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

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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Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2025-01-01
Series:Cell Reports
Subjects:
CP: Immunology
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124724015742
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Summary: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.
ISSN:2211-1247

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