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Immunity ; 56(11): 2602-2620.e10, 2023 Nov 14.
Article in English | MEDLINE | ID: mdl-37967532

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.


Subject(s)
Cytomegalovirus , Viral Envelope Proteins , Infant, Newborn , Humans , Membrane Glycoproteins , Antibodies, Neutralizing , Memory B Cells , Antibodies, Viral , Single-Cell Analysis
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