8ELI

Broadly neutralizing antibody VRC34-combo.1 in complex with HIV fusion peptide (residue 512-519)

Summary for 8ELI

• Entry DOI: 10.2210/pdb8eli/pdb
• Descriptor: VRC34-combo.1 Fab Light chain, VRC34-combo.1 Fab Heavy chain, Fusion peptide, ... (4 entities in total)
• Functional Keywords: hiv, vrc34, fusion peptide, broadly neutralizing, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 48163.80

Authors

Xu, K.,Kwong, P.D. (deposition date: 2022-09-24, release date: 2023-09-27, Last modification date: 2024-11-13)

Primary citation

Banach, B.B.,Pletnev, S.,Olia, A.S.,Xu, K.,Zhang, B.,Rawi, R.,Bylund, T.,Doria-Rose, N.A.,Nguyen, T.D.,Fahad, A.S.,Lee, M.,Lin, B.C.,Liu, T.,Louder, M.K.,Madan, B.,McKee, K.,O'Dell, S.,Sastry, M.,Schon, A.,Bui, N.,Shen, C.H.,Wolfe, J.R.,Chuang, G.Y.,Mascola, J.R.,Kwong, P.D.,DeKosky, B.J.
Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site.
Nat Commun, 14:7593-7593, 2023

PubMed 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.

PubMed: 37989731
DOI: 10.1038/s41467-023-42098-5

Experimental method

X-RAY DIFFRACTION (1.49 Å)