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Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site

Author

Listed:
  • Bailey B. Banach

    (The University of Kansas)

  • Sergei Pletnev

    (National Institutes of Health)

  • Adam S. Olia

    (National Institutes of Health)

  • Kai Xu

    (National Institutes of Health
    The Ohio State University)

  • Baoshan Zhang

    (National Institutes of Health)

  • Reda Rawi

    (National Institutes of Health)

  • Tatsiana Bylund

    (National Institutes of Health)

  • Nicole A. Doria-Rose

    (National Institutes of Health)

  • Thuy Duong Nguyen

    (The University of Kansas)

  • Ahmed S. Fahad

    (The University of Kansas)

  • Myungjin Lee

    (National Institutes of Health)

  • Bob C. Lin

    (National Institutes of Health)

  • Tracy Liu

    (National Institutes of Health)

  • Mark K. Louder

    (National Institutes of Health)

  • Bharat Madan

    (The University of Kansas)

  • Krisha McKee

    (National Institutes of Health)

  • Sijy O’Dell

    (National Institutes of Health)

  • Mallika Sastry

    (National Institutes of Health)

  • Arne Schön

    (John Hopkins University)

  • Natalie Bui

    (The University of Kansas)

  • Chen-Hsiang Shen

    (National Institutes of Health)

  • Jacy R. Wolfe

    (The University of Kansas)

  • Gwo-Yu Chuang

    (National Institutes of Health)

  • John R. Mascola

    (National Institutes of Health)

  • Peter D. Kwong

    (National Institutes of Health)

  • Brandon J. DeKosky

    (The University of Kansas
    The University of Kansas
    Massachusetts Institute of Technology
    The Ragon Institute of MGH, MIT, and Harvard)

Abstract

The HIV-1 fusion peptide (FP) represents a promising vaccine target, but global FP sequence diversity among circulating strains has limited anti-FP antibodies to ~60% neutralization breadth. Here we evolve the FP-targeting antibody VRC34.01 in vitro to enhance FP-neutralization using site saturation mutagenesis and yeast display. Successive rounds of directed evolution by iterative selection of antibodies for binding to resistant HIV-1 strains establish a variant, VRC34.01_mm28, as a best-in-class antibody with 10-fold enhanced potency compared to the template antibody and ~80% breadth on a cross-clade 208-strain neutralization panel. Structural analyses demonstrate that the improved paratope expands the FP binding groove to accommodate diverse FP sequences of different lengths while also recognizing the HIV-1 Env backbone. These data reveal critical antibody features for enhanced neutralization breadth and potency against the FP site of vulnerability and accelerate clinical development of broad HIV-1 FP-targeting vaccines and therapeutics.

Suggested Citation

  • Bailey B. Banach & Sergei Pletnev & Adam S. Olia & Kai Xu & Baoshan Zhang & Reda Rawi & Tatsiana Bylund & Nicole A. Doria-Rose & Thuy Duong Nguyen & Ahmed S. Fahad & Myungjin Lee & Bob C. Lin & Tracy , 2023. "Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42098-5
    DOI: 10.1038/s41467-023-42098-5
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    References listed on IDEAS

    as
    1. Sonu Kumar & Anita Sarkar & Pavel Pugach & Rogier W. Sanders & John P. Moore & Andrew B. Ward & Ian A. Wilson, 2019. "Capturing the inherent structural dynamics of the HIV-1 envelope glycoprotein fusion peptide," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    2. Nicole A. Doria-Rose & Chaim A. Schramm & Jason Gorman & Penny L. Moore & Jinal N. Bhiman & Brandon J. DeKosky & Michael J. Ernandes & Ivelin S. Georgiev & Helen J. Kim & Marie Pancera & Ryan P. Staup, 2014. "Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies," Nature, Nature, vol. 509(7498), pages 55-62, May.
    3. Laura M. Walker & Michael Huber & Katie J. Doores & Emilia Falkowska & Robert Pejchal & Jean-Philippe Julien & Sheng-Kai Wang & Alejandra Ramos & Po-Ying Chan-Hui & Matthew Moyle & Jennifer L. Mitcham, 2011. "Broad neutralization coverage of HIV by multiple highly potent antibodies," Nature, Nature, vol. 477(7365), pages 466-470, September.
    4. Kim-Marie A. Dam & Christopher O. Barnes & Harry B. Gristick & Till Schoofs & Priyanthi N. P. Gnanapragasam & Michel C. Nussenzweig & Pamela J. Bjorkman, 2022. "HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
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