Journal of Virology · 1991 · 165 citations · 19 references
Life SciencesInfectious DiseasesMolecular BiologyMolecular VirologyVaccinologyVirologyAnimal VirusesRodent Infectious DiseasesViral GenomicsViral InfectionsViral VaccinesDirected MutagenesisPoliovirus VaccinesVaccine Strain DevelopmentVaccine Strain SelectionViral AttenuationViral Capsid Gene Genetics
The poliovirus P2/P712 strain is an attenuated virus closely related to the type 2 Sabin vaccine strain, and prior mouse‑model studies mapped its attenuation determinants to the 5′ noncoding region and a central region encoding VP1, 2Apro, 2B, and part of 2C. The study aimed to identify specific attenuation determinants of P2/P712 by constructing recombinants with the mouse‑adapted P2/Lansing strain and determining their neurovirulence in mice. Recombinant viruses were created by inserting candidate VP1 and 5′ noncoding region sequences from the vaccine‑associated isolate P2/P117 into a P2/Lansing‑P2/P712 backbone, and neurovirulence was assessed in mice. Neurovirulence assays mapped the central attenuation determinant to VP1, revealing that A‑481 in the 5′ noncoding region and Ile‑143 in VP1 are the major determinants, which also attenuated neurovirulence in transgenic mice and represent general determinants of attenuation.
The poliovirus P2/P712 strain is an attenuated virus that is closely related to the type 2 Sabin vaccine strain. By using a mouse model for poliomyelitis, sequences responsible for attenuation of the P2/P712 strain were previously mapped to the 5' noncoding region of the genome and a central region encoding VP1, 2Apro, 2B, and part of 2C. To identify specific determinants that attenuate the P2/P712 strain, recombinants between this virus and the mouse-adapted P2/Lansing were constructed and their neurovirulence in mice was determined. By using this approach, the attenuation determinant in the central region was mapped to capsid protein VP1. Candidate attenuating sequences in VP1 and the 5' noncoding region were identified by comparing the P2/P712 sequence with that of vaccine-associated isolate P2/P117, and the P2/117 sequences were introduced into the P2/Lansing-P2/P712 recombinants by site-directed mutagenesis. Results of neurovirulence assays in mice indicate that an A at nucleotide 481 in the 5' noncoding region and isoleucine (Ile) at position 143 of capsid protein VP1 are the major determinants of attenuation of P2/P712. These determinants also attenuated neurovirulence in transgenic mice expressing human poliovirus receptors, a new model for poliomyelitis in which virulent viruses are not host restricted. These results demonstrate that A-481 and Ile-143 are general determinants of attenuation.
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A simple method of estimating 50 per cent end points
Hr Muench · Medical Entomology and Zoology · 1938 · 8.4K citations
Three-Dimensional Structure of Poliovirus at 2.9 Å Resolution
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