Identification of mutations contributing to the reduced virulence of a modified strain of respiratory syncytial virus

The nucleotide sequences of the genome of the RSS-2 wild type strain of respiratory syncytial (RS) virus, which is known to induce upper respiratory tract infection in adults, and that of the attenuated ts1C candidate vaccine derived from it by three cycles of mutagenesis and selection of temperatur...

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Bibliographic Details
Published in:	Vaccine Vol. 14; no. 17; pp. 1637 - 1646
Main Authors:	Tolley, Kurt P., Marriott, Anthony C., Simpson, Anna, Plows, David J., Matthews, David A., Longhurst, Sharon J., Evans, Johanna E., Johnson, Jennifer L., Cane, Patricia A., Randolph, Valerie B., Easton, Andrew J., Pringle, Craig R.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-12-1996 Elsevier
Subjects:	Adult Animals attenuation Biological and medical sciences Bronchiolitis - virology Cloning, Molecular Codon codon usage Fundamental and applied biological sciences. Psychology Genetics Genome, Viral Humans Infant Microbiology Mutation Paramyxoviridae - genetics Reference Values respiratory syncytial virus respiratory syncytial virus genome sequence Respiratory Syncytial Virus, Human - genetics Respiratory Syncytial Virus, Human - pathogenicity Sequence Analysis, DNA Sigmodontinae Temperature-sensitive mutants vaccine Virology Virulence vaccine attenuation Temperature-sensitive mutants respiratory syncytial virus genome sequence codon usage Virus Human respiratory syncytial virus Gene Virulence Attenuation Pneumovirus Paramyxoviridae Temperature sensitive mutation
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Summary:	The nucleotide sequences of the genome of the RSS-2 wild type strain of respiratory syncytial (RS) virus, which is known to induce upper respiratory tract infection in adults, and that of the attenuated ts1C candidate vaccine derived from it by three cycles of mutagenesis and selection of temperature-sensitive (ts) mutants, have been determined. Comparison of the sequences has located the genetic changes which contribute to the reduced pathogenicity in adults of the candidate vaccine. Thirty-seven nucleotide changes distinguish the wild type and ts1C, 13 of which confer amino acid substitutions; no mutations are present in extragenic regions. Partial nucleotide sequencing of the genomes of the first stage ts mutant ( ts1A) and the second stage ts mutant ( ts1B), which were intermediates in the derivation of the third stage mutant ts1C, established that five mutations resulting in amino acid substitutions had been induced in the first cycle of mutagenesis, one in the second cycle, and seven in the third cycle. The unique mutation differentiating ts1B from ts1A substitutes an alanine for a threonine at residue 736 in the polymerase (L) protein. The occurrence of a mutation in ts1C inducing substitution of a phenylalanine for a serine residue at an adjacent site (731) suggests that mutations in this region of the polymerase can have significant attenuating effects. The data suggest also that a mutation in the F gene may contribute to the attenuated phenotype.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0264-410X 1873-2518
DOI:	10.1016/S0264-410X(96)00136-3