Epitope convergence of broadly HIV-1 neutralizing IgA and IgG antibody lineages in a viremic controller

Author:

Lorin Valérie123ORCID,Fernández Ignacio45ORCID,Masse-Ranson Guillemette67ORCID,Bouvin-Pley Mélanie8ORCID,Molinos-Albert Luis M.12ORCID,Planchais Cyril12ORCID,Hieu Thierry12ORCID,Péhau-Arnaudet Gérard9ORCID,Hrebík Dominik10ORCID,Girelli-Zubani Giulia67ORCID,Fiquet Oriane67ORCID,Guivel-Benhassine Florence511ORCID,Sanders Rogier W.1213ORCID,Walker Bruce D.1415ORCID,Schwartz Olivier511ORCID,Scheid Johannes F.16ORCID,Dimitrov Jordan D.17ORCID,Plevka Pavel10ORCID,Braibant Martine8ORCID,Seaman Michael S.18ORCID,Bontems François419ORCID,Di Santo James P.67ORCID,Rey Félix A.45ORCID,Mouquet Hugo12ORCID

Affiliation:

1. Laboratory of Humoral Immunology, Department of Immunology, Institut Pasteur, Paris, France 1

2. Institut national de la santé et de la recherche médicale U1222, Paris, France 2

3. Université de Paris, Sorbonne Paris Cité, Paris, France 3

4. Structural Virology Unit, Department of Virology, Institut Pasteur, Paris, France 4

5. Centre national de la recherche scientifique URA3015, Paris, France 5

6. Innate Immunity Unit, Department of Immunology, Institut Pasteur, Paris, France 6

7. Institut national de la santé et de la recherche médicale U1223, Paris, France 7

8. Université de Tours, Institut national de la santé et de la recherche médicale U1259, Tours, France 8

9. Imagopole, Plate-Forme de Microscopie Ultrastructurale and UMR 3528, Institut Pasteur, Paris, France 9

10. Central European Institute of Technology, Masaryk University, Brno, Czech Republic 10

11. Virus and Immunity Unit, Department of Virology, Institut Pasteur, Paris, France 11

12. Department of Medical Microbiology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands 12

13. Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 13

14. Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Cambridge, MA 14

15. Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 15

16. Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 16

17. Centre de Recherche des Cordeliers, Institut national de la santé et de la recherche médicale, Sorbonne Université, Université de Paris, Paris, France 17

18. Beth Israel Deaconess Medical Center, Boston, MA 18

19. Institut de Chimie des Substances Naturelles, Centre national de la recherche scientifique, Université Paris Saclay, Gif-sur-Yvette, France 19

Abstract

Decrypting the B cell ontogeny of HIV-1 broadly neutralizing antibodies (bNAbs) is paramount for vaccine design. Here, we characterized IgA and IgG bNAbs of three distinct B cell lineages in a viremic controller, two of which comprised only IgG+ or IgA+ blood memory B cells; the third combined both IgG and IgA clonal variants. 7-269 bNAb in the IgA-only lineage displayed the highest neutralizing capacity despite limited somatic mutation, and delayed viral rebound in humanized mice. bNAbs in all three lineages targeted the N332 glycan supersite. The 2.8-Å resolution cryo-EM structure of 7-269-BG505 SOSIP.664 complex showed a similar pose as 2G12, on an epitope mainly composed of sugar residues comprising the N332 and N295 glycans. Binding and cryo-EM structural analyses showed that antibodies from the two other lineages interact mostly with glycans N332 and N386. Hence, multiple B cell lineages of IgG and IgA bNAbs focused on a unique HIV-1 site of vulnerability can codevelop in HIV-1 viremic controllers.

Funder

French Government

NIH

Agence National de Recherche sur le SIDA et les hépatites virales

France Génomique

Infrastructures en Biologie Santé et Agronomie

Vaccine Research Institute

Institut Pasteur

Institut national de la santé et de la recherche médicale

Milieu Intérieur Program

European Research Council

Gilead Sciences

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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