Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site
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s41467-023-42098-5.pdf
Description
Published version
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5.34 MB
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Author(s)
Banach, Bailey B
Pletnev, Sergei
Olia, Adam S
Xu, Kai
Zhang, Baoshan
Rawi, Reda
Bylund, Tatsiana
Doria-Rose, Nicole A
Nguyen, Thuy Duong
Fahad, Ahmed S
Date Issued
2023
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Banach, B.B., Pletnev, S., Olia, A.S. et al. Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site. Nat Commun 14, 7593 (2023).
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Ragon Institute of MGH, MIT and Harvard
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DOI of Published Version
https://doi.org/10.1038/s41467-023-42098-5
