Antigenic variants of yellow fever virus with an altered neurovirulence phenotype in mice.
The live-attenuated yellow fever (YF) vaccine virus, strain 17D-204, has long been known to consist of a heterologous population of virions. Gould et al. (J. Gen. Virol. 70, 1889-1894 (1989)) previously demonstrated 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 without this epitope, designated 17D(+wt) and 17D(-wt), respectively. These variants were employed here in an investigation of YF virus pathogenesis in the mouse model. Both the 17D-204 parent and the 17D(+wt) variant viruses were lethal for adult outbred mice by the intracerebral route of inoculation. However, the 17D(-wt) variant was significantly attenuated (18% mortality rate) and replicated to much lower titer in the brains of infected mice. A single amino acid substitution in the envelope (E) protein at E-240 (Ala-->Val) was identified as responsible for the restricted replication of the 17D(-wt) variant in vivo. The 17D(+wt) variant has an additional second-site mutation, believed to encode a reversion to the neurovirulence phenotype of the 17D-204 parent virus. The amino acid substitution in the E protein at E-173 (Thr-->Ile) of the 17D(+wt) variant which results in the appearance of the wild-type-specific epitope or nucleotide changes in the 5' and 3' noncoding regions of the virus are proposed as a candidates.
Ryman
K D
KD
Center for Tropical Diseases, University of Texas Medical Branch at Galveston 77555, USA.
Xie
H
H
Ledger
T N
TN
Campbell
G A
GA
Barrett
A D
AD
D000818:Animals; D000940:Antigenic Variation; D000956:Antigens, Viral / Q000235:genetics*; D001921:Brain / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012367:RNA, Viral / Q000032:analysis; D014759:Viral Envelope Proteins / Q000235:genetics; D014774:Virulence; D015004:Yellow Fever / Q000473:pathology / Q000821:virology*; D015005:Yellow fever virus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity*
D000956:Antigens, Viral; D012367:RNA, Viral; D014759:Viral Envelope Proteins; C078400:yellow fever virus envelope protein E