Faculty, Staff and Student Publications
Publication Date
11-21-2023
Journal
Nature Communications
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.
Keywords
Humans, HIV-1, HIV Antibodies, Antibodies, Neutralizing, Peptides, Amino Acid Sequence, Vaccines, Subunit, HIV Infections, Neutralization Tests, env Gene Products, Human Immunodeficiency Virus
DOI
10.1038/s41467-023-42098-5
PMID
37989731
PMCID
PMC10663459
PubMedCentral® Posted Date
November 2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Sciences Commons, Oncology Commons
Comments
Associated Data
PMID: 37989731