Structural basis for the neutralization of hepatitis E virus by a cross-genotype antibody

Cell Res. 2015 May;25(5):604-20. doi: 10.1038/cr.2015.34. Epub 2015 Mar 20.

Abstract

Hepatitis E virus (HEV), a non-enveloped, positive-sense, single-stranded RNA virus, is a major cause of enteric hepatitis. Classified into the family Hepeviridae, HEV comprises four genotypes (genotypes 1-4), which belong to a single serotype. We describe a monoclonal antibody (mAb), 8G12, which equally recognizes all four genotypes of HEV, with ∼ 2.53-3.45 nM binding affinity. The mAb 8G12 has a protective, neutralizing capacity, which can significantly block virus infection in host cells. Animal studies with genotypes 1, 3 and 4 confirmed the cross-genotype neutralizing capacity of 8G12 and its effective prevention of hepatitis E disease. The complex crystal structures of 8G12 with the HEV E2s domain (the most protruded region of the virus capsid) of the abundant genotypes 1 and 4 were determined at 4.0 and 2.3 Å resolution, respectively. These structures revealed that 8G12 recognizes both genotypes through the epitopes in the E2s dimerization region. Structure-based mutagenesis and cell-model assays with virus-like particles identified several conserved residues (Glu549, Lys554 and Gly591) that are essential for 8G12 neutralization. Moreover, the epitope of 8G12 is identified as a key epitope involved in virus-host interactions. These findings will help develop a common strategy for the prevention of the most abundant form of HEV infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / therapeutic use*
  • Biosensing Techniques
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / immunology*
  • Genotype
  • Hepatitis E / prevention & control
  • Hepatitis E / virology
  • Hepatitis E virus / immunology*
  • Hepatitis E virus / pathogenicity
  • Macaca mulatta

Substances

  • Antibodies, Neutralizing
  • Epitopes