Impact of yellow fever virus envelope protein on wild-type and vaccine epitopes and tissue tropism

The envelope (E) protein of flaviviruses is functionally associated with viral tissue tropism and pathogenicity. For yellow fever virus (YFV), viscerotropic disease primarily involving the liver is pathognomonic for wild-type (WT) infection. In contrast, the live-attenuated vaccine (LAV) strain 17D does not cause viscerotropic disease and reversion to virulence is associated with neurotropic disease. The relationship between structure-function of the E protein for WT strain Asibi and its LAV derivative 17D strain is poorly understood; however, changes to WT and vaccine epitopes have been associated with changes in virulence. Here, a panel of Asibi and 17D infectious clone mutants were generated with single-site mutations at the one membrane residue and each of the eight E protein amino acid substitutions that distinguish the two strains. The mutants were characterized with respect to WT-specific and vaccine-specific monoclonal antibodies (mAbs) binding to virus plus binding of virus to brain, liver, and lung membrane receptor preparations (MRPs) generated from AG129 mice. This approach shows that amino acids in the YFV E protein domains (ED) I and II contain the WT E protein epitope, which overlap with those that mediate YFV binding to mouse liver. Furthermore, amino acids in EDIII associated with the vaccine epitope overlap with those that facilitate YFV binding mouse brain MRPs. Taken together, these data suggest that the YFV E protein is a key determinant in the phenotype of WT and 17D vaccine strains of YFV.