E Protein Domain III Determinants of Yellow Fever Virus 17DVaccine Strain Enhance Binding to Glycosaminoglycans,Impede Virus Spread, and Attenuate Virulence

Date

2008

Authors

Lee, Eva
Lobigs, Mario

Journal Title

Journal ISSN

Volume Title

Publisher

American Society for Microbiology

Abstract

The yellow fever virus (YFV) 17D strain is one of the most effective live vaccines for human use, but the in vivo mechanisms for virulence attenuation of the vaccine and the corresponding molecular determinants remain elusive. The vaccine differs phenotypically from wild-type YFV by the loss of viscerotropism, despite replicative fitness in cell culture, and genetically by 20 amino acid changes predominantly located in the envelope (E) protein. We show that three residues in E protein domain III inhibit spread of 17D in extraneural tissues and attenuate virulence in type I/II interferon-deficient mice. One of these residues (Arg380) is a dominant glycosaminoglycan-binding determinant, which mainly accounts for more rapid in vivo clearance of 17D from the bloodstream in comparison to 17D-derived variants with wild-type-like E protein. While other mutations will account for loss of neurotropism and phenotypic stability, the described impact of E protein domain III changes on virus dissemination and virulence is the first rational explanation for the safety of the 17D vaccine in humans.

Description

Keywords

Keywords: arginine; envelope protein; glycosaminoglycan; yellow fever vaccine; animal cell; animal experiment; animal model; animal tissue; article; binding affinity; blood flow; comparative study; controlled study; drug safety; genetic stability; in vivo study; mo

Citation

Source

Journal of Virology

Type

Journal article

Book Title

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2037-12-31