Structure of engineered hepatitis C virus E1E2 ectodomain in complex with neutralizing antibodies

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• Hepatitis C virus (HCV) poses a significant global health challenge, causing chronic liver disease and liver cancer.
• The E1E2 surface glycoprotein is the primary target for neutralizing antibodies against HCV.
• Developing effective HCV vaccines is difficult due to challenges in preparing soluble E1E2 ectodomains.

Purpose of the Study:

• To determine the cryo-electron microscopy (cryo-EM) structure of an engineered, secreted E1E2 ectodomain from HCV genotype 1b.
• To analyze the structural basis of neutralization by specific antibodies (AR4A, HEPC74, IGH520).
• To provide insights for the rational design of secreted E1E2 antigens for vaccine development.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structure of the engineered E1E2 ectodomain.
• The E1E2 ectodomain was engineered for secretion and stabilization.
• Complexes of E1E2 with neutralizing antibodies AR4A, HEPC74, and IGH520 were analyzed.

Main Results:

• The cryo-EM structure of the secreted E1E2 ectodomain was successfully obtained.
• The overall architecture of the engineered E1E2 concurs with native full-length E1E2.
• The epitope of the broadly neutralizing antibody AR4A was mapped to a region bridging the E2 core and E1, explaining its neutralization mechanism.

Conclusions:

• The study presents the structure of a membrane-liberated E1E2 complex that retains native structural features.
• Understanding the E1E2 heterodimer structure is vital for designing effective HCV vaccines.
• This work facilitates the development of secreted E1E2 antigens for future HCV vaccine candidates.