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Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies

Author

Listed:
  • Rory Henderson

    (Duke University Medical Center
    Duke University Medical Center)

  • Kara Anasti

    (Duke University Medical Center)

  • Kartik Manne

    (Duke University Medical Center)

  • Victoria Stalls

    (Duke University Medical Center)

  • Carrie Saunders

    (Duke University Medical Center)

  • Yishak Bililign

    (Duke University Medical Center)

  • Ashliegh Williams

    (Duke University Medical Center)

  • Pimthada Bubphamala

    (Duke University Medical Center)

  • Maya Montani

    (Duke University Medical Center)

  • Sangita Kachhap

    (Duke University Medical Center)

  • Jingjing Li

    (Duke University Medical Center)

  • Chuancang Jaing

    (Duke University Medical Center)

  • Amanda Newman

    (Duke University Medical Center)

  • Derek W. Cain

    (Duke University Medical Center
    Duke University Medical Center)

  • Xiaozhi Lu

    (Duke University Medical Center)

  • Sravani Venkatayogi

    (Duke University Medical Center)

  • Madison Berry

    (Duke University Medical Center)

  • Kshitij Wagh

    (Duke University Medical Center)

  • Bette Korber

    (Los Alamos National Laboratory
    The New Mexico Consortium)

  • Kevin O. Saunders

    (Duke University Medical Center
    Duke University Medical Center)

  • Ming Tian

    (Boston Children’s Hospital
    Harvard Medical School)

  • Fred Alt

    (Boston Children’s Hospital
    Harvard Medical School)

  • Kevin Wiehe

    (Duke University Medical Center
    Duke University Medical Center)

  • Priyamvada Acharya

    (Duke University Medical Center
    Duke University Medical Center
    Duke University)

  • S. Munir Alam

    (Duke University Medical Center
    Duke University Medical Center
    Duke University School of Medicine)

  • Barton F. Haynes

    (Duke University Medical Center
    Duke University Medical Center)

Abstract

Vaccine development targeting rapidly evolving pathogens such as HIV-1 requires induction of broadly neutralizing antibodies (bnAbs) with conserved paratopes and mutations, and in some cases, the same Ig-heavy chains. The current trial-and-error search for immunogen modifications that improve selection for specific bnAb mutations is imprecise. Here, to precisely engineer bnAb boosting immunogens, we use molecular dynamics simulations to examine encounter states that form when antibodies collide with the HIV-1 Envelope (Env). By mapping how bnAbs use encounter states to find their bound states, we identify Env mutations predicted to select for specific antibody mutations in two HIV-1 bnAb B cell lineages. The Env mutations encode antibody affinity gains and select for desired antibody mutations in vivo. These results demonstrate proof-of-concept that Env immunogens can be designed to directly select for specific antibody mutations at residue-level precision by vaccination, thus demonstrating the feasibility of sequential bnAb-inducing HIV-1 vaccine design.

Suggested Citation

  • Rory Henderson & Kara Anasti & Kartik Manne & Victoria Stalls & Carrie Saunders & Yishak Bililign & Ashliegh Williams & Pimthada Bubphamala & Maya Montani & Sangita Kachhap & Jingjing Li & Chuancang J, 2024. "Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53120-9
    DOI: 10.1038/s41467-024-53120-9
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    References listed on IDEAS

    as
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