Acquisition of the ts phenotype by a chemically mutagenized cold-passaged human respiratory syncytial virus vaccine candidate results from the acquisition of a single mutation in the polymerase (L) gene

A cold-passaged (cp) temperature-sensitive (ts) mutant of human respiratory syncytial virus designated RSV cpts-248 was previously derived by random chemical mutagenesis of the non-ts mutant cp-RSV that possesses one or more host range mutations. We previously demonstrated in rodents and seronegativ...

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Bibliographic Details
Published in:Virus genes 1996, Vol.13 (3), p.269-273
Main Authors: Crowe, Jr, J E, Firestone, C Y, Whitehead, S S, Collins, P L, Murphy, B R
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cercopithecus aethiops
Cold Temperature
DNA, Viral
DNA-Directed RNA Polymerases - genetics
Genes, Viral
Humans
Molecular Sequence Data
Mutagenesis
Phenotype
Respiratory Syncytial Virus, Human - enzymology
Respiratory Syncytial Virus, Human - genetics
Vero Cells
Viral Proteins - genetics
Viral Vaccines - genetics
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Summary:A cold-passaged (cp) temperature-sensitive (ts) mutant of human respiratory syncytial virus designated RSV cpts-248 was previously derived by random chemical mutagenesis of the non-ts mutant cp-RSV that possesses one or more host range mutations. We previously demonstrated in rodents and seronegative chimpanzees that the cpts-248 virus is more attenuated than cp-RSV and is more stable genetically than previously isolated RSV ts mutants. In the present study, we determined that the acquisition of the ts phenotype and the increased attenuation of the cpts-248 virus are associated with a single nucleotide substitution at nucleotide 10,989 that results in a change in the coding region (amino acid position 831) of the polymerase gene. The identification of this attenuating ts mutation is important because cpts-248 was used as the parent virus for the generation of a number of further attenuated mutants that are currently being evaluated as candidate vaccine strains in clinical trials in infants. Furthermore, technology now exists to rationally design new vaccine candidates by incorporating multiple attenuating mutations, such as the one identified here, into infectious viruses that are genetically stable and appropriately attenuated.
ISSN:0920-8569
1572-994X
DOI:10.1007/BF00366988