An optimized hepatitis C virus E2 glycoprotein core adopts a functional homodimer that efficiently blocks virus entry

Kathleen McCaffrey, Irene Boo, Catherine M. Owczarek, Matthew P. Hardy, Matthew Anthony Perugini, Louis J Fabri, Pierre Scotney, Pantelis Poumbourios, Heidi E. Drummer

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Abstract

The hepatitis C virus (HCV) envelope glycoprotein E2 is the major target of broadly neutralizing antibodies in vivo and is the focus of efforts in the rational design of a universal B cell vaccine against HCV. The E2 glycoprotein exhibits a high degree of amino acid variability which localizes to three discrete regions: hypervariable region 1 (HVR1), hypervariable region 2 (HVR2), and the intergenotypic variable region (igVR). All three variable regions contribute to immune evasion and/or isolate-specific structural variations, both important considerations for vaccine design. A high-resolution structural definition of the intact HCV envelope glycoprotein complex containing E1 and E2 remains to be elucidated, while crystallographic structures of a recombinant E2 ectodomain failed to resolve HVR1, HVR2, and a major neutralization determinant adjacent to HVR1. To obtain further information on E2, we characterized the role of all three variable regions in E2 ectodomain folding and function in the context of a recombinant ectodomain fragment (rE2). We report that removal of the variable regions accelerates binding to the major host cell receptor CD81 and that simultaneous deletion of HVR2 and the igVR is required to maintain wild-type CD81-binding characteristics. The removal of the variable regions also rescued the ability of rE2 to form a functional homodimer. We propose that the rE2 core provides novel insights into the role of the variable motifs in the higher-order assembly of the E2 ectodomain and may have implications for E1E2 structure on the virion surface.

Original languageEnglish
Article numbere01668-16
Number of pages18
JournalJournal of Virology
Volume91
Issue number5
DOIs
Publication statusPublished - Mar 2017

Keywords

  • CD81 receptor
  • Glycoproteins
  • Hepatitis C virus

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