Journal Article

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

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

2023

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/1 / 101/28 / 45/22 / 45/23 / 45/70 / 60 APPLIED LIFE SCIENCES / 631/250/255/1901 / 692/4017 / 82/1 / 82/47 / 82/80 / 82/81 / Amino Acid Sequence / Antibodies / Antibodies, Neutralizing / Binding sites / Directed evolution / env Gene Products, Human Immunodeficiency Virus / Evolution / Grooves / HIV / HIV Antibodies / HIV Infections / HIV-1 - genetics / Human immunodeficiency virus / Humanities and Social Sciences / Humans / multidisciplinary / Neutralization / Neutralization Tests / Peptides / Saturation mutagenesis / Science / Science & Technology - Other Topics / Science (multidisciplinary) / Vaccines / Vaccines, Subunit / Yeast