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Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization

Abstract

The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows efficient neutralization via V3 only by rare, broadly neutralizing glycan-dependent antibodies targeting the closed prefusion trimer but not by abundant antibodies that access the V3 crown on open trimers after CD4 attachment. Here, we report on a distinct category of V3-specific inhibitors based on designed ankyrin repeat protein (DARPin) technology that reinstitute the CD4-bound state as a key neutralization target with up to >90% breadth. Broadly neutralizing DARPins (bnDs) bound V3 solely on open envelope and recognized a four-turn amphipathic α-helix in the carboxy-terminal half of V3 (amino acids 314-324), which we termed 'αV3C'. The bnD contact surface on αV3C was as conserved as the CD4 binding site. Molecular dynamics and escape mutation analyses underscored the functional relevance of αV3C, highlighting the potential of αV3C-based inhibitors and, more generally, of postattachment inhibition of HIV-1.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry

04 Faculty of Medicine > Institute of Medical Virology
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Structural Biology
Life Sciences > Molecular Biology
Language:English
Date:21 August 2023
Deposited On:24 Nov 2023 13:22
Last Modified:30 Oct 2024 02:37
Publisher:Nature Publishing Group
ISSN:1545-9985
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41594-023-01062-z
PubMed ID:37605043
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  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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