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 Dittmer; Oliver Witzke; Manuel Koch; Brent J. Ryckman; Ramin Lotfi; Jason S. McLellan; Adalbert Krawczyk; Christian Sinzger; Florian Klein

doi:10.1016/j.immuni.2023.10.009

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 journal › Article › peer-review

5 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 UL_128/130/131A 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 language	English
Pages (from-to)	2602-2620.e10
Journal	Immunity
Volume	56
Issue number	11
DOIs	https://doi.org/10.1016/j.immuni.2023.10.009
State	Published - Nov 14 2023

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2023.10.009

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Zehner, M., Alt, M., Ashurov, A., Goldsmith, J. A., Spies, R., Weiler, N., Lerma, J., Gieselmann, L., Stöhr, D., Gruell, H., Schultz, E. P., Kreer, C., Schlachter, L., Janicki, H., Laib Sampaio, K., Stegmann, C., Nemetchek, M. D., Dähling, S., Ullrich, L., ... Klein, F. (2023). Single-cell analysis of memory B cells from top neutralizers reveals multiple sites of vulnerability within HCMV Trimer and Pentamer. Immunity, 56(11), 2602-2620.e10. https://doi.org/10.1016/j.immuni.2023.10.009

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

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.",

keywords = "HCMV, Pentamer, Trimer, antiviral therapy, broadly neutralizing antibody, cryogenic electron microscopy, epitope map, neutralizaton mechanisms, single B cell",

author = "Matthias Zehner and Mira Alt and Artem Ashurov and Goldsmith, {Jory A.} and Rebecca Spies and Nina Weiler and Justin Lerma and Lutz Gieselmann and Dagmar St{\"o}hr and Henning Gruell and Schultz, {Eric P.} and Christoph Kreer and Linda Schlachter and Hanna Janicki and {Laib Sampaio}, Kerstin and Cora Stegmann and Nemetchek, {Michelle D.} and Sabrina D{\"a}hling and Leon Ullrich and Ulf Dittmer and Oliver Witzke and Manuel Koch and Ryckman, {Brent J.} and Ramin Lotfi and McLellan, {Jason S.} and Adalbert Krawczyk and Christian Sinzger and Florian Klein",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = nov,

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doi = "10.1016/j.immuni.2023.10.009",

language = "English",

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Zehner, M, Alt, M, Ashurov, A, Goldsmith, JA, Spies, R, Weiler, N, Lerma, J, Gieselmann, L, Stöhr, D, Gruell, H, Schultz, EP, Kreer, C, Schlachter, L, Janicki, H, Laib Sampaio, K, Stegmann, C, Nemetchek, MD, Dähling, S, Ullrich, L, Dittmer, U, Witzke, O, Koch, M, Ryckman, BJ, Lotfi, R, McLellan, JS, Krawczyk, A, Sinzger, C & Klein, F 2023, 'Single-cell analysis of memory B cells from top neutralizers reveals multiple sites of vulnerability within HCMV Trimer and Pentamer', Immunity, vol. 56, no. 11, pp. 2602-2620.e10. https://doi.org/10.1016/j.immuni.2023.10.009

TY - JOUR

T1 - Single-cell analysis of memory B cells from top neutralizers reveals multiple sites of vulnerability within HCMV Trimer and Pentamer

AU - Zehner, Matthias

AU - Alt, Mira

AU - Ashurov, Artem

AU - Goldsmith, Jory A.

AU - Spies, Rebecca

AU - Weiler, Nina

AU - Lerma, Justin

AU - Gieselmann, Lutz

AU - Stöhr, Dagmar

AU - Gruell, Henning

AU - Schultz, Eric P.

AU - Kreer, Christoph

AU - Schlachter, Linda

AU - Janicki, Hanna

AU - Laib Sampaio, Kerstin

AU - Stegmann, Cora

AU - Nemetchek, Michelle D.

AU - Dähling, Sabrina

AU - Ullrich, Leon

AU - Dittmer, Ulf

AU - Witzke, Oliver

AU - Koch, Manuel

AU - Ryckman, Brent J.

AU - Lotfi, Ramin

AU - McLellan, Jason S.

AU - Krawczyk, Adalbert

AU - Sinzger, Christian

AU - Klein, Florian

PY - 2023/11/14

Y1 - 2023/11/14

N2 - 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.

AB - 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.

KW - HCMV

KW - Pentamer

KW - Trimer

KW - antiviral therapy

KW - broadly neutralizing antibody

KW - cryogenic electron microscopy

KW - epitope map

KW - neutralizaton mechanisms

KW - single B cell

UR - http://www.scopus.com/inward/record.url?scp=85176143061&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2023.10.009

DO - 10.1016/j.immuni.2023.10.009

M3 - Article

C2 - 37967532

AN - SCOPUS:85176143061

SN - 1074-7613

VL - 56

SP - 2602-2620.e10

JO - Immunity

JF - Immunity

IS - 11

ER -

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

Abstract

Keywords

UN SDGs

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