Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site

Bailey B. Banach, Sergei Pletnev, Adam S. Olia, Kai Xu, Baoshan Zhang, Reda Rawi, Tatsiana Bylund, Nicole A. Doria-Rose, Thuy Duong Nguyen, Ahmed S. Fahad, Myungjin Lee, Bob C. Lin, Tracy Liu, Mark K. Louder, Bharat Madan, Krisha McKee, Sijy O’Dell, Mallika Sastry, Arne Schön, Natalie Bui, Chen-Hsiang Shen, Jacy R. Wolfe, Gwo-Yu Chuang, John R. Mascola, Peter D. Kwong () and Brandon J. DeKosky ()
Additional contact information
Bailey B. Banach: The University of Kansas
Sergei Pletnev: National Institutes of Health
Adam S. Olia: National Institutes of Health
Kai Xu: National Institutes of Health
Baoshan Zhang: National Institutes of Health
Reda Rawi: National Institutes of Health
Tatsiana Bylund: National Institutes of Health
Nicole A. Doria-Rose: National Institutes of Health
Thuy Duong Nguyen: The University of Kansas
Ahmed S. Fahad: The University of Kansas
Myungjin Lee: National Institutes of Health
Bob C. Lin: National Institutes of Health
Tracy Liu: National Institutes of Health
Mark K. Louder: National Institutes of Health
Bharat Madan: The University of Kansas
Krisha McKee: National Institutes of Health
Sijy O’Dell: National Institutes of Health
Mallika Sastry: National Institutes of Health
Arne Schön: John Hopkins University
Natalie Bui: The University of Kansas
Chen-Hsiang Shen: National Institutes of Health
Jacy R. Wolfe: The University of Kansas
Gwo-Yu Chuang: National Institutes of Health
John R. Mascola: National Institutes of Health
Peter D. Kwong: National Institutes of Health
Brandon J. DeKosky: The University of Kansas

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42098-5

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