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TitleSingle-cell analysis of memory B cells from top neutralizers reveals multiple sites of vulnerability within HCMV Trimer and Pentamer.
Journal, issue, pagesImmunity, Vol. 56, Issue 11, Page 2602-2620.e10, Year 2023
Publish dateNov 14, 2023
AuthorsMatthias 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 Dittmer / Oliver Witzke / Manuel Koch / Brent J Ryckman / Ramin Lotfi / Jason S McLellan / Adalbert Krawczyk / Christian Sinzger / Florian Klein /
PubMed AbstractHuman cytomegalovirus (HCMV) can cause severe diseases in fetuses, newborns, and immunocompromised individuals. Currently, no vaccines are approved, and treatment options are limited. Here, we ...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 UL 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.
External linksImmunity / PubMed:37967532
MethodsEM (single particle)
Resolution2.9 - 3.4 Å
Structure data

EMDB-41158: CS2it1p2_F7K local refinement for HCMV Trimer in complex with CS2it1p2_F7K Fab and CS4tt1p1_E3K Fab
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-41180: Global reconstruction for HCMV Pentamer in complex with CS2pt1p2_A10L Fab and CS3pt1p4_C1L Fab
Method: EM (single particle) / Resolution: 3.4 Å

Source
  • Human betaherpesvirus 5
  • Homo sapiens (human)

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