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

Author

Listed:
  • Nikolas Friedrich

    (University of Zurich (UZH))

  • Emanuel Stiegeler

    (University of Zurich (UZH)
    Roche Diagnostics GmbH)

  • Matthias Glögl

    (University of Zurich (UZH))

  • Thomas Lemmin

    (University of Zurich (UZH)
    ETH Zurich
    Università della Svizzera italiana (USI))

  • Simon Hansen

    (University of Zurich (UZH)
    NGM Bio, 333 Oysterpoint Blvd)

  • Claus Kadelka

    (Iowa State University)

  • Yufan Wu

    (University of Zurich (UZH)
    Innovent Biologics Inc)

  • Patrick Ernst

    (University of Zurich (UZH)
    University of Zurich)

  • Liridona Maliqi

    (University of Zurich (UZH))

  • Caio Foulkes

    (University of Zurich (UZH))

  • Mylène Morin

    (University of Zurich (UZH)
    BeiGene Switzerland GmbH)

  • Mustafa Eroglu

    (University of Zurich (UZH)
    Janssen Vaccines AG)

  • Thomas Liechti

    (University of Zurich (UZH)
    ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH)

  • Branislav Ivan

    (University of Zurich (UZH)
    University Hospital Basel)

  • Thomas Reinberg

    (University of Zurich (UZH))

  • Jonas V. Schaefer

    (University of Zurich (UZH)
    Novartis Institutes for BioMedical Research, Chemical Biology & Therapeutics (CBT), Novartis Pharma AG)

  • Umut Karakus

    (University of Zurich (UZH))

  • Stephan Ursprung

    (University of Zurich (UZH)
    University of Cambridge School of Clinical Medicine, Department of Radiology)

  • Axel Mann

    (University of Zurich (UZH)
    Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED))

  • Peter Rusert

    (University of Zurich (UZH))

  • Roger D. Kouyos

    (University of Zurich (UZH)
    University Hospital Zurich (USZ))

  • John A. Robinson

    (University of Zurich (UZH))

  • Huldrych F. Günthard

    (University of Zurich (UZH)
    University Hospital Zurich (USZ))

  • Andreas Plückthun

    (University of Zurich (UZH))

  • Alexandra Trkola

    (University of Zurich (UZH))

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.

Suggested Citation

  • Nikolas Friedrich & Emanuel Stiegeler & Matthias Glögl & Thomas Lemmin & Simon Hansen & Claus Kadelka & Yufan Wu & Patrick Ernst & Liridona Maliqi & Caio Foulkes & Mylène Morin & Mustafa Eroglu & Thom, 2021. "Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27075-0
    DOI: 10.1038/s41467-021-27075-0
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    References listed on IDEAS

    as
    1. Md Munan Shaik & Hanqin Peng & Jianming Lu & Sophia Rits-Volloch & Chen Xu & Maofu Liao & Bing Chen, 2019. "Structural basis of coreceptor recognition by HIV-1 envelope spike," Nature, Nature, vol. 565(7739), pages 318-323, January.
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