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

Antibodies, Neutralizing / immunology Cell Line, Tumor Epitopes / genetics HEK293 Cells HIV Antibodies / immunology HIV-1 / genetics Humans Immunoglobulin G / immunology Molecular Docking Simulation Molecular Dynamics Simulation Mutation Protein Binding Protein Conformation env Gene Products, Human Immunodeficiency Virus / chemistry

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
18 11 2021

Historique:

received: 25 01 2021

accepted: 03 11 2021

entrez: 19 11 2021

pubmed: 20 11 2021

medline: 28 12 2021

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-021-27075-0 PMID: 34795280 PMC: PMC8602657

pubmed: 34795280

doi: 10.1038/s41467-021-27075-0

pii: 10.1038/s41467-021-27075-0

pmc: PMC8602657

doi:

Substances chimiques

Antibodies, Neutralizing 0

Epitopes 0

HIV Antibodies 0

Immunoglobulin G 0

env Gene Products, Human Immunodeficiency Virus 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

Pagination

6705

Informations de copyright

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