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.

Details

Title
Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site
Author
Banach, Bailey B. 1 ; Pletnev, Sergei 2 ; Olia, Adam S. 2 ; Xu, Kai 3 ; Zhang, Baoshan 2 ; Rawi, Reda 2   VIAFID ORCID Logo  ; Bylund, Tatsiana 2 ; Doria-Rose, Nicole A. 2   VIAFID ORCID Logo  ; Nguyen, Thuy Duong 4 ; Fahad, Ahmed S. 4 ; Lee, Myungjin 2   VIAFID ORCID Logo  ; Lin, Bob C. 2 ; Liu, Tracy 2 ; Louder, Mark K. 2   VIAFID ORCID Logo  ; Madan, Bharat 4 ; McKee, Krisha 2 ; O’Dell, Sijy 2 ; Sastry, Mallika 2 ; Schön, Arne 5 ; Bui, Natalie 4 ; Shen, Chen-Hsiang 2 ; Wolfe, Jacy R. 4 ; Chuang, Gwo-Yu 2 ; Mascola, John R. 2 ; Kwong, Peter D. 2   VIAFID ORCID Logo  ; DeKosky, Brandon J. 6   VIAFID ORCID Logo 

 The University of Kansas, Bioengineering Graduate Program, Lawrence, USA (GRID:grid.266515.3) (ISNI:0000 0001 2106 0692) 
 National Institutes of Health, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
 National Institutes of Health, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); The Ohio State University, Department of Veterinary Biosciences, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943) 
 The University of Kansas, Department of Pharmaceutical Chemistry, Lawrence, USA (GRID:grid.266515.3) (ISNI:0000 0001 2106 0692) 
 John Hopkins University, Department of Biology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
 The University of Kansas, Department of Pharmaceutical Chemistry, Lawrence, USA (GRID:grid.266515.3) (ISNI:0000 0001 2106 0692); The University of Kansas, Department of Chemical Engineering, Lawrence, USA (GRID:grid.266515.3) (ISNI:0000 0001 2106 0692); Massachusetts Institute of Technology, Department of Chemical Engineering, Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786); The Ragon Institute of MGH, MIT, and Harvard, Cambridge, USA (GRID:grid.461656.6) (ISNI:0000 0004 0489 3491) 
Pages
7593
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2892155826
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.