Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site
Bailey B. Banach, S. 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, Brandon J. DeKosky
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.