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

Humans HIV-1 Amino Acids Antibodies Binding Sites Molecular Conformation

Journal

Nature structural & molecular biology

ISSN: 1545-9985

Titre abrégé: Nat Struct Mol Biol

Pays: United States

ID NLM: 101186374

Informations de publication

Date de publication:
09 2023

Historique:

received: 23 09 2022

accepted: 11 07 2023

medline: 14 9 2023

pubmed: 22 8 2023

entrez: 21 8 2023

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41594-023-01062-z PMID: 37605043 PMC: PMC10497408

pubmed: 37605043

doi: 10.1038/s41594-023-01062-z

pii: 10.1038/s41594-023-01062-z

pmc: PMC10497408

doi:

Substances chimiques

Amino Acids 0

Antibodies 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1323-1336

Subventions

Organisme : Bill & Melinda Gates Foundation

ID : INV-016167

Pays : United States

Informations de copyright

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