The conserved bridging domain on HCV E1E2 glycoprotein complex is targeted by neutralizing antibodies from diverse lineages
Year: 2026
Type: article
Abstract: The induction of potent and cross-reactive neutralizing antibody (nAb) responses remains a challenge in vaccine development against antigenically diverse viruses such as hepatitis C virus (HCV). The HCV E1E2 glycoprotein complex contains two major neutralizing sites: the neutralizing face (NF) and the less explored bridging domain (BD). Here, we characterized 25 BD-targeting nAbs isolated from infection or immunization. These antibodies arise from diverse B cell lineages but share convergent CDRH3 features. Epitope mapping by alanine scanning and negative-stain electron microscopy revealed overlapping epitopes on BD spanning antigenic regions AR4 and AR5, with variable back layer engagement. The crystal structure of a non-human primate BD nAb RM3-26 in complex with E2 uncovered a back layer-directed recognition mode analogous to that of the human nAb hcab40. Together, BD- and NF-directed nAbs exhibited additivity in their neutralization, highlighting BD as a conserved site of vulnerability on HCV and a valuable target for rational vaccine design.
Source: Cell Reports
Language: English
Topic: Hepatitis C virus research
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: U.S. Department of Energy, National Institutes of Health, Office of Science, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Basic Energy Sciences, Biological and Environmental Research, Argonne National Laboratory, Brookhaven National Laboratory, SLAC National Accelerator Laboratory
Awards: G102163711, G107546177, G1229526393, G1285306620, G1286251239, G1313983767, G1664757510, G171842289, G1847291448, G1867732070, G2287611682, G2371548206, G241279073, G262532246, G262962599, G2857925935, G303061748, G3075337988, G3127483976, G3147859762, G3152346458, G315621713, Development of standardized immunoassays and virus panels for HCV vaccine research, G3262563802, G357145406, G3913106684, G409777406, G4130418780, G4202012489, G4235786860, G426311843, G4269941704, G4356617607, G4581610328, G495301720, G498139845, G5276889681, G5387317844, G5535608740, G5570207115, G5607048534, G5765906131, G6072549038, G618388848, MOLECULAR GENETIC ANALYSIS OF THE DROSOPHILA 205K MAP, G6550344761, G6848031779, G6918803902, G6965541988, G7283024673, G7396808078, G7463374569, G7583137537, G7863156295, G8207748872, G8382000481, G8473838722, G8925327636, GM/CA@APS: A Macromolecular Crystallography Resource, Rational design and efficacy testing of vaccines against HCV, A Synchrotron Radiation Structural Biology Resource, Broadly Effective HCV Vaccine, Durable Alteration of the Human Immune system after Infection or Immunotherapy, Understanding human antibody responses to chronic viral hepatitis C, G911061179, G969889393, G993149817
OpenAlex ID: W4416013917