Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage

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

doi:10.1016/j.celrep.2024.115223

Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage

Cell Rep. 2025 Jan 17;44(1):115223. doi: 10.1016/j.celrep.2024.115223. Online ahead of print.

Authors

Rosemarie D Mason¹, Baoshan Zhang¹, Nicholas C Morano², Chen-Hsiang Shen¹, Krisha McKee¹, Ashley Heimann¹, Renguang Du¹, Alexandra F Nazzari¹, Shelby Hodges³, Tapan Kanai³, Bob C Lin¹, Mark K Louder¹, Nicole A Doria-Rose¹, Tongqing Zhou¹, Lawrence Shapiro⁴, Mario Roederer¹, Peter D Kwong⁴, Jason Gorman⁵

Affiliations

¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
² Aaron Diamond AIDS Research Center and Department of Biochemistry and Molecular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
³ Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
⁴ Vaccine 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, USA.
⁵ Vaccine 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. Electronic address: [email protected].

PMID: 39826122
DOI: 10.1016/j.celrep.2024.115223

Abstract

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.

Keywords: CAP256-VRC26.25; CP: Immunology; HIV-1 envelope trimer; PCT64; PG9; RHA1.V2.01; V2-apex antibody; antibody evolution; bNAb; broadly neutralizing antibody; tyrosine sulfation.

Published by Elsevier Inc.