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Engaging an HIV vaccine target through the acquisition of low B cell affinity

Author

Listed:
  • Larance Ronsard

    (The Massachusetts Institute of Technology and Harvard University)

  • Ashraf S. Yousif

    (The Massachusetts Institute of Technology and Harvard University)

  • Faez Amokrane Nait Mohamed

    (The Massachusetts Institute of Technology and Harvard University)

  • Jared Feldman

    (The Massachusetts Institute of Technology and Harvard University)

  • Vintus Okonkwo

    (The Massachusetts Institute of Technology and Harvard University)

  • Caitlin McCarthy

    (The Massachusetts Institute of Technology and Harvard University)

  • Julia Schnabel

    (The Massachusetts Institute of Technology and Harvard University)

  • Timothy Caradonna

    (The Massachusetts Institute of Technology and Harvard University)

  • Ralston M. Barnes

    (Bristol-Myers Squibb)

  • Daniel Rohrer

    (Bristol-Myers Squibb)

  • Nils Lonberg

    (Bristol-Myers Squibb)

  • Aaron Schmidt

    (The Massachusetts Institute of Technology and Harvard University
    Harvard Medical School)

  • Daniel Lingwood

    (The Massachusetts Institute of Technology and Harvard University)

Abstract

Low affinity is common for germline B cell receptors (BCR) seeding development of broadly neutralizing antibodies (bnAbs) that engage hypervariable viruses, including HIV. Antibody affinity selection is also non-homogenizing, insuring the survival of low affinity B cell clones. To explore whether this provides a natural window for expanding human B cell lineages against conserved vaccine targets, we deploy transgenic mice mimicking human antibody diversity and somatic hypermutation (SHM) and immunize with simple monomeric HIV glycoprotein envelope immunogens. We report an immunization regimen that focuses B cell memory upon the conserved CD4 binding site (CD4bs) through both conventional affinity maturation and reproducible expansion of low affinity BCR clones with public patterns in SHM. In the latter instance, SHM facilitates target acquisition by decreasing binding strength. This suggests that permissive B cell selection enables the discovery of antibody epitopes, in this case an HIV bnAb site.

Suggested Citation

  • Larance Ronsard & Ashraf S. Yousif & Faez Amokrane Nait Mohamed & Jared Feldman & Vintus Okonkwo & Caitlin McCarthy & Julia Schnabel & Timothy Caradonna & Ralston M. Barnes & Daniel Rohrer & Nils Lonb, 2023. "Engaging an HIV vaccine target through the acquisition of low B cell affinity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40918-2
    DOI: 10.1038/s41467-023-40918-2
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    References listed on IDEAS

    as
    1. Jeong Hyun Lee & Henry J. Sutton & Christopher A. Cottrell & Ivy Phung & Gabriel Ozorowski & Leigh M. Sewall & Rebecca Nedellec & Catherine Nakao & Murillo Silva & Sara T. Richey & Jonathan L. Torres , 2022. "Long-primed germinal centres with enduring affinity maturation and clonal migration," Nature, Nature, vol. 609(7929), pages 998-1004, September.
    2. Daniel Lingwood & Patrick M. McTamney & Hadi M. Yassine & James R. R. Whittle & Xiaoti Guo & Jeffrey C. Boyington & Chih-Jen Wei & Gary J. Nabel, 2012. "Structural and genetic basis for development of broadly neutralizing influenza antibodies," Nature, Nature, vol. 489(7417), pages 566-570, September.
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