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Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site
Banach, Bailey B. Pletnev, Sergei Olia, Adam S. Xu, Kai Zhang, Baoshan Rawi, Reda Bylund, Tatsiana Doria-Rose, Nicole A. Nguyen, Thuy Duong Fahad, Ahmed S.
Banach, Bailey B.
Pletnev, Sergei
Olia, Adam S.
Xu, Kai
Zhang, Baoshan
Rawi, Reda
Bylund, Tatsiana
Doria-Rose, Nicole A.
Nguyen, Thuy Duong
Fahad, Ahmed S.
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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.
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Date
2023-11-21
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Publisher
Nature Research
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Keywords
HIV infections, Molecular medicine
Citation
Banach BB, Pletnev S, Olia AS, Xu K, Zhang B, Rawi R, Bylund T, Doria-Rose NA, Nguyen TD, Fahad AS, Lee M, Lin BC, Liu T, Louder MK, Madan B, McKee K, O'Dell S, Sastry M, Schön A, Bui N, Shen CH, Wolfe JR, Chuang GY, Mascola JR, Kwong PD, DeKosky BJ. Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site. Nat Commun. 2023 Nov 21;14(1):7593. doi: 10.1038/s41467-023-42098-5. PMID: 37989731; PMCID: PMC10663459