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The conserved bridging domain on HCV E1E2 glycoprotein complex is targeted by neutralizing antibodies from diverse lineages

  • Fang Chen1
  • Yen Thi Kim Nguyen2
  • Yi-Zong Lee2
  • Erick Giang1
  • Sing Chau Lau1
  • Yukiye Koide1
  • Shr-Hau Hung1
  • Lynn A. Ueno2
  • Linling He2
  • Eric A. Toth3
  • Thomas R. Fuerst3
  • Georg M. Lauer4
4 more authors
  • Robyn L. Stanfield2
  • Jiang Zhu1
  • Ian A. Wilson2
  • Mansun Law1
4 affiliations
  1. 1Department of Immunology and Microbiology and the Scripps Research Institute, La Jolla, CA 92037, USA
  2. 2Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
  3. 3Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA
  4. 4Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
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Abstract

SUMMARY: The bridging domain (BD) region on hepatitis C virus (HCV) E1E2 glycoprotein complex is a conserved, E1-dependent conformational site of vulnerability formed by E2 residues 646–704. Given its importance for rational vaccine design, here, we characterized the genetic, structural, functional, and epitope features of 25 BD-directed nAbs isolated from HCV-infected individuals or immunized macaques. These antibodies derive from diverse B cell lineages but frequently display recurrent CDRH3 motifs and recognize overlapping epitopes spanning antigenic regions AR4 and AR5, with variable engagement of the E2 back layer (BL) region. A crystal structure of the macaque nAb RM3-26 bound to E2 core domain reveals a BL-directed binding mode analogous to the human nAb hcab40. Importantly, BD-directed nAbs achieve broad neutralization with minimal somatic hypermutation at contact residues and act additively with neutralizing face-directed antibodies. Together, these findings underscore BD as a promising target for rational HCV vaccine design.

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Cite

BibTeXRIS
BibTeX
@article{chen2026conserved,
  title = {{The conserved bridging domain on HCV E1E2 glycoprotein complex is targeted by neutralizing antibodies from diverse lineages}},
  author = {Fang Chen and Yen Thi Kim Nguyen and Yi-Zong Lee and Erick Giang and Sing Chau Lau and Yukiye Koide and Shr-Hau Hung and Lynn A. Ueno and Linling He and Eric A. Toth and Thomas R. Fuerst and Georg M. Lauer and Robyn L. Stanfield and Jiang Zhu and Ian A. Wilson and Mansun Law},
  journal = {Cell reports},
  year = {2026},
  month = aug,
  doi = {10.1016/j.celrep.2026.117760},
  url = {https://europepmc.org/article/PMC/PMC13719106},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - The conserved bridging domain on HCV E1E2 glycoprotein complex is targeted by neutralizing antibodies from diverse lineages
AU  - Fang Chen
AU  - Yen Thi Kim Nguyen
AU  - Yi-Zong Lee
AU  - Erick Giang
AU  - Sing Chau Lau
AU  - Yukiye Koide
AU  - Shr-Hau Hung
AU  - Lynn A. Ueno
AU  - Linling He
AU  - Eric A. Toth
AU  - Thomas R. Fuerst
AU  - Georg M. Lauer
AU  - Robyn L. Stanfield
AU  - Jiang Zhu
AU  - Ian A. Wilson
AU  - Mansun Law
PY  - 2026
DA  - 2026/08/04
JO  - Cell reports
DO  - 10.1016/j.celrep.2026.117760
UR  - https://europepmc.org/article/PMC/PMC13719106
AB  - SUMMARY: The bridging domain (BD) region on hepatitis C virus (HCV) E1E2 glycoprotein complex is a conserved, E1-dependent conformational site of vulnerability formed by E2 residues 646–704. Given its importance for rational vaccine design, here, we characterized the genetic, structural, functional, and epitope features of 25 BD-directed nAbs isolated from HCV-infected individuals or immunized macaques. These antibodies derive from diverse B cell lineages but frequently display recurrent CDRH3 motifs and recognize overlapping epitopes spanning antigenic regions AR4 and AR5, with variable engagement of the E2 back layer (BL) region. A crystal structure of the macaque nAb RM3-26 bound to E2 core domain reveals a BL-directed binding mode analogous to the human nAb hcab40. Importantly, BD-directed nAbs achieve broad neutralization with minimal somatic hypermutation at contact residues and act additively with neutralizing face-directed antibodies. Together, these findings underscore BD as a promising target for rational HCV vaccine design.
SN  - 2211-1247
ER  -