Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization.
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Authors
Stiegeler, Emanuel
Glögl, Matthias
Lemmin, Thomas
Hansen, Simon
Wu, Yufan
Maliqi, Liridona
Foulkes, Caio
Morin, Mylène
Eroglu, Mustafa
Liechti, Thomas
Ivan, Branislav
Reinberg, Thomas
Schaefer, Jonas V
Karakus, Umut
Mann, Axel
Rusert, Peter
Publication Date
2021-11-18Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Volume
12
Issue
1
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Friedrich, N., Stiegeler, E., Glögl, M., Lemmin, T., Hansen, S., Kadelka, C., Wu, Y., et al. (2021). Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization.. Nat Commun, 12 (1) https://doi.org/10.1038/s41467-021-27075-0
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.
Keywords
Cell Line, Tumor, Humans, HIV-1, Immunoglobulin G, HIV Antibodies, Epitopes, Protein Conformation, Protein Binding, Mutation, env Gene Products, Human Immunodeficiency Virus, Molecular Dynamics Simulation, Antibodies, Neutralizing, HEK293 Cells, Molecular Docking Simulation
Sponsorship
Swiss National Science Foundation (166676, 152663, 190705, 310030, 172790, 192689, 179571, 314730, 142411, 155851, 148522)
Identifiers
PMC8602657, 34795280
External DOI: https://doi.org/10.1038/s41467-021-27075-0
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332402
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