Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site
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 s...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42098-5 |
| _version_ | 1797452136412348416 |
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| author | Bailey B. Banach Sergei Pletnev Adam S. Olia Kai Xu Baoshan Zhang Reda Rawi Tatsiana Bylund Nicole A. Doria-Rose Thuy Duong Nguyen Ahmed S. Fahad Myungjin Lee Bob C. Lin Tracy Liu Mark K. Louder Bharat Madan Krisha McKee Sijy O’Dell Mallika Sastry Arne Schön Natalie Bui Chen-Hsiang Shen Jacy R. Wolfe Gwo-Yu Chuang John R. Mascola Peter D. Kwong Brandon J. DeKosky |
| author_facet | Bailey B. Banach Sergei Pletnev Adam S. Olia Kai Xu Baoshan Zhang Reda Rawi Tatsiana Bylund Nicole A. Doria-Rose Thuy Duong Nguyen Ahmed S. Fahad Myungjin Lee Bob C. Lin Tracy Liu Mark K. Louder Bharat Madan Krisha McKee Sijy O’Dell Mallika Sastry Arne Schön Natalie Bui Chen-Hsiang Shen Jacy R. Wolfe Gwo-Yu Chuang John R. Mascola Peter D. Kwong Brandon J. DeKosky |
| author_sort | Bailey B. Banach |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T15:04:24Z |
| format | Article |
| id | doaj.art-e636e8ff307e4e158f7f9667c39522e1 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T15:04:24Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e636e8ff307e4e158f7f9667c39522e12023-11-26T13:45:59ZengNature PortfolioNature Communications2041-17232023-11-0114111710.1038/s41467-023-42098-5Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide siteBailey B. Banach0Sergei Pletnev1Adam S. Olia2Kai Xu3Baoshan Zhang4Reda Rawi5Tatsiana Bylund6Nicole A. Doria-Rose7Thuy Duong Nguyen8Ahmed S. Fahad9Myungjin Lee10Bob C. Lin11Tracy Liu12Mark K. Louder13Bharat Madan14Krisha McKee15Sijy O’Dell16Mallika Sastry17Arne Schön18Natalie Bui19Chen-Hsiang Shen20Jacy R. Wolfe21Gwo-Yu Chuang22John R. Mascola23Peter D. Kwong24Brandon J. DeKosky25Bioengineering Graduate Program, The University of KansasVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartment of Pharmaceutical Chemistry, The University of KansasDepartment of Pharmaceutical Chemistry, The University of KansasVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartment of Pharmaceutical Chemistry, The University of KansasVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartment of Biology, John Hopkins UniversityDepartment of Pharmaceutical Chemistry, The University of KansasVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartment of Pharmaceutical Chemistry, The University of KansasVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartment of Pharmaceutical Chemistry, The University of KansasAbstract 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.https://doi.org/10.1038/s41467-023-42098-5 |
| spellingShingle | Bailey B. Banach Sergei Pletnev Adam S. Olia Kai Xu Baoshan Zhang Reda Rawi Tatsiana Bylund Nicole A. Doria-Rose Thuy Duong Nguyen Ahmed S. Fahad Myungjin Lee Bob C. Lin Tracy Liu Mark K. Louder Bharat Madan Krisha McKee Sijy O’Dell Mallika Sastry Arne Schön Natalie Bui Chen-Hsiang Shen Jacy R. Wolfe Gwo-Yu Chuang John R. Mascola Peter D. Kwong Brandon J. DeKosky Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site Nature Communications |
| 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://doi.org/10.1038/s41467-023-42098-5 |
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