Mutation in NS5 protein attenuates mouse neurovirulence of yellow fever 17D vaccine virus.
The 17D-204 vaccine manufactured in South Africa (17D-204-SA) and a large plaque variant (17D-LP) derived from it were highly virulent in adult mice. The LD50 of 17D-LP virus was 0-2 p.f.u. for mice following intracerebral inoculation. In comparison, a medium plaque variant derived from 17D-LP, termed 17D-MP virus, was found to be attenuated in adult mice following the same route of inoculation (> 10(4) p.f.u./LD50). Replication of 17D-MP virus was decreased in infected mouse brains compared to 17D-LP virus. Also, 17D-MP virus was slightly temperature sensitive at 39.5 degrees C. Compared to its parent viruses, 17D-204-SA and 17D-LP, 17D-MP virus had one unique mutation at nt 8045 in the genome which resulted in a single amino acid substitution (Pro --> Ser) at residue 137 of the NS5 protein and appeared to be the mutation responsible for the attenuation of 17D-MP virus. This is the first time that altered virulence of a flavivirus caused by mutation in a non-structural protein gene, other than NS1, has been reported.
Xie
H
H
Center for Tropical Diseases, and Department of Pathology, University of Texas Medical Branch, Galveston 77555-0605, USA.
Ryman
K D
KD
Campbell
G A
GA
Barrett
A D
AD
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000821:virology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004279:DNA, Viral; D005260:Female; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D014613:Vaccines, Attenuated; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D010948:Viral Plaque Assay; D014765:Viral Vaccines; D014774:Virulence; D015005:Yellow fever virus / Q000235:genetics / Q000472:pathogenicity*
D004279:DNA, Viral; C096041:NS5 protein, flavivirus; D014613:Vaccines, Attenuated; D017361:Viral Nonstructural Proteins; D014765:Viral Vaccines