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Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site.
- Source :
-
Nature communications [Nat Commun] 2023 Nov 21; Vol. 14 (1), pp. 7593. Date of Electronic Publication: 2023 Nov 21. - Publication Year :
- 2023
-
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&#95;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.<br /> (© 2023. The Author(s).)
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 37989731
- Full Text :
- https://doi.org/10.1038/s41467-023-42098-5