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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.
Antibodies targeting the HIV-1 fusion peptide rarely achieve more than 60% neutralization breadth. Here, the authors develop an anti-FP antibody enhancing its potency to 80% and structurally resolve the expanded FP-binding site that allows the antibody to target diverse viral variants.
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1 The University of Kansas, Bioengineering Graduate Program, Lawrence, USA (GRID:grid.266515.3) (ISNI:0000 0001 2106 0692)
2 National Institutes of Health, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165)
3 National Institutes of Health, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); The Ohio State University, Department of Veterinary Biosciences, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943)
4 The University of Kansas, Department of Pharmaceutical Chemistry, Lawrence, USA (GRID:grid.266515.3) (ISNI:0000 0001 2106 0692)
5 John Hopkins University, Department of Biology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311)
6 The University of Kansas, Department of Pharmaceutical Chemistry, Lawrence, USA (GRID:grid.266515.3) (ISNI:0000 0001 2106 0692); The University of Kansas, Department of Chemical Engineering, Lawrence, USA (GRID:grid.266515.3) (ISNI:0000 0001 2106 0692); Massachusetts Institute of Technology, Department of Chemical Engineering, Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786); The Ragon Institute of MGH, MIT, and Harvard, Cambridge, USA (GRID:grid.461656.6) (ISNI:0000 0004 0489 3491)