Structural basis for the neutralization and genotype specificity of hepatitis E virus

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• Hepatitis E virus (HEV) causes acute hepatitis, with no current vaccines available.
• A previously identified monoclonal antibody, 8C11, neutralizes HEV genotype I by blocking viral entry.

Purpose of the Study:

• To elucidate the structural basis of 8C11 antibody recognition and neutralization of HEV.
• To understand the genotype specificity of the 8C11 antibody.

Main Methods:

• Determined the complex crystal structure of 8C11 Fab with HEV E2s(I) domain.
• Performed site-directed mutagenesis and cell-based assays.
• Determined the structure of HEV E2s(IV) and modeled its complex with 8C11.

Main Results:

• Identified critical 8C11 epitopes on HEV E2s(I), with Arg(512) being crucial for interaction and neutralization.
• Demonstrated that 8C11 specifically neutralizes HEV genotype I, not other genotypes.
• Revealed that amino acid 497 in E2s is a key determinant for 8C11 genotype specificity, as swapping this residue altered antibody reactivity.

Conclusions:

• The structural and functional studies provide a molecular understanding of 8C11-mediated HEV neutralization.
• The findings highlight the potential for developing genotype-specific antibody-based therapeutics for Hepatitis E.