Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Mar 19;93(6):2370–2375. doi: 10.1073/pnas.93.6.2370

Internal ribosomal entry site substitution eliminates neurovirulence in intergeneric poliovirus recombinants.

M Gromeier 1, L Alexander 1, E Wimmer 1
PMCID: PMC39803  PMID: 8637880

Abstract

Neuropathogenicity of poliovirus can be attenuated by mutations in the internal ribosomal entry site (IRES) within the 5' nontranslated region of its genome. The Sabin vaccine strains used in prevention of poliomyelitis carry such mutations in their IRES elements. In addition, mutations within the structural and nonstructural proteins of Sabin strains may equally contribute to the attenuation phenotype. Despite their effectiveness as vaccines, the Sabin strains retain a neuropathogenic potential in animal models for poliomyelitis and, at a very low rate, they can cause poliomyelitis in vaccine recipients. The elimination of the neurocytopathic phenotype was achieved through the exchange of the entire poliovirus IRES with its counterpart from human rhinovirus type 2 without affecting growth properties in nonneuronal cells. The attenuating effect of the human rhinovirus type 2 IRES within the context of a poliovirus genome has been mapped to the 3' portion of this genetic element.

Full text

PDF
2373

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agol V. I., Drozdov S. G., Ivannikova T. A., Kolesnikova M. S., Korolev M. B., Tolskaya E. A. Restricted growth of attenuated poliovirus strains in cultured cells of a human neuroblastoma. J Virol. 1989 Sep;63(9):4034–4038. doi: 10.1128/jvi.63.9.4034-4038.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alexander L., Lu H. H., Wimmer E. Polioviruses containing picornavirus type 1 and/or type 2 internal ribosomal entry site elements: genetic hybrids and the expression of a foreign gene. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1406–1410. doi: 10.1073/pnas.91.4.1406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Borman A., Howell M. T., Patton J. G., Jackson R. J. The involvement of a spliceosome component in internal initiation of human rhinovirus RNA translation. J Gen Virol. 1993 Sep;74(Pt 9):1775–1788. doi: 10.1099/0022-1317-74-9-1775. [DOI] [PubMed] [Google Scholar]
  4. Gromeier M., Lu H. H., Wimmer E. Mouse neuropathogenic poliovirus strains cause damage in the central nervous system distinct from poliomyelitis. Microb Pathog. 1995 Apr;18(4):253–267. doi: 10.1016/S0882-4010(05)80002-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Hahn H., Palmenberg A. C. Encephalomyocarditis viruses with short poly(C) tracts are more virulent than their mengovirus counterparts. J Virol. 1995 Apr;69(4):2697–2699. doi: 10.1128/jvi.69.4.2697-2699.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hambidge S. J., Sarnow P. Translational enhancement of the poliovirus 5' noncoding region mediated by virus-encoded polypeptide 2A. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10272–10276. doi: 10.1073/pnas.89.21.10272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hellen C. U., Witherell G. W., Schmid M., Shin S. H., Pestova T. V., Gil A., Wimmer E. A cytoplasmic 57-kDa protein that is required for translation of picornavirus RNA by internal ribosomal entry is identical to the nuclear pyrimidine tract-binding protein. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7642–7646. doi: 10.1073/pnas.90.16.7642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Horie H., Koike S., Kurata T., Sato-Yoshida Y., Ise I., Ota Y., Abe S., Hioki K., Kato H., Taya C. Transgenic mice carrying the human poliovirus receptor: new animal models for study of poliovirus neurovirulence. J Virol. 1994 Feb;68(2):681–688. doi: 10.1128/jvi.68.2.681-688.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jang S. K., Davies M. V., Kaufman R. J., Wimmer E. Initiation of protein synthesis by internal entry of ribosomes into the 5' nontranslated region of encephalomyocarditis virus RNA in vivo. J Virol. 1989 Apr;63(4):1651–1660. doi: 10.1128/jvi.63.4.1651-1660.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jang S. K., Kräusslich H. G., Nicklin M. J., Duke G. M., Palmenberg A. C., Wimmer E. A segment of the 5' nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J Virol. 1988 Aug;62(8):2636–2643. doi: 10.1128/jvi.62.8.2636-2643.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jang S. K., Pestova T. V., Hellen C. U., Witherell G. W., Wimmer E. Cap-independent translation of picornavirus RNAs: structure and function of the internal ribosomal entry site. Enzyme. 1990;44(1-4):292–309. doi: 10.1159/000468766. [DOI] [PubMed] [Google Scholar]
  12. Jang S. K., Wimmer E. Cap-independent translation of encephalomyocarditis virus RNA: structural elements of the internal ribosomal entry site and involvement of a cellular 57-kD RNA-binding protein. Genes Dev. 1990 Sep;4(9):1560–1572. doi: 10.1101/gad.4.9.1560. [DOI] [PubMed] [Google Scholar]
  13. Koike S., Taya C., Kurata T., Abe S., Ise I., Yonekawa H., Nomoto A. Transgenic mice susceptible to poliovirus. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):951–955. doi: 10.1073/pnas.88.3.951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. La Monica N., Racaniello V. R. Differences in replication of attenuated and neurovirulent polioviruses in human neuroblastoma cell line SH-SY5Y. J Virol. 1989 May;63(5):2357–2360. doi: 10.1128/jvi.63.5.2357-2360.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lu H. H., Yang C. F., Murdin A. D., Klein M. H., Harber J. J., Kew O. M., Wimmer E. Mouse neurovirulence determinants of poliovirus type 1 strain LS-a map to the coding regions of capsid protein VP1 and proteinase 2Apro. J Virol. 1994 Nov;68(11):7507–7515. doi: 10.1128/jvi.68.11.7507-7515.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Meerovitch K., Svitkin Y. V., Lee H. S., Lejbkowicz F., Kenan D. J., Chan E. K., Agol V. I., Keene J. D., Sonenberg N. La autoantigen enhances and corrects aberrant translation of poliovirus RNA in reticulocyte lysate. J Virol. 1993 Jul;67(7):3798–3807. doi: 10.1128/jvi.67.7.3798-3807.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mendelsohn C. L., Wimmer E., Racaniello V. R. Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell. 1989 Mar 10;56(5):855–865. doi: 10.1016/0092-8674(89)90690-9. [DOI] [PubMed] [Google Scholar]
  18. Molla A., Jang S. K., Paul A. V., Reuer Q., Wimmer E. Cardioviral internal ribosomal entry site is functional in a genetically engineered dicistronic poliovirus. Nature. 1992 Mar 19;356(6366):255–257. doi: 10.1038/356255a0. [DOI] [PubMed] [Google Scholar]
  19. Nomoto A., Omata T., Toyoda H., Kuge S., Horie H., Kataoka Y., Genba Y., Nakano Y., Imura N. Complete nucleotide sequence of the attenuated poliovirus Sabin 1 strain genome. Proc Natl Acad Sci U S A. 1982 Oct;79(19):5793–5797. doi: 10.1073/pnas.79.19.5793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pelletier J., Sonenberg N. Internal binding of eucaryotic ribosomes on poliovirus RNA: translation in HeLa cell extracts. J Virol. 1989 Jan;63(1):441–444. doi: 10.1128/jvi.63.1.441-444.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pelletier J., Sonenberg N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature. 1988 Jul 28;334(6180):320–325. doi: 10.1038/334320a0. [DOI] [PubMed] [Google Scholar]
  22. Ren R. B., Costantini F., Gorgacz E. J., Lee J. J., Racaniello V. R. Transgenic mice expressing a human poliovirus receptor: a new model for poliomyelitis. Cell. 1990 Oct 19;63(2):353–362. doi: 10.1016/0092-8674(90)90168-e. [DOI] [PubMed] [Google Scholar]
  23. Ren R., Racaniello V. R. Human poliovirus receptor gene expression and poliovirus tissue tropism in transgenic mice. J Virol. 1992 Jan;66(1):296–304. doi: 10.1128/jvi.66.1.296-304.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sonenberg N. Poliovirus translation. Curr Top Microbiol Immunol. 1990;161:23–47. doi: 10.1007/978-3-642-75602-3_2. [DOI] [PubMed] [Google Scholar]
  25. Sutter R. W., Patriarca P. A., Brogan S., Malankar P. G., Pallansch M. A., Kew O. M., Bass A. G., Cochi S. L., Alexander J. P., Hall D. B. Outbreak of paralytic poliomyelitis in Oman: evidence for widespread transmission among fully vaccinated children. Lancet. 1991 Sep 21;338(8769):715–720. doi: 10.1016/0140-6736(91)91442-w. [DOI] [PubMed] [Google Scholar]
  26. Wimmer E., Hellen C. U., Cao X. Genetics of poliovirus. Annu Rev Genet. 1993;27:353–436. doi: 10.1146/annurev.ge.27.120193.002033. [DOI] [PubMed] [Google Scholar]
  27. Yin F. H., Lomax N. B. Host range mutants of human rhinovirus in which nonstructural proteins are altered. J Virol. 1983 Nov;48(2):410–418. doi: 10.1128/jvi.48.2.410-418.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES