ANTIGENIC VARIANTS OF YELLOW-FEVER VIRUS WITH AN ALTERED NEUROVIRULENCE PHENOTYPE IN MICE

The live-attenuated yellow fever (YF) vaccine virus, strain 17D-204, h as long been known to consist of a heterologous population of virions. Gould et al. CI. Gen. Virol. 70, 1889-1894 (1989)) previously demonst rated that variant viruses exhibiting a YF wild-type-specific envelope (E) protein epitope are present at low frequency in the vaccine pool and were able to isolate representative virus variants with and withou t this epitope, designated 17D(+wt) and 17D(-wt), respectively. These Variants were employed here in an investigation of YF Virus pathogenes is in the mouse model. Both the 17D-204 parent and the 17D(+wt) varian t viruses were lethal for adult outbred mice by the intracerebral rout e of inoculation. However, the 17D(-wt) Variant was significantly atte nuated (18% mortality rate) and replicated to much lower titer in the brains of infected mice. A single amino acid substitution in the envel ope (E) protein at E-240 (Ala --> Val) was identified as responsible f or the restricted replication of the 17D(-wt) Variant in vivo. The 17D (+wt) variant has an additional second-site mutation, believed to enco de a reversion to the neurovirulence phenotype of the 17D-204 parent v irus. The amino acid substitution in the E protein at E-173 (Thr --> l ie) of the 17D(+wt) variant which results in the appearance of the wil d-type-specific epitope or nucleotide changes in the 5' and 3' noncodi ng regions of the virus are proposed as a candidates. (C) 1997 Academi c Press.