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. 1993 Dec 15;90(24):11733–11737. doi: 10.1073/pnas.90.24.11733

A translation-attenuating intraleader open reading frame is selected on coronavirus mRNAs during persistent infection.

M A Hofmann 1, S D Senanayake 1, D A Brian 1
PMCID: PMC48058  PMID: 8265618

Abstract

Short open reading frames within the 5' leader of some eukaryotic mRNAs are known to regulate the rate of translation initiation on the downstream open reading frame. By employing the polymerase chain reaction, we learned that the 5'-terminal 5 nt on the common leader sequence of bovine coronavirus subgenomic mRNAs were heterogeneous and hypervariable throughout early infection in cell culture and that as a persistent infection became established, termini giving rise to a common 33-nt intraleader open reading frame were selected. Since the common leader is derived from the genomic 5' end during transcription, a common focus of origin for the heterogeneity is expected. The intraleader open reading frame was shown by in vitro translation studies to attenuate translation of downstream open reading frames in a cloned bovine coronavirus mRNA molecule. Selection of an intraleader open reading frame resulting in a general attenuation of mRNA translation and a consequent attenuation of virus replication may, therefore, be a mechanism by which coronaviruses and possibly other RNA viruses with a similar transcriptional strategy maintain a persistent infection.

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Selected References

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

  1. Bishop D. H., Gay M. E., Matsuoko Y. Nonviral heterogeneous sequences are present at the 5' ends of one species of snowshoe hare bunyavirus S complementary RNA. Nucleic Acids Res. 1983 Sep 24;11(18):6409–6418. doi: 10.1093/nar/11.18.6409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bouloy M., Plotch S. J., Krug R. M. Globin mRNAs are primers for the transcription of influenza viral RNA in vitro. Proc Natl Acad Sci U S A. 1978 Oct;75(10):4886–4890. doi: 10.1073/pnas.75.10.4886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown T. D., Boursnell M. E., Binns M. M. A leader sequence is present on mRNA A of avian infectious bronchitis virus. J Gen Virol. 1984 Aug;65(Pt 8):1437–1442. doi: 10.1099/0022-1317-65-8-1437. [DOI] [PubMed] [Google Scholar]
  4. Brown T. D., Boursnell M. E., Binns M. M., Tomley F. M. Cloning and sequencing of 5' terminal sequences from avian infectious bronchitis virus genomic RNA. J Gen Virol. 1986 Feb;67(Pt 2):221–228. doi: 10.1099/0022-1317-67-2-221. [DOI] [PubMed] [Google Scholar]
  5. Dermody T. S., Nibert M. L., Wetzel J. D., Tong X., Fields B. N. Cells and viruses with mutations affecting viral entry are selected during persistent infections of L cells with mammalian reoviruses. J Virol. 1993 Apr;67(4):2055–2063. doi: 10.1128/jvi.67.4.2055-2063.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Garcin D., Kolakofsky D. Tacaribe arenavirus RNA synthesis in vitro is primer dependent and suggests an unusual model for the initiation of genome replication. J Virol. 1992 Mar;66(3):1370–1376. doi: 10.1128/jvi.66.3.1370-1376.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Geballe A. P., Mocarski E. S. Translational control of cytomegalovirus gene expression is mediated by upstream AUG codons. J Virol. 1988 Sep;62(9):3334–3340. doi: 10.1128/jvi.62.9.3334-3340.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hirano A., Ayata M., Wang A. H., Wong T. C. Functional analysis of matrix proteins expressed from cloned genes of measles virus variants that cause subacute sclerosing panencephalitis reveals a common defect in nucleocapsid binding. J Virol. 1993 Apr;67(4):1848–1853. doi: 10.1128/jvi.67.4.1848-1853.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hofmann M. A., Brian D. A. A PCR-enhanced method for determining the 5' end sequence of mRNAs. PCR Methods Appl. 1991 Aug;1(1):43–45. doi: 10.1101/gr.1.1.43. [DOI] [PubMed] [Google Scholar]
  10. Hofmann M. A., Brian D. A. Sequencing PCR DNA amplified directly from a bacterial colony. Biotechniques. 1991 Jul;11(1):30–31. [PubMed] [Google Scholar]
  11. Hofmann M. A., Sethna P. B., Brian D. A. Bovine coronavirus mRNA replication continues throughout persistent infection in cell culture. J Virol. 1990 Sep;64(9):4108–4114. doi: 10.1128/jvi.64.9.4108-4114.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Innis M. A., Myambo K. B., Gelfand D. H., Brow M. A. DNA sequencing with Thermus aquaticus DNA polymerase and direct sequencing of polymerase chain reaction-amplified DNA. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9436–9440. doi: 10.1073/pnas.85.24.9436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kamahora T., Soe L. H., Lai M. M. Sequence analysis of nucleocapsid gene and leader RNA of human coronavirus OC43. Virus Res. 1989 Jan;12(1):1–9. doi: 10.1016/0168-1702(89)90048-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kolakofsky D., Hacker D. Bunyavirus RNA synthesis: genome transcription and replication. Curr Top Microbiol Immunol. 1991;169:143–159. doi: 10.1007/978-3-642-76018-1_5. [DOI] [PubMed] [Google Scholar]
  15. Kozak M. An analysis of vertebrate mRNA sequences: intimations of translational control. J Cell Biol. 1991 Nov;115(4):887–903. doi: 10.1083/jcb.115.4.887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Krug R. M. Priming of influenza viral RNA transcription by capped heterologous RNAs. Curr Top Microbiol Immunol. 1981;93:125–149. doi: 10.1007/978-3-642-68123-3_6. [DOI] [PubMed] [Google Scholar]
  17. Lai M. M., Baric R. S., Brayton P. R., Stohlman S. A. Characterization of leader RNA sequences on the virion and mRNAs of mouse hepatitis virus, a cytoplasmic RNA virus. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3626–3630. doi: 10.1073/pnas.81.12.3626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lai M. M. Coronavirus: organization, replication and expression of genome. Annu Rev Microbiol. 1990;44:303–333. doi: 10.1146/annurev.mi.44.100190.001511. [DOI] [PubMed] [Google Scholar]
  19. Lapps W., Hogue B. G., Brian D. A. Sequence analysis of the bovine coronavirus nucleocapsid and matrix protein genes. Virology. 1987 Mar;157(1):47–57. doi: 10.1016/0042-6822(87)90312-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lavi E., Gilden D. H., Highkin M. K., Weiss S. R. Persistence of mouse hepatitis virus A59 RNA in a slow virus demyelinating infection in mice as detected by in situ hybridization. J Virol. 1984 Aug;51(2):563–566. doi: 10.1128/jvi.51.2.563-566.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Makino S., Lai M. M. High-frequency leader sequence switching during coronavirus defective interfering RNA replication. J Virol. 1989 Dec;63(12):5285–5292. doi: 10.1128/jvi.63.12.5285-5292.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Murray R. S., Brown B., Brian D., Cabirac G. F. Detection of coronavirus RNA and antigen in multiple sclerosis brain. Ann Neurol. 1992 May;31(5):525–533. doi: 10.1002/ana.410310511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Petersen R. B., Moustakas A., Hackett P. B. A mutation in the short 5'-proximal open reading frame on Rous sarcoma virus RNA alters virus production. J Virol. 1989 Nov;63(11):4787–4796. doi: 10.1128/jvi.63.11.4787-4796.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Petty I. T., Edwards M. C., Jackson A. O. Systemic movement of an RNA plant virus determined by a point substitution in a 5' leader sequence. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8894–8897. doi: 10.1073/pnas.87.22.8894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Raju R., Raju L., Hacker D., Garcin D., Compans R., Kolakofsky D. Nontemplated bases at the 5' ends of Tacaribe virus mRNAs. Virology. 1990 Jan;174(1):53–59. doi: 10.1016/0042-6822(90)90053-t. [DOI] [PubMed] [Google Scholar]
  26. Sawicki S. G., Sawicki D. L. Coronavirus transcription: subgenomic mouse hepatitis virus replicative intermediates function in RNA synthesis. J Virol. 1990 Mar;64(3):1050–1056. doi: 10.1128/jvi.64.3.1050-1056.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schreiber S. S., Kamahora T., Lai M. M. Sequence analysis of the nucleocapsid protein gene of human coronavirus 229E. Virology. 1989 Mar;169(1):142–151. doi: 10.1016/0042-6822(89)90050-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sedman S. A., Good P. J., Mertz J. E. Leader-encoded open reading frames modulate both the absolute and relative rates of synthesis of the virion proteins of simian virus 40. J Virol. 1989 Sep;63(9):3884–3893. doi: 10.1128/jvi.63.9.3884-3893.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Senanayake S. D., Hofmann M. A., Maki J. L., Brian D. A. The nucleocapsid protein gene of bovine coronavirus is bicistronic. J Virol. 1992 Sep;66(9):5277–5283. doi: 10.1128/jvi.66.9.5277-5283.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sethna P. B., Hofmann M. A., Brian D. A. Minus-strand copies of replicating coronavirus mRNAs contain antileaders. J Virol. 1991 Jan;65(1):320–325. doi: 10.1128/jvi.65.1.320-325.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sethna P. B., Hung S. L., Brian D. A. Coronavirus subgenomic minus-strand RNAs and the potential for mRNA replicons. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5626–5630. doi: 10.1073/pnas.86.14.5626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Shieh C. K., Soe L. H., Makino S., Chang M. F., Stohlman S. A., Lai M. M. The 5'-end sequence of the murine coronavirus genome: implications for multiple fusion sites in leader-primed transcription. Virology. 1987 Feb;156(2):321–330. doi: 10.1016/0042-6822(87)90412-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Siddell S., Wege H., ter Meulen V. The structure and replication of coronaviruses. Curr Top Microbiol Immunol. 1982;99:131–163. doi: 10.1007/978-3-642-68528-6_4. [DOI] [PubMed] [Google Scholar]
  34. Spaan W., Delius H., Skinner M., Armstrong J., Rottier P., Smeekens S., van der Zeijst B. A., Siddell S. G. Coronavirus mRNA synthesis involves fusion of non-contiguous sequences. EMBO J. 1983;2(10):1839–1844. doi: 10.1002/j.1460-2075.1983.tb01667.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Stein S. B., Zhang L., Roos R. P. Influence of Theiler's murine encephalomyelitis virus 5' untranslated region on translation and neurovirulence. J Virol. 1992 Jul;66(7):4508–4517. doi: 10.1128/jvi.66.7.4508-4517.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Stewart J. N., Mounir S., Talbot P. J. Human coronavirus gene expression in the brains of multiple sclerosis patients. Virology. 1992 Nov;191(1):502–505. doi: 10.1016/0042-6822(92)90220-J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Stohlman S. A., Baric R. S., Nelson G. N., Soe L. H., Welter L. M., Deans R. J. Specific interaction between coronavirus leader RNA and nucleocapsid protein. J Virol. 1988 Nov;62(11):4288–4295. doi: 10.1128/jvi.62.11.4288-4295.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Werner M., Feller A., Messenguy F., Piérard A. The leader peptide of yeast gene CPA1 is essential for the translational repression of its expression. Cell. 1987 Jun 19;49(6):805–813. doi: 10.1016/0092-8674(87)90618-0. [DOI] [PubMed] [Google Scholar]
  39. de Vries A. A., Chirnside E. D., Bredenbeek P. J., Gravestein L. A., Horzinek M. C., Spaan W. J. All subgenomic mRNAs of equine arteritis virus contain a common leader sequence. Nucleic Acids Res. 1990 Jun 11;18(11):3241–3247. doi: 10.1093/nar/18.11.3241. [DOI] [PMC free article] [PubMed] [Google Scholar]

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