EMD-41180
Global reconstruction for HCMV Pentamer in complex with CS2pt1p2_A10L Fab and CS3pt1p4_C1L Fab
EMD-41180
Single-particle3.4 Å
Deposition: 05/07/2023Map released: 09/08/2023
Last modified: 21/02/2024
Sample Organism:
Human betaherpesvirus 5,
Homo sapiens
Sample: HCMV Pentamer in complex with CS2pt1p2_A10L Fab and CS3pt1p4_C1L Fab
Deposition Authors: Goldsmith JG, McLellan JS
Sample: HCMV Pentamer in complex with CS2pt1p2_A10L Fab and CS3pt1p4_C1L Fab
Deposition Authors: Goldsmith JG, McLellan JS
Single-cell analysis of memory B cells from top neutralizers reveals multiple sites of vulnerability within HCMV Trimer and Pentamer.
Zehner M,
Alt M,
Ashurov A,
Goldsmith JA,
Spies R,
Weiler N,
Lerma J,
Gieselmann L,
Stohr D,
Gruell H,
Schultz EP 
,
Kreer C ,
Schlachter L,
Janicki H,
Laib Sampaio K,
Stegmann C,
Nemetchek MD ,
Dahling S,
Ullrich L ,
Dittmer U,
Witzke O,
Koch M ,
Ryckman BJ,
Lotfi R,
McLellan JS,
Krawczyk A,
Sinzger C,
Klein F
(2023) Immunity , 56 , 2602 - 2620.e10
,
Kreer C ,
Schlachter L,
Janicki H,
Laib Sampaio K,
Stegmann C,
Nemetchek MD ,
Dahling S,
Ullrich L ,
Dittmer U,
Witzke O,
Koch M ,
Ryckman BJ,
Lotfi R,
McLellan JS,
Krawczyk A,
Sinzger C,
Klein F
(2023) Immunity , 56 , 2602 - 2620.e10
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.
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.