8tco
HCMV Trimer in complex with CS2it1p2_F7K Fab and CS4tt1p1_E3K Fab
Structural highlights
FunctionGH_HCMVA The heterodimer glycoprotein H-glycoprotein L is required for the fusion of viral and plasma membranes leading to virus entry into the host cell. Following initial binding to host receptor, membrane fusion is mediated by the fusion machinery composed of gB and the heterodimer gH/gL. May also be involved in the fusion between the virion envelope and the outer nuclear membrane during virion morphogenesis (By similarity). In human cytomegalovirus, forms two distincts complexes to mediate viral entry, a trimer and a pentamer at the surface of the virion envelope. The gH-gL-gO trimer is required for infection in fibroblasts by interacting with host PDGFRA, and in glioblastoma cells by interacting with host EPHA2. The gH-gL-UL128-UL130-UL131A pentamer is essential for viral entry in epithelial, endothelial and myeloid cells via interaction with host NRP2 (By similarity).[UniProtKB:Q6SW67][HAMAP-Rule:MF_04033] Publication Abstract from PubMedHuman 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. 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 Immunity. 2023 Nov 14;56(11):2602-2620.e10. doi: 10.1016/j.immuni.2023.10.009. PMID:37967532[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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