Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2025
|
| Online Access: | https://hdl.handle.net/1721.1/158240 |
| _version_ | 1824458396030468096 |
|---|---|
| author | 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 Lee, Myungjin Lin, Bob C Liu, Tracy Louder, Mark K Madan, Bharat McKee, Krisha O’Dell, Sijy Sastry, Mallika Schön, Arne Bui, Natalie Shen, Chen-Hsiang Wolfe, Jacy R Chuang, Gwo-Yu Mascola, John R Kwong, Peter D DeKosky, Brandon J |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering 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 Lee, Myungjin Lin, Bob C Liu, Tracy Louder, Mark K Madan, Bharat McKee, Krisha O’Dell, Sijy Sastry, Mallika Schön, Arne Bui, Natalie Shen, Chen-Hsiang Wolfe, Jacy R Chuang, Gwo-Yu Mascola, John R Kwong, Peter D DeKosky, Brandon J |
| author_sort | Banach, Bailey B |
| collection | MIT |
| description | 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. |
| first_indexed | 2025-02-19T04:25:13Z |
| format | Article |
| id | mit-1721.1/158240 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2025-02-19T04:25:13Z |
| publishDate | 2025 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1582402025-02-18T23:54:24Z 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 Lee, Myungjin Lin, Bob C Liu, Tracy Louder, Mark K Madan, Bharat McKee, Krisha O’Dell, Sijy Sastry, Mallika Schön, Arne Bui, Natalie Shen, Chen-Hsiang Wolfe, Jacy R Chuang, Gwo-Yu Mascola, John R Kwong, Peter D DeKosky, Brandon J Massachusetts Institute of Technology. Department of Chemical Engineering Ragon Institute of MGH, MIT and Harvard 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. 2025-02-18T23:54:22Z 2025-02-18T23:54:22Z 2023 2025-02-18T23:31:02Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/158240 Banach, B.B., Pletnev, S., Olia, A.S. et al. Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site. Nat Commun 14, 7593 (2023). en 10.1038/s41467-023-42098-5 Nature Communications Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Springer Science and Business Media LLC |
| spellingShingle | 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 Lee, Myungjin Lin, Bob C Liu, Tracy Louder, Mark K Madan, Bharat McKee, Krisha O’Dell, Sijy Sastry, Mallika Schön, Arne Bui, Natalie Shen, Chen-Hsiang Wolfe, Jacy R Chuang, Gwo-Yu Mascola, John R Kwong, Peter D DeKosky, Brandon J Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site |
| title | Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site |
| title_full | Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site |
| title_fullStr | Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site |
| title_full_unstemmed | Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site |
| title_short | Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site |
| title_sort | antibody directed evolution reveals a mechanism for enhanced neutralization at the hiv 1 fusion peptide site |
| url | https://hdl.handle.net/1721.1/158240 |
| work_keys_str_mv | AT banachbaileyb antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT pletnevsergei antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT oliaadams antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT xukai antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT zhangbaoshan antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT rawireda antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT bylundtatsiana antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT doriarosenicolea antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT nguyenthuyduong antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT fahadahmeds antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT leemyungjin antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT linbobc antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT liutracy antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT loudermarkk antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT madanbharat antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT mckeekrisha antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT odellsijy antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT sastrymallika antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT schonarne antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT buinatalie antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT shenchenhsiang antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT wolfejacyr antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT chuanggwoyu antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT mascolajohnr antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT kwongpeterd antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite AT dekoskybrandonj antibodydirectedevolutionrevealsamechanismforenhancedneutralizationatthehiv1fusionpeptidesite |