Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization

Nikolas Friedrich, Emanuel Stiegeler, Matthias Glögl, Thomas Lemmin, Simon Hansen, Claus Kadelka, Yufan Wu, Patrick Ernst, Liridona Maliqi, Caio Foulkes, Mylène Morin, Mustafa Eroglu, Thomas Liechti, Branislav Ivan, Thomas Reinberg, Jonas V. Schaefer, Umut Karakus, Stephan Ursprung, Axel Mann, Peter Rusert, Roger D. Kouyos, John A. Robinson, Huldrych F. Günthard, Andreas Plückthun and Alexandra Trkola ()
Additional contact information
Nikolas Friedrich: University of Zurich (UZH)
Emanuel Stiegeler: University of Zurich (UZH)
Matthias Glögl: University of Zurich (UZH)
Thomas Lemmin: University of Zurich (UZH)
Simon Hansen: University of Zurich (UZH)
Claus Kadelka: Iowa State University
Yufan Wu: University of Zurich (UZH)
Patrick Ernst: University of Zurich (UZH)
Liridona Maliqi: University of Zurich (UZH)
Caio Foulkes: University of Zurich (UZH)
Mylène Morin: University of Zurich (UZH)
Mustafa Eroglu: University of Zurich (UZH)
Thomas Liechti: University of Zurich (UZH)
Branislav Ivan: University of Zurich (UZH)
Thomas Reinberg: University of Zurich (UZH)
Jonas V. Schaefer: University of Zurich (UZH)
Umut Karakus: University of Zurich (UZH)
Stephan Ursprung: University of Zurich (UZH)
Axel Mann: University of Zurich (UZH)
Peter Rusert: University of Zurich (UZH)
Roger D. Kouyos: University of Zurich (UZH)
John A. Robinson: University of Zurich (UZH)
Huldrych F. Günthard: University of Zurich (UZH)
Andreas Plückthun: University of Zurich (UZH)
Alexandra Trkola: University of Zurich (UZH)

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract The V3 loop of the HIV-1 envelope (Env) protein elicits a vigorous, but largely non-neutralizing antibody response directed to the V3-crown, whereas rare broadly neutralizing antibodies (bnAbs) target the V3-base. Challenging this view, we present V3-crown directed broadly neutralizing Designed Ankyrin Repeat Proteins (bnDs) matching the breadth of V3-base bnAbs. While most bnAbs target prefusion Env, V3-crown bnDs bind open Env conformations triggered by CD4 engagement. BnDs achieve breadth by focusing on highly conserved residues that are accessible in two distinct V3 conformations, one of which resembles CCR5-bound V3. We further show that these V3-crown conformations can, in principle, be attacked by antibodies. Supporting this conclusion, analysis of antibody binding activity in the Swiss 4.5 K HIV-1 cohort (n = 4,281) revealed a co-evolution of V3-crown reactivities and neutralization breadth. Our results indicate a role of V3-crown responses and its conformational preferences in bnAb development to be considered in preventive and therapeutic approaches.

Date: 2021
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DOI: 10.1038/s41467-021-27075-0

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