Structural basis for breadth development in the HIV-1 V3-glycan targeting DH270 antibody clonal lineage

Rory Henderson (), Ye Zhou, Victoria Stalls, Kevin Wiehe, Kevin O. Saunders, Kshitij Wagh, Kara Anasti, Maggie Barr, Robert Parks, S. Munir Alam, Bette Korber, Barton F. Haynes (), Alberto Bartesaghi () and Priyamvada Acharya ()
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Rory Henderson: Duke University School of Medicine
Ye Zhou: Duke University
Victoria Stalls: Duke University School of Medicine
Kevin Wiehe: Duke University School of Medicine
Kevin O. Saunders: Duke University School of Medicine
Kshitij Wagh: Los Alamos National Laboratory
Kara Anasti: Duke University School of Medicine
Maggie Barr: Duke University School of Medicine
Robert Parks: Duke University School of Medicine
S. Munir Alam: Duke University School of Medicine
Bette Korber: Los Alamos National Laboratory
Barton F. Haynes: Duke University School of Medicine
Alberto Bartesaghi: Duke University
Priyamvada Acharya: Duke University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Antibody affinity maturation enables adaptive immune responses to a wide range of pathogens. In some individuals broadly neutralizing antibodies develop to recognize rapidly mutating pathogens with extensive sequence diversity. Vaccine design for pathogens such as HIV-1 and influenza has therefore focused on recapitulating the natural affinity maturation process. Here, we determine structures of antibodies in complex with HIV-1 Envelope for all observed members and ancestral states of the broadly neutralizing HIV-1 V3-glycan targeting DH270 antibody clonal B cell lineage. These structures track the development of neutralization breadth from the unmutated common ancestor and define affinity maturation at high spatial resolution. By elucidating contacts mediated by key mutations at different stages of antibody development we identified sites on the epitope-paratope interface that are the focus of affinity optimization. Thus, our results identify bottlenecks on the path to natural affinity maturation and reveal solutions for these that will inform immunogen design aimed at eliciting a broadly neutralizing immune response by vaccination.

Date: 2023
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DOI: 10.1038/s41467-023-38108-1

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