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

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Lorin, Valerie | Fernández, Ignacio | Masse-Ranson, Guillemette | Bouvin-Pley, Mélanie | Molinos-Albert, Luis, M. | Planchais, Cyril | Hieu, Thierry | Péhau-Arnaudet, Gérard | Hrebík, Dominik | Girelli-Zubani, Giulia | Fiquet, Oriane | Guivel-Benhassine, Florence | Sanders, Rogier, W. | Walker, Bruce, D. | Schwartz, Olivier | Scheid, Johannes, F. | Dimitrov, Jordan, D. | Plevka, Pavel | Braibant, Martine | Seaman, Michael, S. | Bontems, François | Di Santo, James, P. | Rey, Félix, A. | Mouquet, Hugo

Edité par CCSD ; Rockefeller University Press -

International audience. 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.

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