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. 1994 May;68(5):3364–3368. doi: 10.1128/jvi.68.5.3364-3368.1994

A single amino acid change determines persistence of a chimeric Theiler's virus.

N Jarousse 1, R A Grant 1, J M Hogle 1, L Zhang 1, A Senkowski 1, R P Roos 1, T Michiels 1, M Brahic 1, A McAllister 1
PMCID: PMC236827  PMID: 7512164

Abstract

The DA strain of Theiler's virus persists in the central nervous system of mice and causes chronic inflammation and demyelination. On the other hand, the GDVII strain causes an acute encephalitis and does not persist in surviving animals. Series of recombinants between infectious cDNA clones of the genomes of DA and GDVII viruses have been constructed. The analysis of the phenotypes of the recombinant viruses has shown that determinants of persistence and demyelination are present in the capsid proteins of DA virus. Chimeric viruses constructed by the different research groups gave consistent results, with one exception. Chimeras GD1B-2A/DAFL3 and GD1B-2C/DAFL3, which contain part of capsid protein VP2, capsid proteins VP3 and VP1, and different portions of P2 of GDVII in a DA background, were able to persist and cause demyelination. Chimera R4, whose genetic map is identical to that of GD1B-2A/DAFL3, was not. After exchanging the viral chimeras between laboratories and verifying each other's observations, new chimeras were generated in order to explain this difference. Here we report that the discrepancy can be attributed to a single amino acid difference in the sequence of the capsid protein VP2 of the two parental DA strains. DAFL3 (University of Chicago) and the chimeras derived from it, GD1B-2A/DAFL3 and GD1B-2C/DAFL3, contain a Lys at position 141, while TMDA (Institut Pasteur) and R4, the chimera derived from it, contain an Asn in that position. This amino acid is located at the tip of the EF loop, on the rim of the depression spanning the twofold axis of the capsid. These results show that a single amino acid change can confer the ability to persist and demyelinate to a chimeric Theiler's virus, and they pinpoint a region of the viral capsid that is important for this phenotype.

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Selected References

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

  1. Aubert C., Chamorro M., Brahic M. Identification of Theiler's virus infected cells in the central nervous system of the mouse during demyelinating disease. Microb Pathog. 1987 Nov;3(5):319–326. doi: 10.1016/0882-4010(87)90002-7. [DOI] [PubMed] [Google Scholar]
  2. Bureau J. F., Montagutelli X., Lefebvre S., Guénet J. L., Pla M., Brahic M. The interaction of two groups of murine genes determines the persistence of Theiler's virus in the central nervous system. J Virol. 1992 Aug;66(8):4698–4704. doi: 10.1128/jvi.66.8.4698-4704.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  4. Clatch R. J., Miller S. D., Metzner R., Dal Canto M. C., Lipton H. L. Monocytes/macrophages isolated from the mouse central nervous system contain infectious Theiler's murine encephalomyelitis virus (TMEV). Virology. 1990 May;176(1):244–254. doi: 10.1016/0042-6822(90)90249-q. [DOI] [PubMed] [Google Scholar]
  5. Dal Canto M. C., Lipton H. L. Primary demyelination in Theiler's virus infection. An ultrastructural study. Lab Invest. 1975 Dec;33(6):626–637. [PubMed] [Google Scholar]
  6. Fu J., Rodriguez M., Roos R. P. Strains from both Theiler's virus subgroups encode a determinant for demyelination. J Virol. 1990 Dec;64(12):6345–6348. doi: 10.1128/jvi.64.12.6345-6348.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Grant R. A., Filman D. J., Fujinami R. S., Icenogle J. P., Hogle J. M. Three-dimensional structure of Theiler virus. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2061–2065. doi: 10.1073/pnas.89.6.2061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Lehrich J. R., Arnason B. G., Hochberg F. H. Demyelinative myelopathy in mice induced by the DA virus. J Neurol Sci. 1976 Oct;29(2-4):149–160. doi: 10.1016/0022-510x(76)90167-2. [DOI] [PubMed] [Google Scholar]
  9. Lipton H. L. Persistent Theiler's murine encephalomyelitis virus infection in mice depends on plaque size. J Gen Virol. 1980 Jan;46(1):169–177. doi: 10.1099/0022-1317-46-1-169. [DOI] [PubMed] [Google Scholar]
  10. Lipton H. L. Theiler's virus infection in mice: an unusual biphasic disease process leading to demyelination. Infect Immun. 1975 May;11(5):1147–1155. doi: 10.1128/iai.11.5.1147-1155.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Luo M., He C., Toth K. S., Zhang C. X., Lipton H. L. Three-dimensional structure of Theiler murine encephalomyelitis virus (BeAn strain). Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2409–2413. doi: 10.1073/pnas.89.6.2409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Luo M., Vriend G., Kamer G., Minor I., Arnold E., Rossmann M. G., Boege U., Scraba D. G., Duke G. M., Palmenberg A. C. The atomic structure of Mengo virus at 3.0 A resolution. Science. 1987 Jan 9;235(4785):182–191. doi: 10.1126/science.3026048. [DOI] [PubMed] [Google Scholar]
  13. McAllister A., Tangy F., Aubert C., Brahic M. Genetic mapping of the ability of Theiler's virus to persist and demyelinate. J Virol. 1990 Sep;64(9):4252–4257. doi: 10.1128/jvi.64.9.4252-4257.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McAllister A., Tangy F., Aubert C., Brahic M. Molecular cloning of the complete genome of Theiler's virus, strain DA, and production of infectious transcripts. Microb Pathog. 1989 Nov;7(5):381–388. doi: 10.1016/0882-4010(89)90041-7. [DOI] [PubMed] [Google Scholar]
  15. Ohara Y., Stein S., Fu J. L., Stillman L., Klaman L., Roos R. P. Molecular cloning and sequence determination of DA strain of Theiler's murine encephalomyelitis viruses. Virology. 1988 May;164(1):245–255. doi: 10.1016/0042-6822(88)90642-3. [DOI] [PubMed] [Google Scholar]
  16. Ozden S., Tangy F., Chamorro M., Brahic M. Theiler's virus genome is closely related to that of encephalomyocarditis virus, the prototype cardiovirus. J Virol. 1986 Dec;60(3):1163–1165. doi: 10.1128/jvi.60.3.1163-1165.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pevear D. C., Borkowski J., Calenoff M., Oh C. K., Ostrowski B., Lipton H. L. Insights into Theiler's virus neurovirulence based on a genomic comparison of the neurovirulent GDVII and less virulent BeAn strains. Virology. 1988 Jul;165(1):1–12. doi: 10.1016/0042-6822(88)90652-6. [DOI] [PubMed] [Google Scholar]
  18. Pevear D. C., Calenoff M., Rozhon E., Lipton H. L. Analysis of the complete nucleotide sequence of the picornavirus Theiler's murine encephalomyelitis virus indicates that it is closely related to cardioviruses. J Virol. 1987 May;61(5):1507–1516. doi: 10.1128/jvi.61.5.1507-1516.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pritchard A. E., Jensen K., Lipton H. L. Assembly of Theiler's virus recombinants used in mapping determinants of neurovirulence. J Virol. 1993 Jul;67(7):3901–3907. doi: 10.1128/jvi.67.7.3901-3907.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Roos R. P., Stein S., Ohara Y., Fu J. L., Semler B. L. Infectious cDNA clones of the DA strain of Theiler's murine encephalomyelitis virus. J Virol. 1989 Dec;63(12):5492–5496. doi: 10.1128/jvi.63.12.5492-5496.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Roos R. P., Stein S., Routbort M., Senkowski A., Bodwell T., Wollmann R. Theiler's murine encephalomyelitis virus neutralization escape mutants have a change in disease phenotype. J Virol. 1989 Oct;63(10):4469–4473. doi: 10.1128/jvi.63.10.4469-4473.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Stroop W. G., Baringer J. R., Brahic M. Detection of Theiler's virus RNA in mouse central nervous system by in situ hybridization. Lab Invest. 1981 Dec;45(6):504–509. [PubMed] [Google Scholar]
  23. Tangy F., McAllister A., Aubert C., Brahic M. Determinants of persistence and demyelination of the DA strain of Theiler's virus are found only in the VP1 gene. J Virol. 1991 Mar;65(3):1616–1618. doi: 10.1128/jvi.65.3.1616-1618.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Tangy F., McAllister A., Brahic M. Molecular cloning of the complete genome of strain GDVII of Theiler's virus and production of infectious transcripts. J Virol. 1989 Mar;63(3):1101–1106. doi: 10.1128/jvi.63.3.1101-1106.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zhang L., Senkowski A., Shim B., Roos R. P. Chimeric cDNA studies of Theiler's murine encephalomyelitis virus neurovirulence. J Virol. 1993 Jul;67(7):4404–4408. doi: 10.1128/jvi.67.7.4404-4408.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Zurbriggen A., Hogle J. M., Fujinami R. S. Alteration of amino acid 101 within capsid protein VP-1 changes the pathogenicity of Theiler's murine encephalomyelitis virus. J Exp Med. 1989 Dec 1;170(6):2037–2049. doi: 10.1084/jem.170.6.2037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Zurbriggen A., Thomas C., Yamada M., Roos R. P., Fujinami R. S. Direct evidence of a role for amino acid 101 of VP-1 in central nervous system disease in Theiler's murine encephalomyelitis virus infection. J Virol. 1991 Apr;65(4):1929–1937. doi: 10.1128/jvi.65.4.1929-1937.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Zurbriggen A., Yamada M., Thomas C., Fujinami R. S. Restricted virus replication in the spinal cords of nude mice infected with a Theiler's virus variant. J Virol. 1991 Feb;65(2):1023–1030. doi: 10.1128/jvi.65.2.1023-1030.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]

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