Single-cell analysis of memory B cells from top neutralizers reveals multiple sites of vulnerability within HCMV Trimer and Pentamer

Matthias Zehner, Mira Alt, Artem Ashurov, Jory A. Goldsmith, Rebecca Spies, Nina Weiler, Justin Lerma, Lutz Gieselmann, Dagmar Stöhr, Henning Gruell, Eric P. Schultz, Christoph Kreer, Linda Schlachter, Hanna Janicki, Kerstin Laib Sampaio, Cora Stegmann, Michelle D. Nemetchek, Sabrina Dähling, Leon Ullrich, Ulf DittmerOliver Witzke, Manuel Koch, Brent J. Ryckman, Ramin Lotfi, Jason S. McLellan, Adalbert Krawczyk, Christian Sinzger, Florian Klein

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Human cytomegalovirus (HCMV) can cause severe diseases in fetuses, newborns, and immunocompromised individuals. Currently, no vaccines are approved, and treatment options are limited. Here, we analyzed the human B cell response of four HCMV top neutralizers from a cohort of 9,000 individuals. By single-cell analyses of memory B cells targeting the pentameric and trimeric HCMV surface complexes, we identified vulnerable sites on the shared gH/gL subunits as well as complex-specific subunits UL128/130/131A and gO. Using high-resolution cryogenic electron microscopy, we revealed the structural basis of the neutralization mechanisms of antibodies targeting various binding sites. Moreover, we identified highly potent antibodies that neutralized a broad spectrum of HCMV strains, including primary clinical isolates, that outperform known antibodies used in clinical trials. Our study provides a deep understanding of the mechanisms of HCMV neutralization and identifies promising antibody candidates to prevent and treat HCMV infection.

Original languageEnglish
Pages (from-to)2602-2620.e10
JournalImmunity
Volume56
Issue number11
DOIs
StatePublished - Nov 14 2023

Keywords

  • HCMV
  • Pentamer
  • Trimer
  • antiviral therapy
  • broadly neutralizing antibody
  • cryogenic electron microscopy
  • epitope map
  • neutralizaton mechanisms
  • single B cell

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