Journal
CELL RESEARCH
Volume 25, Issue 5, Pages 604-620Publisher
SPRINGERNATURE
DOI: 10.1038/cr.2015.34
Keywords
HEV; cross-genotype neutralizing antibody; immunodominant; epitope
Categories
Funding
- Chinese government: Fujian Provincial Science Fund for Distinguished Young Scholars [2011J06015]
- National Natural Science Foundation [81172885, 81371818]
- International Science and Technology Collaborative Program [2011DFG33050]
- Key Program in New Drug RD [2012ZX09101316, 2014AA021302]
- Academic Research Fund Tier 1 [R154000616112]
- National University of Singapore (NUS), Singapore
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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 similar to 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 angstrom 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.
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