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.

Beth Israel Deaconess Medical Center Boston MA

Central European Institute of Technology Masaryk University Brno Czech Republic

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

Centre national de la recherche scientifique URA3015 Paris France

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

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

Imagopole Plate Forme de Microscopie Ultrastructurale and UMR 3528 Institut Pasteur Paris France

Innate Immunity Unit Department of Immunology Institut Pasteur Paris France

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

Institut national de la santé et de la recherche médicale U1222 Paris France

Institut national de la santé et de la recherche médicale U1223 Paris France

Laboratory of Humoral Immunology Department of Immunology Institut Pasteur Paris France

Laboratory of Molecular Immunology The Rockefeller University New York NY

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

Ragon Institute of Massachusetts General Hospital MIT and Harvard Cambridge MA

Structural Virology Unit Department of Virology Institut Pasteur Paris France

Université de Paris Sorbonne Paris Cité Paris France

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

Virus and Immunity Unit Department of Virology Institut Pasteur Paris France

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