1. Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site.
- Author
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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., Lee, Myungjin, Lin, Bob C., Liu, Tracy, Louder, Mark K., Madan, Bharat, McKee, Krisha, O'Dell, Sijy, Sastry, Mallika, Schön, Arne, and Bui, Natalie
- Subjects
PEPTIDES ,HIV ,IMMUNOGLOBULINS ,MUTAGENESIS ,SPINE ,YEAST ,PROTEIN engineering - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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