Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage
Summary: Broadly neutralizing antibodies (bNAbs) targeting the apex of the HIV-1-envelope (Env) trimer comprise the most potent category of HIV-1 bNAbs and have emerged as promising therapeutics. Here, we investigate the development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage and rep...
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Elsevier
2025-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724015742 |
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| author | Rosemarie D. Mason Baoshan Zhang Nicholas C. Morano Chen-Hsiang Shen Krisha McKee Ashley Heimann Renguang Du Alexandra F. Nazzari Shelby Hodges Tapan Kanai Bob C. Lin Mark K. Louder Nicole A. Doria-Rose Tongqing Zhou Lawrence Shapiro Mario Roederer Peter D. Kwong Jason Gorman |
| author_facet | Rosemarie D. Mason Baoshan Zhang Nicholas C. Morano Chen-Hsiang Shen Krisha McKee Ashley Heimann Renguang Du Alexandra F. Nazzari Shelby Hodges Tapan Kanai Bob C. Lin Mark K. Louder Nicole A. Doria-Rose Tongqing Zhou Lawrence Shapiro Mario Roederer Peter D. Kwong Jason Gorman |
| author_sort | Rosemarie D. Mason |
| collection | DOAJ |
| description | Summary: Broadly neutralizing antibodies (bNAbs) targeting the apex of the HIV-1-envelope (Env) trimer comprise the most potent category of HIV-1 bNAbs and have emerged as promising therapeutics. Here, we investigate the development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage and report cryo-EM structures at 3.4 Å resolution of PGDM1400 and of an improved PGT145 variant (PGT145-R100aS), each bound to the BG505 Env trimer. Cross-species-based engineering improves PGT145 IC80 breadth to near that of PGDM1400. Despite similar breadth and potency, the two antibodies differ in their residue-level interactions with important apex features, including N160 glycans and apex cavity, with residue 100i of PGT145 (sulfated tyrosine) penetrating ∼7 Å farther than residue 100i of PGDM1400 (aspartic acid). While apex-directed bNAbs from other donors use maturation pathways that often converge on analogous residue-level recognition, our results demonstrate that divergent residue-level recognition can occur within the same lineage, thereby enabling improved coverage of escape variants. |
| format | Article |
| id | doaj-art-5e99a8e359cf4be5be6b2acda015accd |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-5e99a8e359cf4be5be6b2acda015accd2025-01-18T05:04:27ZengElsevierCell Reports2211-12472025-01-01441115223Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineageRosemarie D. Mason0Baoshan Zhang1Nicholas C. Morano2Chen-Hsiang Shen3Krisha McKee4Ashley Heimann5Renguang Du6Alexandra F. Nazzari7Shelby Hodges8Tapan Kanai9Bob C. Lin10Mark K. Louder11Nicole A. Doria-Rose12Tongqing Zhou13Lawrence Shapiro14Mario Roederer15Peter D. Kwong16Jason Gorman17Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAAaron Diamond AIDS Research Center and Department of Biochemistry and Molecular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USADivision of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USADivision of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Aaron Diamond AIDS Research Center and Department of Biochemistry and Molecular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Aaron Diamond AIDS Research Center and Department of Biochemistry and Molecular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA; Corresponding authorSummary: Broadly neutralizing antibodies (bNAbs) targeting the apex of the HIV-1-envelope (Env) trimer comprise the most potent category of HIV-1 bNAbs and have emerged as promising therapeutics. Here, we investigate the development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage and report cryo-EM structures at 3.4 Å resolution of PGDM1400 and of an improved PGT145 variant (PGT145-R100aS), each bound to the BG505 Env trimer. Cross-species-based engineering improves PGT145 IC80 breadth to near that of PGDM1400. Despite similar breadth and potency, the two antibodies differ in their residue-level interactions with important apex features, including N160 glycans and apex cavity, with residue 100i of PGT145 (sulfated tyrosine) penetrating ∼7 Å farther than residue 100i of PGDM1400 (aspartic acid). While apex-directed bNAbs from other donors use maturation pathways that often converge on analogous residue-level recognition, our results demonstrate that divergent residue-level recognition can occur within the same lineage, thereby enabling improved coverage of escape variants.http://www.sciencedirect.com/science/article/pii/S2211124724015742CP: Immunology |
| spellingShingle | Rosemarie D. Mason Baoshan Zhang Nicholas C. Morano Chen-Hsiang Shen Krisha McKee Ashley Heimann Renguang Du Alexandra F. Nazzari Shelby Hodges Tapan Kanai Bob C. Lin Mark K. Louder Nicole A. Doria-Rose Tongqing Zhou Lawrence Shapiro Mario Roederer Peter D. Kwong Jason Gorman Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage Cell Reports CP: Immunology |
| title | Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage |
| title_full | Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage |
| title_fullStr | Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage |
| title_full_unstemmed | Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage |
| title_short | Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage |
| title_sort | structural development of the hiv 1 apex directed pgt145 pgdm1400 antibody lineage |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724015742 |
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