Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1997 Jun;71(6):4522–4530. doi: 10.1128/jvi.71.6.4522-4530.1997

dUTPase-minus caprine arthritis-encephalitis virus is attenuated for pathogenesis and accumulates G-to-A substitutions.

P Turelli 1, F Guiguen 1, J F Mornex 1, R Vigne 1, G Quérat 1
PMCID: PMC191673  PMID: 9151845

Abstract

The importance of the virally encoded dUTPase for CAEV replication, invasiveness, pathogenesis, and genetic stability was investigated in goats infected by viruses with single point (DU-G) and deletion (DU-1) mutations of the dUTPase gene (DU gene). The DU gene was found to be dispensable for CAEV replication in vivo as judged by times taken to seroconvert, frequencies of viral isolation, and tissue distribution of viral RNAs. DU- reversion at week 34 in one of three goats infected with the single point mutant DU-G, however, suggested that the viral dUTPase confers some advantages for replication in vivo. Moreover, we show that dUTPase is necessary for the timely development of bilateral arthritic lesions of the carpus. Finally, dUTPase was shown to efficiently prevent accumulation of G-to-A transitions in the viral genome.

Full Text

The Full Text of this article is available as a PDF (869.8 KB).

Selected References

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

  1. Bouhamdan M., Benichou S., Rey F., Navarro J. M., Agostini I., Spire B., Camonis J., Slupphaug G., Vigne R., Benarous R. Human immunodeficiency virus type 1 Vpr protein binds to the uracil DNA glycosylase DNA repair enzyme. J Virol. 1996 Feb;70(2):697–704. doi: 10.1128/jvi.70.2.697-704.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Burns D. P., Desrosiers R. C. Selection of genetic variants of simian immunodeficiency virus in persistently infected rhesus monkeys. J Virol. 1991 Apr;65(4):1843–1854. doi: 10.1128/jvi.65.4.1843-1854.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cork L. C., Hadlow W. J., Crawford T. B., Gorham J. R., Piper R. C. Infectious leukoencephalomyelitis of young goats. J Infect Dis. 1974 Feb;129(2):134–141. doi: 10.1093/infdis/129.2.134. [DOI] [PubMed] [Google Scholar]
  4. Duker N. J., Grant C. L. Alterations in the levels of deoxyuridine triphosphatase, uracil-DNA glycosylase and AP endonuclease during the cell cycle. Exp Cell Res. 1980 Feb;125(2):493–497. doi: 10.1016/0014-4827(80)90145-7. [DOI] [PubMed] [Google Scholar]
  5. Elder J. H., Lerner D. L., Hasselkus-Light C. S., Fontenot D. J., Hunter E., Luciw P. A., Montelaro R. C., Phillips T. R. Distinct subsets of retroviruses encode dUTPase. J Virol. 1992 Mar;66(3):1791–1794. doi: 10.1128/jvi.66.3.1791-1794.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gendelman H. E., Narayan O., Kennedy-Stoskopf S., Kennedy P. G., Ghotbi Z., Clements J. E., Stanley J., Pezeshkpour G. Tropism of sheep lentiviruses for monocytes: susceptibility to infection and virus gene expression increase during maturation of monocytes to macrophages. J Virol. 1986 Apr;58(1):67–74. doi: 10.1128/jvi.58.1.67-74.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gibbs J. S., Lackner A. A., Lang S. M., Simon M. A., Sehgal P. K., Daniel M. D., Desrosiers R. C. Progression to AIDS in the absence of a gene for vpr or vpx. J Virol. 1995 Apr;69(4):2378–2383. doi: 10.1128/jvi.69.4.2378-2383.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gorrell M. D., Brandon M. R., Sheffer D., Adams R. J., Narayan O. Ovine lentivirus is macrophagetropic and does not replicate productively in T lymphocytes. J Virol. 1992 May;66(5):2679–2688. doi: 10.1128/jvi.66.5.2679-2688.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hoch J., Lang S. M., Weeger M., Stahl-Hennig C., Coulibaly C., Dittmer U., Hunsmann G., Fuchs D., Müller J., Sopper S. vpr deletion mutant of simian immunodeficiency virus induces AIDS in rhesus monkeys. J Virol. 1995 Aug;69(8):4807–4813. doi: 10.1128/jvi.69.8.4807-4813.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Johnson P. R., Hamm T. E., Goldstein S., Kitov S., Hirsch V. M. The genetic fate of molecularly cloned simian immunodeficiency virus in experimentally infected macaques. Virology. 1991 Nov;185(1):217–228. doi: 10.1016/0042-6822(91)90769-8. [DOI] [PubMed] [Google Scholar]
  11. Kestler H. W., 3rd, Ringler D. J., Mori K., Panicali D. L., Sehgal P. K., Daniel M. D., Desrosiers R. C. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell. 1991 May 17;65(4):651–662. doi: 10.1016/0092-8674(91)90097-i. [DOI] [PubMed] [Google Scholar]
  12. Kodama T., Mori K., Kawahara T., Ringler D. J., Desrosiers R. C. Analysis of simian immunodeficiency virus sequence variation in tissues of rhesus macaques with simian AIDS. J Virol. 1993 Nov;67(11):6522–6534. doi: 10.1128/jvi.67.11.6522-6534.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lang S. M., Weeger M., Stahl-Hennig C., Coulibaly C., Hunsmann G., Müller J., Müller-Hermelink H., Fuchs D., Wachter H., Daniel M. M. Importance of vpr for infection of rhesus monkeys with simian immunodeficiency virus. J Virol. 1993 Feb;67(2):902–912. doi: 10.1128/jvi.67.2.902-912.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lerner D. L., Wagaman P. C., Phillips T. R., Prospero-Garcia O., Henriksen S. J., Fox H. S., Bloom F. E., Elder J. H. Increased mutation frequency of feline immunodeficiency virus lacking functional deoxyuridine-triphosphatase. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7480–7484. doi: 10.1073/pnas.92.16.7480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lichtenstein D. L., Rushlow K. E., Cook R. F., Raabe M. L., Swardson C. J., Kociba G. J., Issel C. J., Montelaro R. C. Replication in vitro and in vivo of an equine infectious anemia virus mutant deficient in dUTPase activity. J Virol. 1995 May;69(5):2881–2888. doi: 10.1128/jvi.69.5.2881-2888.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mahagaokar S., Orengo A., Rao P. N. The turnover of deoxyuridine triphosphate during the HeLa cell cycle. Exp Cell Res. 1980 Jan;125(1):86–94. doi: 10.1016/0014-4827(80)90192-5. [DOI] [PubMed] [Google Scholar]
  17. McGeoch D. J. Protein sequence comparisons show that the 'pseudoproteases' encoded by poxviruses and certain retroviruses belong to the deoxyuridine triphosphatase family. Nucleic Acids Res. 1990 Jul 25;18(14):4105–4110. doi: 10.1093/nar/18.14.4105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Narayan O., Kennedy-Stoskopf S., Sheffer D., Griffin D. E., Clements J. E. Activation of caprine arthritis-encephalitis virus expression during maturation of monocytes to macrophages. Infect Immun. 1983 Jul;41(1):67–73. doi: 10.1128/iai.41.1.67-73.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Narayan O., Wolinsky J. S., Clements J. E., Strandberg J. D., Griffin D. E., Cork L. C. Slow virus replication: the role of macrophages in the persistence and expression of visna viruses of sheep and goats. J Gen Virol. 1982 Apr;59(Pt 2):345–356. doi: 10.1099/0022-1317-59-2-345. [DOI] [PubMed] [Google Scholar]
  20. Pardo E. G., Gutiérrez C. Cell cycle- and differentiation stage-dependent variation of dUTPase activity in higher plant cells. Exp Cell Res. 1990 Jan;186(1):90–98. doi: 10.1016/0014-4827(90)90214-u. [DOI] [PubMed] [Google Scholar]
  21. Pelletier E., Saurin W., Cheynier R., Letvin N. L., Wain-Hobson S. The tempo and mode of SIV quasispecies development in vivo calls for massive viral replication and clearance. Virology. 1995 Apr 20;208(2):644–652. doi: 10.1006/viro.1995.1195. [DOI] [PubMed] [Google Scholar]
  22. Peluso R., Haase A., Stowring L., Edwards M., Ventura P. A Trojan Horse mechanism for the spread of visna virus in monocytes. Virology. 1985 Nov;147(1):231–236. doi: 10.1016/0042-6822(85)90246-6. [DOI] [PubMed] [Google Scholar]
  23. Perelson A. S., Neumann A. U., Markowitz M., Leonard J. M., Ho D. D. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996 Mar 15;271(5255):1582–1586. doi: 10.1126/science.271.5255.1582. [DOI] [PubMed] [Google Scholar]
  24. Pri-Hadash A., Hareven D., Lifschitz E. A meristem-related gene from tomato encodes a dUTPase: analysis of expression in vegetative and floral meristems. Plant Cell. 1992 Feb;4(2):149–159. doi: 10.1105/tpc.4.2.149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pyles R. B., Sawtell N. M., Thompson R. L. Herpes simplex virus type 1 dUTPase mutants are attenuated for neurovirulence, neuroinvasiveness, and reactivation from latency. J Virol. 1992 Nov;66(11):6706–6713. doi: 10.1128/jvi.66.11.6706-6713.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pyles R. B., Thompson R. L. Mutations in accessory DNA replicating functions alter the relative mutation frequency of herpes simplex virus type 1 strains in cultured murine cells. J Virol. 1994 Jul;68(7):4514–4524. doi: 10.1128/jvi.68.7.4514-4524.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pyper J. M., Clements J. E., Gonda M. A., Narayan O. Sequence homology between cloned caprine arthritis encephalitis virus and visna virus, two neurotropic lentiviruses. J Virol. 1986 May;58(2):665–670. doi: 10.1128/jvi.58.2.665-670.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Saitou N., Nei M. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol. 1987 Jul;4(4):406–425. doi: 10.1093/oxfordjournals.molbev.a040454. [DOI] [PubMed] [Google Scholar]
  29. Saltarelli M., Querat G., Konings D. A., Vigne R., Clements J. E. Nucleotide sequence and transcriptional analysis of molecular clones of CAEV which generate infectious virus. Virology. 1990 Nov;179(1):347–364. doi: 10.1016/0042-6822(90)90303-9. [DOI] [PubMed] [Google Scholar]
  30. Spector R., Boose B. Development and regional distribution of deoxyuridine 5'-triphosphatase in rabbit brain. J Neurochem. 1983 Oct;41(4):1192–1195. doi: 10.1111/j.1471-4159.1983.tb09073.x. [DOI] [PubMed] [Google Scholar]
  31. Steagall W. K., Robek M. D., Perry S. T., Fuller F. J., Payne S. L. Incorporation of uracil into viral DNA correlates with reduced replication of EIAV in macrophages. Virology. 1995 Jul 10;210(2):302–313. doi: 10.1006/viro.1995.1347. [DOI] [PubMed] [Google Scholar]
  32. Terai C., Carson D. A. Pyrimidine nucleotide and nucleic acid synthesis in human monocytes and macrophages. Exp Cell Res. 1991 Apr;193(2):375–381. doi: 10.1016/0014-4827(91)90110-g. [DOI] [PubMed] [Google Scholar]
  33. Terai C., Wasson D. B., Carrera C. J., Carson D. A. Dependence of cell survival on DNA repair in human mononuclear phagocytes. J Immunol. 1991 Dec 15;147(12):4302–4306. [PubMed] [Google Scholar]
  34. Thompson J. D., Higgins D. G., Gibson T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994 Nov 11;22(22):4673–4680. doi: 10.1093/nar/22.22.4673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Threadgill D. S., Steagall W. K., Flaherty M. T., Fuller F. J., Perry S. T., Rushlow K. E., Le Grice S. F., Payne S. L. Characterization of equine infectious anemia virus dUTPase: growth properties of a dUTPase-deficient mutant. J Virol. 1993 May;67(5):2592–2600. doi: 10.1128/jvi.67.5.2592-2600.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Turelli P., Pétursson G., Guiguen F., Mornex J. F., Vigne R., Quérat G. Replication properties of dUTPase-deficient mutants of caprine and ovine lentiviruses. J Virol. 1996 Feb;70(2):1213–1217. doi: 10.1128/jvi.70.2.1213-1217.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wagaman P. C., Hasselkus-Light C. S., Henson M., Lerner D. L., Phillips T. R., Elder J. H. Molecular cloning and characterization of deoxyuridine triphosphatase from feline immunodeficiency virus (FIV). Virology. 1993 Oct;196(2):451–457. doi: 10.1006/viro.1993.1501. [DOI] [PubMed] [Google Scholar]
  38. Wain-Hobson S., Sonigo P., Guyader M., Gazit A., Henry M. Erratic G-->A hypermutation within a complete caprine arthritis-encephalitis virus (CAEV) provirus. Virology. 1995 Jun 1;209(2):297–303. doi: 10.1006/viro.1995.1261. [DOI] [PubMed] [Google Scholar]
  39. Zink M. C., Yager J. A., Myers J. D. Pathogenesis of caprine arthritis encephalitis virus. Cellular localization of viral transcripts in tissues of infected goats. Am J Pathol. 1990 Apr;136(4):843–854. [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES