Genetic Basis of Attenuation of the Sabin Type 2 Vaccine Strain of Poliovirus in Primates

Macadam, Andrew; Pollard, Stuart; Ferguson, Geraldine; Skuce, R. A.; Wood, David; Almond, J. W.; Pd, Minor

doi:10.1006/viro.1993.1003

Cited by 131 publications

(116 citation statements)

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“…Apart from the back mutation at position 3120, all other variable sites differed between ABCD, ABCd, and abcd. No net changes were observed at sites A 481 (in the 5Ј UTR) and U 2909 (in the VP1 region), which are known to be subject to strong negative selection when Sabin 2 replicates in the human intestine (44,49,78,79), and no changes were found at other sites known to vary upon propagation of Sabin 2 in cell culture (69).…”

Section: Vol 80 2006 Deoptimization Of Synonymous Codon Usage In Pomentioning

confidence: 94%

Modulation of Poliovirus Replicative Fitness in HeLa Cells by Deoptimization of Synonymous Codon Usage in the Capsid Region

Burns

Shaw

Campagnoli

et al. 2006

J Virol

226

282

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We replaced degenerate codons for nine amino acids within the capsid region of the Sabin type 2 oral poliovirus vaccine strain with corresponding nonpreferred synonymous codons. Codon replacements were introduced into four contiguous intervals spanning 97% of the capsid region. In the capsid region of the most highly modified virus construct, the effective number of codons used (N C ) fell from 56.2 to 29.8, the number of CG dinucleotides rose from 97 to 302, and the G؉C content increased from 48.4% to 56.4%. Replicative fitness in HeLa cells, measured by plaque areas and virus yields in single-step growth experiments, decreased in proportion to the number of replacement codons. Plaque areas decreased over an ϳ10-fold range, and virus yields decreased over an ϳ65-fold range. Perhaps unexpectedly, the synthesis and processing of viral proteins appeared to be largely unaltered by the restriction in codon usage. In contrast, total yields of viral RNA in infected cells were reduced ϳ3-fold and specific infectivities of purified virions (measured by particle/PFU ratios) decreased ϳ18-fold in the most highly modified virus. The replicative fitness of both codon replacement viruses and unmodified viruses increased with the passage number in HeLa cells. After 25 serial passages (ϳ50 replication cycles), most codon replacements were retained, and the relative fitness of the modified viruses remained well below that of the unmodified virus. The increased replicative fitness of high-passage modified virus was associated with the elimination of several CG dinucleotides. Potential applications for the systematic modulation of poliovirus replicative fitness by deoptimization of codon usage are discussed.The use of synonymous codons at unequal frequencies, the codon usage bias, is characteristic of all biological systems (26,27). The strength and direction of codon usage bias are related to the genomic GϩC content and the relative abundance of different isoaccepting tRNAs (reviewed in references 1, 16, and 53). Codon usage can affect the efficiency of gene expression. In bacteria (Escherichia coli) (26, 75), yeast (Saccharomyces cerevisiae) (5, 27), plants (Arabidopsis thaliana) (12), nematodes (Caenorhabditis elegans) (16), and insects (Drosophila melanogaster) (50), the most highly expressed genes use codons matched to the most abundant tRNAs (2). In contrast, in humans and other vertebrates, codon usage bias is much more strongly correlated with the GϩC content of the isochore where the gene is located (51, 71) than with the breadth or level of gene expression (16) or the number of corresponding tRNA genes (28, 30). Despite the weak correlation between codon usage and the levels of gene expression in mammalian cells (16,71), imbalances between codon usage and tRNA abundance can sharply reduce the levels of gene expression.Optimization of codon composition is frequently required for the efficient expression of genes in heterologous host systems (3,31,67,76). For example, the expression of human immunodeficiency virus type 1 ...

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Section: Vol 80 2006 Deoptimization Of Synonymous Codon Usage In Pomentioning

confidence: 94%

Modulation of Poliovirus Replicative Fitness in HeLa Cells by Deoptimization of Synonymous Codon Usage in the Capsid Region

Burns

Shaw

Campagnoli

et al. 2006

J Virol

226

282

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“…In the sequenced segment of the VP1 coding region (nucleotide positions 2820-2939), the 2-Is sequence was similar to that of Sabin 2 except for an U ~ C substitution which was found at position 2909. This missense mutation in the VP1 region (Ilelaa--+ Thr) is frequently encountered in type 2 vaccine-derived strains (Macadam et al, 1993). This mutation, with that at nucleotide position 481 in the 5 ' N C R is essential for reversion of the Sabin 2 vaccine noncoding region (5'NCR), structural capsid protein (VP4 to VP1) and nonstructural protein (2A to 3D) coding regions and the 3' noncoding region (3'NCR).…”

Section: Hpalimentioning

confidence: 99%

“…The restriction endonucleases used are indicated for each gel. strain towards neurovirulence (Ren et al, 1991;Macadam et al, 1993).…”

Section: Hpalimentioning

confidence: 99%

Tripartite genome organization of a natural type 2 vaccine/nonvaccine recombinant poliovirus

Georgescu

Delpeyroux²,

Crainic³

1995

Journal of General Virology

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Intertypic vaccine/vaccine recombinant polioviruses are frequently isolated from vaccine-associated paralytic poliomyelitis cases (VAPP). We identified a vaccine/ nonvaccine poliovirus recombinant as the causative agent of a lethal VAPP. Partial RNA sequencing revealed a tripartite recombinant structure of the viral genome. This consisted of a central capsid core of vaccine origin flanked by two units of nonvaccine origin. The first nonvaccine genomic unit spanned the whole 5' noncoding region, and the second one almost the entire nonstructural protein-coding region and the 3' noncoding region. Amino acid and nucleotide sequence similarities in the 3' and 5' unidentified regions indicated that the viral donor(s) were poliovirus species, suggesting recombination between a vaccine-derived and a wild poliovirus. The nonvaceine donor(s) could not be identified among the investigated wild polioviruses cocirculating in the same geographical area. This is the first report of a natural recombination event occurring in the 5' genomic extremity of poliovirus. The neurovirulence for transgenic mice and the pathogenicity for humans of the recombinant suggested that the modular genomic organization of this virus might have conferred a selective advantage over its vaccine parent.

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“…Among the best characterized attenuating mutations in the OPV Sabin strains are mutations located in the Internal Ribosome Entry Site (IRES) of the 5'-untranslated region (5'-UTR) (Minor, 1992) (Figure 3). These mutations have been identified in Sabin type 3 poliovirus (472U→C) (Cann et al, 1984), as well as type 2 (481A→G) (Macadam et al, 1993), and type 1 (480G→A and 525U→C) (Otelea et al, 1993); they are believed to selectively affect initiation of translation of viral polyprotein in neuronal cells (Guest et al, 2004;Svitkin et al, 1990). Previously was shown that the content of these revertants www.intechopen.com Viral Genomes -Molecular Structure, Diversity, Gene Expression Mechanisms and Host-Virus Interactions 188 was low in vaccine batches that failed the monkey neurovirulence test (Chumakov et al, 1991).…”

Section: Microarray Assay For Quantitation Of Known Virulent Mutationsmentioning

confidence: 99%

Microarray Techniques for Evaluation of Genetic Stability of Live Viral Vaccines

Laassri¹,

Cherkasova²,

Abu‐Asab³

et al. 2012

Viral Genomes - Molecular Structure, Diversity, Gene Expression Mechanisms and Host-Virus Interactions

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Genetic Basis of Attenuation of the Sabin Type 2 Vaccine Strain of Poliovirus in Primates

Cited by 131 publications

References 0 publications

Modulation of Poliovirus Replicative Fitness in HeLa Cells by Deoptimization of Synonymous Codon Usage in the Capsid Region

Modulation of Poliovirus Replicative Fitness in HeLa Cells by Deoptimization of Synonymous Codon Usage in the Capsid Region

Tripartite genome organization of a natural type 2 vaccine/nonvaccine recombinant poliovirus

Microarray Techniques for Evaluation of Genetic Stability of Live Viral Vaccines

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