alexandra, Chipot, Christophe J., Dehez, François L., Weissenhorn, Winfried, European Commission, Agence Nationale de la Recherche (France), Université Grenoble Alpes, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Eusko Jaurlaritza, Ministerio de Economía y Competitividad (España), Caillat, Christophe [0000-0003-2959-1871], Friedrich, Nikolas [0000-0003-0694-657X], Trkola, Alexandra [0000-0003-1013-876X], Chipot, Christophe J. [0000-0002-9122-1698], Weissenhorn, Winfried [0000-0001-5532-4959], Caillat, Christophe, Guilligay, Delphine, Torralba, Johana, Friedrich, Nikolas, Nieva, José Luis, Trkola, Alexandra, Chipot, Christophe J., Dehez, François L., and Weissenhorn, Winfried

Abstract

The HIV-1 gp120/gp41 trimer undergoes a series of conformational changes in order to catalyze gp41-induced fusion of viral and cellular membranes. Here, we present the crystal structure of gp41 locked in a fusion intermediate state by an MPER-specific neutralizing antibody. The structure illustrates the conformational plasticity of the six membrane anchors arranged asymmetrically with the fusion peptides and the transmembrane regions pointing into different directions. Hinge regions located adjacent to the fusion peptide and the transmembrane region facilitate the conformational flexibility that allows high-affinity binding of broadly neutralizing anti-MPER antibodies. Molecular dynamics simulation of the MPER Ab-stabilized gp41 conformation reveals a possible transition pathway into the final post-fusion conformation with the central fusion peptides forming a hydrophobic core with flanking transmembrane regions. This suggests that MPER-specific broadly neutralizing antibodies can block final steps of refolding of the fusion peptide and the transmembrane region, which is required for completing membrane fusion.

Published
2021

15. The archaeal division protein CdvB1 assembles into polymers that are depolymerized by CdvC

Author

Blanch Jover, A. (author), De Franceschi, N. (author), Fenel, Daphna (author), Weissenhorn, Winfried (author), Dekker, C. (author), Blanch Jover, A. (author), De Franceschi, N. (author), Fenel, Daphna (author), Weissenhorn, Winfried (author), and Dekker, C. (author)

Abstract

The Cdv proteins constitute the cell division system of the Crenarchaea, a machinery closely related to the ESCRT system of eukaryotes. Using a combination of TEM imaging and biochemical assays, we here present an in vitro study of Metallosphaera sedula CdvB1, the Cdv protein that is believed to play a major role in the constricting ring that drives cell division in the Crenarchaea. We show that CdvB1 self-assembles into filaments that are depolymerized by the Vps4-homolog ATPase CdvC. Furthermore, we find that CdvB1 binds to negatively charged lipid membranes and can be detached from the membrane by the action of CdvC. Our findings provide novel insight into one of the main components of the archaeal cell division machinery., BN/Cees Dekker Lab

Published
2022
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16. Structural basis of CHMP2A-CHMP3 ESCRT-III polymer assembly and membrane cleavage

Author

Azad, Kimi, primary, Guilligay, Delphine, additional, Boscheron, Cecile, additional, Maity, Sourav, additional, De Franceschi, Nicola, additional, Sulbaran, Guidenn, additional, Effantin, Gregory, additional, Wang, Haiyan, additional, Kleman, Jean-Philippe, additional, Bassereau, Patricia, additional, Schoehn, Guy, additional, Desfosses, Ambroise, additional, and Weissenhorn, Winfried, additional

Published
2022
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18. The archaeal division protein CdvB1 assembles into polymers that are depolymerized by CdvC

Author

Blanch Jover, Alberto, De Franceschi, Nicola, Fenel, Daphna, Weissenhorn, Winfried, Dekker, Cees, Delft University of Technology (TU Delft), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)

Subjects
cell division, ESCRT-III, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Endosomal Sorting Complexes Required for Transport, Polymers, Archaeal Proteins, Biophysics, Cell Biology, MESH: Archaeal Proteins, macromolecular substances, Biochemistry, Archaea, MESH: Endosomal Sorting Complexes Required for Transport, MESH: Polymers, Structural Biology, MESH: Archaea, CdvB1, Genetics, MESH: Cell Division, Molecular Biology, Cdv system
Abstract

International audience; The Cdv proteins constitute the cell division system of the Crenarchaea, a machinery closely related to the ESCRT system of eukaryotes. Using a combination of TEM imaging and biochemical assays, we here present an in vitro study of Metallosphaera sedula CdvB1, the Cdv protein that is believed to play a major role in the constricting ring that drives cell division in the Crenarchaea. We show that CdvB1 self-assembles into filaments that are depolymerized by the Vps4-homolog ATPase CdvC. Furthermore, we find that CdvB1 binds to negatively charged lipid membranes and can be detached from the membrane by the action of CdvC. Our findings provide novel insight into one of the main components of the archaeal cell division machinery.

Published
2022
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19. Immunization with synthetic SARS-CoV-2 S glycoprotein virus-like particles protects macaques from infection

Author

Sulbaran, Guidenn, primary, Maisonnasse, Pauline, additional, Amen, Axelle, additional, Effantin, Gregory, additional, Guilligay, Delphine, additional, Dereuddre-Bosquet, Nathalie, additional, Burger, Judith A., additional, Poniman, Meliawati, additional, Grobben, Marloes, additional, Buisson, Marlyse, additional, Dergan Dylon, Sebastian, additional, Naninck, Thibaut, additional, Lemaître, Julien, additional, Gros, Wesley, additional, Gallouët, Anne-Sophie, additional, Marlin, Romain, additional, Bouillier, Camille, additional, Contreras, Vanessa, additional, Relouzat, Francis, additional, Fenel, Daphna, additional, Thepaut, Michel, additional, Bally, Isabelle, additional, Thielens, Nicole, additional, Fieschi, Franck, additional, Schoehn, Guy, additional, van der Werf, Sylvie, additional, van Gils, Marit J., additional, Sanders, Rogier W., additional, Poignard, Pascal, additional, Le Grand, Roger, additional, and Weissenhorn, Winfried, additional

Published
2022
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20. Stepwise conformational stabilization of a hiv-1 clade c consensus envelope trimer immunogen impacts the profile of vaccine-induced antibody responses

Author

Hauser, Alexandra, Carnell, George, Held, Kathrin, Sulbaran, Guidenn, Tischbierek, Nadine, Rogers, Lisa, Pollakis, Georgios, Tonks, Paul, Hoelscher, Michael, Ding, Song, Sanders, Rogier W., Geldmacher, Christof, Sattentau, Quentin, Weissenhorn, Winfried, Heeney, Jonathan L., Peterhoff, David, Wagner, Ralf, Medical Microbiology and Infection Prevention, and AII - Infectious diseases

Subjects
Peptide microarray, Consensus, HIV vaccine, Envelope, Centralized sequence, Antibody response, Clade C, Immunization, Stabilized trimer, Immunogen design
Abstract

Stabilization of the HIV-1 Envelope glycoprotein trimer (Env) in its native pre-fusion closed conformation is regarded as one of several requirements for the induction of neutralizing antibody (nAb) responses, which, in turn, will most likely be a prerequisite for the development of an efficacious preventive vaccine. Here, we systematically analyzed how the stepwise stabilization of a clade C consensus (ConC) Env immunogen impacts biochemical and biophysical protein traits such as antigenicity, thermal stability, structural integrity, and particle size distribution. The increasing degree of conformational rigidification positively correlates with favorable protein characteristics, leading to optimized homogeneity of the protein preparations, increased thermal stability, and an overall favorable binding profile of structure-dependent broadly neutralizing antibodies (bnAbs) and non-neutralizing antibodies (non-nAbs). We confirmed that increasing the structural integrity and stability of the Env trimers positively correlates with the quality of induced antibody responses by the immunogens. These and other data contribute to the selection of ConCv5 KIKO as novel Env immunogens for use within the European Union’s H2020 Research Consortium EHVA (European HIV Alliance) for further preclinical analysis and phase 1 clinical development.

Published
2021

22. Immunization with synthetic SARS-CoV-2 S glycoprotein virus-like particles protects Macaques from infection

Author

Sulbaran, Guidenn, primary, Maisonnasse, Pauline, additional, Amen, Axelle, additional, Guilligay, Delphine, additional, Dereuddre-Bosquet, Nathalie, additional, Burger, Judith A., additional, Poniman, Meliawati, additional, Buisson, Marlyse, additional, Dergan Dylon, Sebastian, additional, Naninck, Thibaut, additional, Lemaître, Julien, additional, Gros, Wesley, additional, Gallouët, Anne-Sophie, additional, Marlin, Romain, additional, Bouillier, Camille, additional, Contreras, Vanessa, additional, Relouzat, Francis, additional, Fenel, Daphna, additional, Thepaut, Michel, additional, Bally, Isabelle, additional, Thielens, Nicole, additional, Fieschi, Franck, additional, Schoehn, Guy, additional, van der Werf, Sylvie, additional, van Gils, Marit J., additional, Sanders, Rogier W., additional, Poignard, Pascal, additional, Le Grand, Roger, additional, and Weissenhorn, Winfried, additional

Published
2021
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23. Stepwise Conformational Stabilization of a HIV-1 Clade C Consensus Envelope Trimer Immunogen Impacts the Profile of Vaccine-Induced Antibody Responses

Author

Hauser, Alexandra, primary, Carnell, George, additional, Held, Kathrin, additional, Sulbaran, Guidenn, additional, Tischbierek, Nadine, additional, Rogers, Lisa, additional, Pollakis, Georgios, additional, Tonks, Paul, additional, Hoelscher, Michael, additional, Ding, Song, additional, Sanders, Rogier W., additional, Geldmacher, Christof, additional, Sattentau, Quentin, additional, Weissenhorn, Winfried, additional, Heeney, Jonathan L., additional, Peterhoff, David, additional, and Wagner, Ralf, additional

Published
2021
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24. Additional file 4 of The ESCRT-III isoforms CHMP2A and CHMP2B display different effects on membranes upon polymerization

Author

Alqabandi, Maryam, De Franceschi, Nicola, Sourav Maity, Miguet, Nolwenn, Bally, Marta, Roos, Wouter H., Weissenhorn, Winfried, Bassereau, Patricia, and Mangenot, Stéphanie

Abstract

Additional file 4: Figure S4. Deformation of bare vesicles and vesicles covered with CHMP2A + CHMP3 or CHMP2B + CHMP3. HS-AFM images of a vesicle covered with CHMP2A and CHMP 3 (left column) and a vesicle covered with CHMP2B and CHMP3 proteins (right column). The deformability of the SUVs coated with corresponding proteins upon increased applied force are shown at intermediate force increments of 27% (second panels) and at higher force increment, 81% (third panels).

Published
2021
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25. Additional file 2 of The ESCRT-III isoforms CHMP2A and CHMP2B display different effects on membranes upon polymerization

Author

Alqabandi, Maryam, De Franceschi, Nicola, Sourav Maity, Miguet, Nolwenn, Bally, Marta, Roos, Wouter H., Weissenhorn, Winfried, Bassereau, Patricia, and Mangenot, Stéphanie

Abstract

Additional file 2: Figure S2. Study of CHMP protein-membrane interaction. (A) Optimization of the buffer conditions to optimize the binding of CHMP2B-ΔC (noted here CHMP2B) at 500 nM. Pre-formed vesicles were incubated with CHMP2B-ΔC in buffers with different salt concentrations ranging from 0 mM to 100 mM NaCl (+Tris 25 mM at pH 7.5) and imaged with confocal microscope after 30 min incubation. Lipid signal is shown in magenta and protein signal in green. Scale bar: 5 μm. (B) Confocal image of MBP-CHMP2A-ΔC (noted here CHMP2A) without TEV (Top line) and in the presence of TEV to cleave the MBP tag (Bottom line). Saturated protein fluorescent signal is represented in yellow. Cleavage of MBP tag slightly increases the interaction but induces aggregation. Scale bar: 30 μm. (C) Spinning disk image of GUV incubated with MBP-CHMP2B-ΔC (noted here MBP-CHMP2B) at a concentration of 50 nM (left image, scale bar = 10 μm) and at 200 nm (right image; scale bar = 5 μm). (D) Confocal images of GUV incubated with MBP-CHMP2B-ΔC at a concentration of 1 μM (noted here MBP-CHMP2B), submitted to an osmotic pressure difference equal to 150% (Osmolarity inside and outside the GUV are respectively 120 mOsm.L− 1 and 315 mOsm.L− 1). Scale bar: 10 μm.

Published
2021
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26. Additional file 7 of The ESCRT-III isoforms CHMP2A and CHMP2B display different effects on membranes upon polymerization

Author

Alqabandi, Maryam, De Franceschi, Nicola, Sourav Maity, Miguet, Nolwenn, Bally, Marta, Roos, Wouter H., Weissenhorn, Winfried, Bassereau, Patricia, and Mangenot, Stéphanie

Abstract

Additional file 7: Figures S6. Test of mutual interaction between CHMP2B and CHMP3 in solution. CHMP2B-ΔC (first gel) and CHMP3-FL (second gel) in Hepes Buffer have been deposited on a sucrose gradient. 100 μL of CHMP2B-ΔC at 10 μM has been incubated with 100 μl CHMP3FL at 10 μM and deposit on a sucrose gradient (third gel). No aggregation is observed on the bottom of the gradient. The presence of CHMP3 does not induce CHMP2B aggregation.

Published
2021
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27. Additional file 6 of The ESCRT-III isoforms CHMP2A and CHMP2B display different effects on membranes upon polymerization

Author

Alqabandi, Maryam, De Franceschi, Nicola, Sourav Maity, Miguet, Nolwenn, Bally, Marta, Roos, Wouter H., Weissenhorn, Winfried, Bassereau, Patricia, and Mangenot, Stéphanie

Abstract

Additional file 6: Figure S5. Deformation of bare vesicles and vesicles covered with CHMP proteins. (A) Reduction of vesicle height under increasing force for bare vesicles. ‘Zero’ force increment represents the minimum imaging force (~ 150 pN). (B) Example of deformation for a ~ 60 nm vesicle over increasing force up to 80% of the initial imaging force. (C) Represents the transformation of vesicle height to relative height for each point for the curve in D. (D) represents the relative height vs force increment for all the curves from panel A for bare SUVs. (E) represents the relative height vs force increment for SUV covered with CHMP2B (left), CHMP2B + CHMP3 (middle) and CHMP2A + CHMP3 (right).

Published
2021
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28. Additional file 1 of The ESCRT-III isoforms CHMP2A and CHMP2B display different effects on membranes upon polymerization

Author

Alqabandi, Maryam, De Franceschi, Nicola, Sourav Maity, Miguet, Nolwenn, Bally, Marta, Roos, Wouter H., Weissenhorn, Winfried, Bassereau, Patricia, and Mangenot, Stéphanie

Subjects
macromolecular substances
Abstract

Additional file 1: Figure S1. Evolution of the ESCRT-III complex. (A) Table illustrating the ESCRT-III complex function, origin and homologs in S. cerevisiae and H. sapiens. (B) Distribution of Vps2 and Vps24 genes across Eukaryotes showing the presence of two Vps2 genes in high organisms. (C) Table illustrating the implication of ESCRT-III subunits in different subcellular locations in S. cerevisiae and H. sapiens. The names are the human homologs in case of S. cerevisiae.

Published
2021
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29. Structure of HIV-1 gp41 with its Membrane Anchors Targeted by Neutralizing Antibodies

Author

Bioquímica y biología molecular, Biokimika eta biologia molekularra, Caillat, Christophe, Guilligay, Delphine, Torralba Iturbe, Johana, Friedrich, Nikolas, Nieva Escandón, José Luis, Trkola, Alexandra, Chipot, Christophe J., Dehez, Francois L., Weissenhorn, Winfried, Bioquímica y biología molecular, Biokimika eta biologia molekularra, Caillat, Christophe, Guilligay, Delphine, Torralba Iturbe, Johana, Friedrich, Nikolas, Nieva Escandón, José Luis, Trkola, Alexandra, Chipot, Christophe J., Dehez, Francois L., and Weissenhorn, Winfried

Abstract

The HIV-1 gp120/gp41 trimer undergoes a series of conformational changes in order to catalyze gp41-induced fusion of viral and cellular membranes. Here, we present the crystal structure of gp41 locked in a fusion intermediate state by an MPER-specific neutralizing antibody. The structure illustrates the conformational plasticity of the six membrane anchors arranged asymmetrically with the fusion peptides and the transmembrane regions pointing into different directions. Hinge regions located adjacent to the fusion peptide and the transmembrane region facilitate the conformational flexibility that allows high-affinity binding of broadly neutralizing anti-MPER antibodies. Molecular dynamics simulation of the MPER Ab-stabilized gp41 conformation reveals a possible transition pathway into the final post-fusion conformation with the central fusion peptides forming a hydrophobic core with flanking transmembrane regions. This suggests that MPER-specific broadly neutralizing antibodies can block final steps of refolding of the fusion peptide and the transmembrane region, which is required for completing membrane fusion.

Published
2021

30. Structure of HIV-1 gp41 with its membrane anchors targeted by neutralizing antibodies

Author

Caillat, Christophe; https://orcid.org/0000-0003-2959-1871, Guilligay, Delphine, Torralba, Johana, Friedrich, Nikolas; https://orcid.org/0000-0003-0694-657X, Nieva, Jose L, Trkola, Alexandra; https://orcid.org/0000-0003-1013-876X, Chipot, Christophe J; https://orcid.org/0000-0002-9122-1698, Dehez, François L, Weissenhorn, Winfried; https://orcid.org/0000-0001-5532-4959, Caillat, Christophe; https://orcid.org/0000-0003-2959-1871, Guilligay, Delphine, Torralba, Johana, Friedrich, Nikolas; https://orcid.org/0000-0003-0694-657X, Nieva, Jose L, Trkola, Alexandra; https://orcid.org/0000-0003-1013-876X, Chipot, Christophe J; https://orcid.org/0000-0002-9122-1698, Dehez, François L, and Weissenhorn, Winfried; https://orcid.org/0000-0001-5532-4959

Abstract

The HIV-1 gp120/gp41 trimer undergoes a series of conformational changes in order to catalyze gp41-induced fusion of viral and cellular membranes. Here, we present the crystal structure of gp41 locked in a fusion intermediate state by an MPER-specific neutralizing antibody. The structure illustrates the conformational plasticity of the six membrane anchors arranged asymmetrically with the fusion peptides and the transmembrane regions pointing into different directions. Hinge regions located adjacent to the fusion peptide and the transmembrane region facilitate the conformational flexibility that allows high-affinity binding of broadly neutralizing anti-MPER antibodies. Molecular dynamics simulation of the MPER Ab-stabilized gp41 conformation reveals a possible transition pathway into the final post-fusion conformation with the central fusion peptides forming a hydrophobic core with flanking transmembrane regions. This suggests that MPER-specific broadly neutralizing antibodies can block final steps of refolding of the fusion peptide and the transmembrane region, which is required for completing membrane fusion.

Published
2021

35. Crystal structure and size-dependent neutralization properties of HK20, a human monoclonal antibody binding to the highly conserved heptad repeat 1 of gp41

Author

Sabin, Charles, Corti, Davide, Buzon, Victor, Seaman, Mike S., Hulsik, David Lutje, Hinz, Andreas, Vanzetta, Fabrizia, Agatic, Gloria, Silacci, Chiara, Mainetti, Lara, Scarlatti, Gabriella, Sallusto, Federica, Weiss, Robin, Lanzavecchia, Antonio, Weissenhorn, Winfried, Sabin, Charles, Corti, Davide, Buzon, Victor, Seaman, Mike S., Hulsik, David Lutje, Hinz, Andreas, Vanzetta, Fabrizia, Agatic, Gloria, Silacci, Chiara, Mainetti, Lara, Scarlatti, Gabriella, Sallusto, Federica, Weiss, Robin, Lanzavecchia, Antonio, and Weissenhorn, Winfried

Abstract

The human monoclonal antibody (mAb) HK20 neutralizes a broad spectrum of primary HIV-1 isolates by targeting the highly conserved heptad repeat 1 (HR1) of gp41, which is transiently exposed during HIV-1 entry. Here we present the crystal structure of the HK20 Fab in complex with a gp41 mimetic 5-Helix at 2.3 A° resolution. HK20 employs its heavy chain CDR H2 and H3 loops to bind into a conserved hydrophobic HR1 pocket that is occupied by HR2 residues in the gp41 post fusion conformation. Compared to the previously described HR1-specific mAb D5, HK20 approaches its epitope with a different angle which might favor epitope access and thus contribute to its higher neutralization breadth and potency. Comparison of the neutralization activities of HK20 IgG, Fab and scFv employing both single cycle and multiple cycle neutralization assays revealed much higher potencies for the smaller Fab and scFv over IgG, implying that the target site is difficult to access for complete antibodies. Nevertheless, two thirds of sera from HIV-1 infected individuals contain significant titers of HK20-inhibiting antibodies. The breadth of neutralization of primary isolates across all clades, the higher potencies for Cclade viruses and the targeting of a distinct site as compared to the fusion inhibitor T-20 demonstrate the potential of HK20 scFv as a therapeutic tool.

Published
2019

36. Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals

Author

Corti, Davide, Langedijk, Johannes P. M., Hinz, Andreas, Seaman, Michael S., Vanzetta, Fabrizia, Fernandez-Rodriguez, Blanca M., Silacci, Chiara, Pinna, Debora, Jarrossay, David, Balla-Jhagjhoorsingh, Sunita, Willems, Betty, Zekveld, Maria J., Dreja, O’Sullivan, Eithne, Pade, Corinna, Orkin, Chloe, Jeffs, Simon A., Montefiori, David C., David, Davis, Weissenhorn, Winfried, McKnight, Aine, Heeney, Jonathan L., Sallusto, Federica, Sattentau, Quentin J., Weiss, robin A., Lanzavecchia, Antonio, Corti, Davide, Langedijk, Johannes P. M., Hinz, Andreas, Seaman, Michael S., Vanzetta, Fabrizia, Fernandez-Rodriguez, Blanca M., Silacci, Chiara, Pinna, Debora, Jarrossay, David, Balla-Jhagjhoorsingh, Sunita, Willems, Betty, Zekveld, Maria J., Dreja, O’Sullivan, Eithne, Pade, Corinna, Orkin, Chloe, Jeffs, Simon A., Montefiori, David C., David, Davis, Weissenhorn, Winfried, McKnight, Aine, Heeney, Jonathan L., Sallusto, Federica, Sattentau, Quentin J., Weiss, robin A., and Lanzavecchia, Antonio

Abstract

Background The isolation of human monoclonal antibodies (mAbs) that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine. Methods and Findings We immortalized IgG+ memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env) in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16) specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194) bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20) with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity. Conclusions This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.

Published
2019

37. CHMP1B is a target of USP8/UBPY regulated by ubiquitin during endocytosis

Author

Crespo-Yàñez, Xènia, Aguilar-Gurrieri, Carmen, Jacomin, Anne-Claire, Journet, Agnès, Mortier, Magda, Taillebourg, Emmanuel, Soleilhac, Emmanuelle, Weissenhorn, Winfried, Fauvarque, Marie-Odile, Schweisguth, François, Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), ARC Foundation: DOC20130606618, FRM FDT20160435289, ANR-10-LABX-0049/10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-14-CE09-0003,ESCRTfission,Mécanique de fission membranaire induite par ESCRT-III(2014), Genetics and Chemogenomics (GenChem), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Thomas, Frank, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, and Appel à projets générique - Mécanique de fission membranaire induite par ESCRT-III - - ESCRTfission2014 - ANR-14-CE09-0003 - Appel à projets générique - VALID

Subjects
Polymers, [SDV]Life Sciences [q-bio], Cell Membranes, Cultured tumor cells, Biochemistry, Drosophila Proteins, Post-Translational Modification, Amino Acids, ComputingMilieux_MISCELLANEOUS, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Organic Compounds, Drosophila Melanogaster, Eukaryota, Animal Models, Endocytosis, Precipitation Techniques, ErbB Receptors, Insects, Protein Transport, Chemistry, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Macromolecules, Experimental Organism Systems, Physical Sciences, Cell lines, Drosophila, Female, Cellular Structures and Organelles, Basic Amino Acids, Biological cultures, Ubiquitin Thiolesterase, Protein Binding, Research Article, Arthropoda, lcsh:QH426-470, Materials by Structure, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Materials Science, Immunoblotting, Molecular Probe Techniques, Endosomes, macromolecular substances, Research and Analysis Methods, Model Organisms, Endopeptidases, Animals, Humans, Immunoprecipitation, HeLa cells, Molecular Biology Techniques, Molecular Biology, Endosomal Sorting Complexes Required for Transport, Ubiquitin, Lysine, Cell Membrane, Organic Chemistry, Ubiquitination, Chemical Compounds, Organisms, Biology and Life Sciences, Proteins, Cell Biology, Cell cultures, Polymer Chemistry, Invertebrates, QP, lcsh:Genetics, HEK293 Cells
Abstract

Integration and down-regulation of cell growth and differentiation signals rely on plasma membrane receptor endocytosis and sorting towards either recycling vesicles or degradative lysosomes via multivesicular bodies (MVB). In this process, the endosomal sorting complex-III required for transport (ESCRT-III) controls membrane deformation and scission triggering intraluminal vesicle (ILV) formation at early endosomes. Here, we show that the ESCRT-III member CHMP1B can be ubiquitinated within a flexible loop known to undergo conformational changes during polymerization. We demonstrate further that CHMP1B is deubiquitinated by the ubiquitin specific protease USP8 (syn. UBPY) and found fully devoid of ubiquitin in a ~500 kDa large complex that also contains its ESCRT-III partner IST1. Moreover, EGF stimulation induces the rapid and transient accumulation of ubiquitinated forms of CHMP1B on cell membranes. Accordingly, CHMP1B ubiquitination is necessary for CHMP1B function in both EGF receptor trafficking in human cells and wing development in Drosophila. Based on these observations, we propose that CHMP1B is dynamically regulated by ubiquitination in response to EGF and that USP8 triggers CHMP1B deubiquitination possibly favoring its subsequent assembly into a membrane-associated ESCRT-III polymer., Author summary In multicellular organisms, the interpretation and transmission of cell growth and differentiation signals strongly rely on plasma membrane receptors. Once activated by their ligands, these receptors activate downstream signaling cascades and are rapidly internalized into intracellular vesicles that fuse inside the cell to form the endosomal compartment. From there, the receptors are sorted towards either recycling vesicles or degradative lysosomes via multivesicular bodies. Receptors sorting therefore plays a crucial role in the integration and regulation of intracellular signals during development and numerous physio-pathological processes. It requires extensive membrane remodeling and scission events at the level of the endosomal compartment by so-called ESCRT proteins, including CHMP1B. In this study, we provide evidence for dynamic regulation of CHMP1B function and subcellular localization by ubiquitin linkage. We also show the contribution of the ubiquitin specific protease USP8 in this regulation, which is a known actor of intracellular trafficking and Cushing’s disease.

Published
2018
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41. Tumor suppression of novel anti–PD-1 antibodies mediated through CD28 costimulatory pathway

Author

Fenwick, Craig, primary, Loredo-Varela, Juan-Luis, additional, Joo, Victor, additional, Pellaton, Céline, additional, Farina, Alex, additional, Rajah, Navina, additional, Esteves-Leuenberger, Line, additional, Decaillon, Thibaut, additional, Suffiotti, Madeleine, additional, Noto, Alessandra, additional, Ohmiti, Khalid, additional, Gottardo, Raphael, additional, Weissenhorn, Winfried, additional, and Pantaleo, Giuseppe, additional

Published
2019
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45. Induction of Tier 1 HIV Neutralizing Antibodies by Envelope Trimers Incorporated into a Replication Competent Vesicular Stomatitis Virus Vector

Author

Bresk, C., primary, Hofer, Tamara, additional, Wilmschen, Sarah, additional, Krismer, Marina, additional, Beierfuß, Anja, additional, Effantin, Grégory, additional, Weissenhorn, Winfried, additional, Hogan, Michael, additional, Jordan, Andrea, additional, Gelman, Rebecca, additional, Montefiori, David, additional, Liao, Hua-Xin, additional, Schmitz, Joern, additional, Haynes, Barton, additional, von Laer, Dorothee, additional, and Kimpel, Janine, additional

Published
2019
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48. Structural Basis for Broad HIV-1 Neutralization by a Novel MPER-Specific Human Broadly Neutralizing Antibody

Author

Pinto, Dora, primary, Fenwick, Craig, additional, Caillat, Christophe, additional, Silacci, Chiara, additional, Guseva, Serafima, additional, Dehez, François, additional, Chipot, Christophe, additional, Barbieri, Sonia, additional, Minola, Andrea, additional, Jarrossay, David, additional, Tomaras, Georgia D., additional, Shen, Xiaoying, additional, Riva, Agostino, additional, Tarkowski, Maciej, additional, Schwartz, Olivier, additional, Bruel, Timothée, additional, Dufloo, Jérémy, additional, Seaman, Michael S., additional, Montefiori, David C., additional, Lanzavecchia, Antonio, additional, Corti, Davide, additional, Pantaleo, Giuseppe, additional, and Weissenhorn, Winfried, additional

Published
2019
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49. Novel anti-PD-1 antibodies not acting through PD-1/pdl-1 blockade that enhance tumor clearance.

Author

Fenwick, Craig, primary, Loredo-Varela, Juan-Luis, additional, Joo, Victor, additional, Pellaton, Celine, additional, Farina, Alex, additional, Rajah, Navina, additional, Decaillon, Thibaut, additional, Esteves-Leuenberger, Line, additional, Suffiotti, Madeleine, additional, Ohmiti, Khalid, additional, Gottardo, Raphael, additional, Weissenhorn, Winfried, additional, and Pantaleo, Giuseppe, additional

Published
2018
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