Coronavirus Replication, Transcription, and RNA Recombination

  • Robbert G. van der Most
  • Willy J. M. Spaan
Part of the The Viruses book series (VIRS)


With the advent of recombinant DNA technology, our knowledge of the transcription and replication processes of positive-strand RNA viruses has increased profoundly. A major breakthrough in this field has been the development of full-length cDNA clones from which infectious RNA transcripts can be made. Such clones have now been constructed for members of the Picorna-(Racaniello and Baltimore, 1981), Biomo- (Ahlquist et al., 1984), Alpha- (Rice et al., 1987) and Flaviviridae (Lai et al., 1991; Rice et al., 1989). Unfortunately, the enormous length of the coronavirus genome has hampered the construction of a full-length cDNA clone so far.


Infectious Bronchitis Virus Mouse Hepatitis Virus Negative Strand Brome Mosaic Virus Feline Infectious Peritonitis Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ahlquist, P., French, R., Janda, M., and Loesch-Fries, L. S., 1984, Multicomponent RNA plant virus infection derived from cloned viral cDNA, Proc. Natl. Acad. Sci. USA 81:7066.PubMedCrossRefGoogle Scholar
  2. Allison, R., Thompson, C., and Ahlquist, P., 1990, Regeneration of a functional RNA virus genome by recombination between deletion mutants and requirement for cowpea chlorotic mottle virus 3a and coat proteins for systemic infection, Proc. Natl. Acad. Sci. USA 87:1820.PubMedCrossRefGoogle Scholar
  3. Andino, R., Rieckhof, G. E., Achacoso, P. L., and Baltimore, D., 1993, Poliovirus RNA synthesis utilizes an RNP complex formed around the 5’-end of viral RNA, EMBO J. 12:3587.PubMedGoogle Scholar
  4. Armstrong, J., Niemann, H., Smeekens, S., Rottier, P., and Warren, G., 1984, Sequence and topology of a model intracellular membrane protein, El glycoprotein, from a coronavirus, Nature 308:751.PubMedCrossRefGoogle Scholar
  5. Baker, S. C., and Lai, M. M., 1990, An in vitro system for the leader-primed transcription of coronavirus mRNAs, EMBO J. 9:4173.PubMedGoogle Scholar
  6. Baker, S. C., Shieh, C. K., Soe, L. H., Chang, M. F., Vannier, D. M., and Lai, M. M., 1989, Identification of a domain required for autoproteolytic cleavage of murine coronavirus gene A polypro-tein, J. Virol. 63:3693.PubMedGoogle Scholar
  7. Baker, S. C., Yokomori, K., Dong, S., Carlisle, R., Gorbalenya, A. E., Koonin, E. V., and Lai, M. M. C., 1993, Identification of the catalytic sites of a papain-like cysteine proteinase of murine coronavirus, J. Virol. 67:6056.PubMedGoogle Scholar
  8. Banner, L. R., and Lai, M. M., 1991, Random nature of coronavirus RNA recombination in the absence of selection pressure, Virology 185:441.PubMedCrossRefGoogle Scholar
  9. Banner, L. R., Keck, J. G., and Lai, M. M. C., 1990, A clustering of RNA recombination sites adjacent to a hypervariable region of the peplomer gene of murine coronavirus, Virology 175:548.PubMedCrossRefGoogle Scholar
  10. Baric, R. S., Stohlman, S. A., Razavi, M. K., and Lai, M. M., 1985, Characterization of leader-related small RNAs in coronavirus-infected cells: Further evidence for leader-primed mechanism of transcription, Virus. Res. 3:19.PubMedCrossRefGoogle Scholar
  11. Baric, R. S., Shieh, C. K., Stohlman, S. A., and Lai, M. M., 1987, Analysis of intracellular small RNAs of mouse hepatitis virus: evidence for discontinuous transcription, Virology 156:342.PubMedCrossRefGoogle Scholar
  12. Baric, R. S., Fu, K., Schaad, M. C., and Stohlman, S. A., 1990, Establishing a genetic recombination map for murine coronavirus strain A59 complementation groups, Virology 177:646.PubMedCrossRefGoogle Scholar
  13. Brian, D. A., Chang, R.-Y., Hofmann, M. A., and Sethna, P. B., 1994, Role of subgenomic minus-strand RNA in coronavirus replication, Arch. Virol. (Suppl.) 9:173.Google Scholar
  14. Budzilowicz, C. J., Wilczynski, S. P., and Weiss, S. R., 1985, Three intergenic regions of coronavirus mouse hepatitis virus strain A59 genome RNA contain a common nucleotide sequence that is homologous to the 3’ end of the viral mRNA leader sequence, J. Virol. 53:834.PubMedGoogle Scholar
  15. Bujarski, J. J., and Kaesberg, P., 1986, Genetic recombination in a multipartite plant virus, Nature 321:528.PubMedCrossRefGoogle Scholar
  16. Cooper, P. D., 1968, A genetic map of poliovirus temperature-sensitive mutants, Virology 35:584.PubMedCrossRefGoogle Scholar
  17. de Groot, R. J., ter Haar, R. J., Horzinek, M. C., and van der Zeijst, B. A. M., 1987, Intracellular RNAs of the feline infectious peritonitis coronavirus strain 79–1146, J. Gen. Virol. 68:995.PubMedCrossRefGoogle Scholar
  18. de Groot, R. J., van der Most, R. G., and Spaan, W. J. M., 1992, The fitness of defective interfering murine coronavirus DI-a and its derivatives is decreased by nonsense and frameshift mutations, J. Virol. 66:5898.PubMedGoogle Scholar
  19. Denison, M., and Perlman, S., 1987, Identification of putative polymerase gene product in cells infected with murine coronavirus A59, Virology 157:565.PubMedCrossRefGoogle Scholar
  20. Denison, M. R., Zoltick, P. W., Leibowitz, J. L., Pachuk, C. J., and Weiss, S. R., 1991, Identification of polypeptides encoded in open reading frame-1b of the putative polymerase gene of the murine coronavirus mouse hepatitis virus-a59, J. Virol. 65:3076.PubMedGoogle Scholar
  21. Denison, M. R., Zoltick, P. W., Hughes, S. A., Giangreco, B., Olson, A. L., Perlman, S., Leibowitz, J. L., and Weiss, S. R., 1992, Intracellular processing of the N-terminal ORF la proteins of the coronavirus MHV-A59 requires multiple proteolytic events, Virology 189:274.PubMedCrossRefGoogle Scholar
  22. Fosmire, J. A., Hwang, K., and Makino, S., 1992, Identification and characterization of a coronavirus packaging signal, J. Virol. 66:3522.PubMedGoogle Scholar
  23. French, R., and Ahlquist, P., 1988, Characterization and engineering of sequences controlling in vitro synthesis of brome mosaic virus subgenomic RNA, J. Virol. 62:2411.PubMedGoogle Scholar
  24. Fuerst, T. R., Niles, E. G., Studier, F. W., and Moss, B., 1986, Eukaryotic transient-expression system based on recombinant vaccinia virus that synthesizes bacteriophage T7 RNA polymerase, Proc. Natl. Acad. Sci. USA 83:8122.PubMedCrossRefGoogle Scholar
  25. Fumya, T., and Lai, M. M. C., 1993, Three different cellular proteins bind to complementary sites of the 5’-end-positive and 3’-end-negative strands of mouse hepatitis virus RNA, J. Virol. 67:7215.Google Scholar
  26. Hofmann, M. A., Sethna, P. B., and Brian, D. A., 1990, Bovine coronavirus mRNA replication continues throughout persistent infection in cell culture, J. Virol. 64:4108.PubMedGoogle Scholar
  27. Hofmann, M. A., Chang, R.-Y., Ku, S., and Brian, D. A., 1993, Leader-mRNA junction sequences are unique for each subgenomic mRNA species in the bovine coronavirus and remain so throughout persistent infection, Virology 196:163.PubMedCrossRefGoogle Scholar
  28. Jacobs, L., Spaan, W. J. M., Horzinek, M. C., and van der Zeijst, B. A. M., 1981, Synthesis of subgenomic mRNAs of mouse hepatitis virus is initiated independently: Evidence from UV transcription mapping, J. Virol. 39:401.PubMedGoogle Scholar
  29. Jarvis, T. C., and Kirkegaard, K., 1991, The polymerase in its labyrinth: Mechanisms and implications of RNA recombination, Trends Genet. 7(6):186.PubMedCrossRefGoogle Scholar
  30. Jarvis, T. C., and Kirkegaard, K., 1992, Poliovirus RNA recombination: Mechanistic studies in the absence of selection, EMBO J. 11:3135.PubMedGoogle Scholar
  31. Jeong, Y. S., and Makino, S., 1992, Mechanism of coronavirus transcription: Duration of primary transcription initiation activity and effects of subgenomic RNA transcription on RNA replication, J. Virol. 66:3339.PubMedGoogle Scholar
  32. Jeong, Y. S., and Makino, S., 1994, Evidence for coronavirus discontinuous transcription, J. Virol. 68:2615.PubMedGoogle Scholar
  33. Joo, M., and Makino, S., 1992, Mutagenic analysis of the coronavirus intergenic consensus sequence, J. Virol. 66:6330.PubMedGoogle Scholar
  34. Keck, J. G., Matsushima, G. K., Makino, S., Fleming, J. O., Vannier, D. M., Stohlman, S. A., and Lai, M. M., 1988a, In vivo RNA-RNA recombination of coronavirus in mouse brain, J. Virol. 62:1810.PubMedGoogle Scholar
  35. Keck, J. G., Soe, L. H., Makino, S., Stohlman, S. A., and Lai, M. M., 1988b, RNA recombination of murine corona viruses: recombination between fusion-positive mouse hepatitis virus A59 and fusion-negative mouse hepatitis virus 2, J. Virol. 62:1989.Google Scholar
  36. Kim, Y.-N., Jeong, Y. S., and Makino, S., 1993a, Analysis of cis-acting sequences essential for coronavirus defective interfering RNA replication, Virology 197:53.PubMedCrossRefGoogle Scholar
  37. Kim, Y.-N., Lai, M. M. C., and Makino, S., 1993b, Generation and selection of coronavirus defective interfering RNA with large open reading frame by RNA recombination and possible editing, Virology 194:244.PubMedCrossRefGoogle Scholar
  38. King, A. M., McCahon, D., Slade, W. R., and Newman, J. W., 1982, Recombination in RNA, Cell 29:921.PubMedCrossRefGoogle Scholar
  39. Kirkegaard, K., and Baltimore, D., 1986, The mechanism of RNA recombination in poliovirus, Cell 47:433.PubMedCrossRefGoogle Scholar
  40. Koetzner, C. A., Parker, M. M., Ricard, C. S., Sturman, L. S., and Masters, P. S., 1992, Repair and mutagenesis of the genome of a deletion mutant of the coronavirus mouse hepatitis virus by targeted RNA recombination, J. Virol. 66:1841.PubMedGoogle Scholar
  41. Konings, D. A. M., Bredenbeek, P. J., Noten, J. F. H., Hogeweg, P., and Spaan, W. J. M., 1988, Differential premature termination of transcription as a proposed mechanism for the regulation of coronavirus gene expression, Nucleic Acids Res. 16:10849.PubMedCrossRefGoogle Scholar
  42. Kusters, J. G., Jager, E. J., Niesters, H. G., and van der Zeijst, B. A., 1990, Sequence evidence for RNA recombination in field isolates of avian coronavirus infectious bronchitis virus, Vaccine 8:605.PubMedCrossRefGoogle Scholar
  43. Lai, C.-J., Zhao, B., Hori, H., and Bray, M., 1991, Infectious RNA transcribed from stably cloned full-length cDNA of dengue type 4 virus, Proc. Natl. Acad. Sci. USA 88:5139.PubMedCrossRefGoogle Scholar
  44. Lai, M. M. C., 1990, Coronavirus—organization, replication and expression of genome, Annu. Rev. Microbiol. 44:303.PubMedCrossRefGoogle Scholar
  45. Lai, M. M. C., 1992, RNA recombination in animal and plant viruses, Microbiol. Rev. 56:61.PubMedGoogle Scholar
  46. Lai, M. M. C., Patton, C. D., and Stohlman, S. A., 1982, Replication of mouse hepatitis virus: Negative-stranded RNA and replicative form RNA are of genome length, J. Virol. 44:487.PubMedGoogle Scholar
  47. Lai, M. M., Baric, R. S., Brayton, P. R., and Stohlman, S. A., 1984, Characterization of leader RNA sequences on the virion and mRNAs of mouse hepatitis virus, a cytoplasmic RNA virus, Proc. Natl. Acad. Sci. USA 81:3626.PubMedCrossRefGoogle Scholar
  48. Lai, M. M., Baric, R. S., Makino, S., Keck, J. G., Egbert, J., Leibowitz, J. L., and Stohlman, S. A., 1985, Recombination between nonsegmented RNA genomes of murine coronaviruses, J. Virol. 56:449.PubMedGoogle Scholar
  49. La Monica, N., Yokomori, K., and Lai, M. M., 1992, Coronavirus mRNA synthesis: Identification of novel transcription initiation signals which are differentially regulated by different leader sequences, Virology 188:402.PubMedCrossRefGoogle Scholar
  50. Lemm, J. A., and Rice, C. M., 1993a, Assembly of functional Sindbis virus RNA replication complexes: Requirement for coexpression of pl23 and p34, J. Virol. 67:1905.PubMedGoogle Scholar
  51. Lemm, J. A., and Rice, C. M., 1993b, Roles of nonstructural polyproteins and cleavage products in regulating Sindbis virus RNA replication and transcription, J. Virol. 67:1916.PubMedGoogle Scholar
  52. Liao, C. L., and Lai, M. M., 1992, RNA recombination in a coronavirus: Recombination between viral genomic RNA and transfected RNA fragments, J. Virol. 66:6117.PubMedGoogle Scholar
  53. Lin, Y.-J., and Lai, M. M. C., 1993, Deletion mapping of a mouse hepatitis virus defective interfering RNA reveals the requirement of an internal and discontinuous sequence for replication, J. Virol. 67:6110.PubMedGoogle Scholar
  54. Lin, Y.-J., Liao, C.-L., and Lai, M. M. C., 1994, Identification of the cis-acting signal for minus-strand RNA synthesis of a murine coronavirus: Implications for the role of minus-strand RNA in RNA replication and transcription, J. Virol. 68:8131.PubMedGoogle Scholar
  55. Makino, S., and Joo, M., 1993, Effect of intergenic consensus sequence flanking sequences on coronavirus transcription, J. Virol. 67:3304.PubMedGoogle Scholar
  56. Makino, S., and Lai, M. M. C., 1989a, High-frequency leader sequence switching during coronavirus defective interfering RNA replication, J. Virol. 63:5285.PubMedGoogle Scholar
  57. Makino, S., and Lai, M. M. C., 1989b, Evolution of the 5’-end of genomic RNA of murine coronaviruses during passages in vitro, Virology 169:227.CrossRefGoogle Scholar
  58. Makino, S., Fujioka, N., and Fujiwara, K., 1985, Structure of the intracellular defective viral RNAs of defective interfering particles of mouse hepatitis virus, J. Virol. 54:329.PubMedGoogle Scholar
  59. Makino, S., Stohlman, S. A., and Lai, M. M., 1986a, Leader sequences of murine coronavirus mRNAs can be freely reassorted: Evidence for the role of free leader RNA in transcription, Proc. Natl. Acad. Sci. USA 83:4204.PubMedCrossRefGoogle Scholar
  60. Makino, S., Keck, J. G., Stohlman, S. A., and Lai, M. M., 1986b, High-frequency RNA recombination of murine coronaviruses, J. Virol 57:729.PubMedGoogle Scholar
  61. Makino, S., Fleming, J. O., Keck, J. G., Stohlman, S. A., and Lai, M. M., 1987, RNA recombination of coronaviruses: Localization of neutralizing epitopes and neuropathogenic determinants on the carboxyl terminus of peplomers, Proc. Natl. Acad. Sci. USA 84:6567.PubMedCrossRefGoogle Scholar
  62. Makino, S., Shieh, C. K., Soe, L. H., Baker, S. C., and Lai, M. M., 1988a, Primary structure and translation of a defective interfering RNA of murine coronavirus, Virology 166:550.PubMedCrossRefGoogle Scholar
  63. Makino, S., Soe, L. H., Shieh, C., and Lai, M. M. C., 1988b, Discontinuous transcription generates heterogeneity at the leader fusion sites of coronavirus mRNAs, J. Virol. 62:3870.PubMedGoogle Scholar
  64. Makino, S., Yokomori, K., and Lai, M. M., 1990, Analysis of efficiently packaged defective interfering RNAs of murine coronavirus: Localization of a possible RNA-packaging signal, J. Virol. 64:6045.PubMedGoogle Scholar
  65. Makino, S., Joo, M., and Makino, J. K., 1991, A system for study of coronavirus mRNA synthesis: A regulated, expressed subgenomic defective interfering RNA results from intergenic site insertion, J. Virol. 65:6031.PubMedGoogle Scholar
  66. Masters, P. S., Koetzner, C. A., Kerr, C. A., and Heo, Y., 1994, Optimization of targeted RNA recombination and mapping of a novel nucleocapsid gene mutation in the coronavirus mouse hepatitis virus, J. Virol. 68:328.PubMedGoogle Scholar
  67. Racaniello, V. R., and Baltimore, D., 1981, Cloned poliovirus complementary DNA is infectious in mammalian cells, Science 214:916.PubMedCrossRefGoogle Scholar
  68. Rice, C. M., Levis, R., Strauss, J. H., and Huang, H. V., 1987, Production of infectious RNA transcripts from Sindbis virus cDNA clones: Mapping of lethal mutations, rescue of a temperature-sensitive marker, and in vitro mutagenesis to generate defined mutants, J. Virol. 61:3809.PubMedGoogle Scholar
  69. Rice, C. M., Grakoui, A., Galler, R., and Chambers, T. J., 1989, Transcription of infectious yellow fever virus RNA from full-length cDNA templates produced by in vitro ligation, New Biol. 1:285.PubMedGoogle Scholar
  70. Sawicki, S. G., and Sawicki, D. L., 1990, Coronavirus transcription: Subgenomic mouse hepatitis virus replicative intermediates function in RNA synthesis, J. Virol. 64:1050.PubMedGoogle Scholar
  71. Schaad, M. C., and Baric, R. S., 1994, Genetics of mouse hepatitis virus transcription: Evidence that subgenomic negative strands are functional templates, J. Virol. 68:8169.PubMedGoogle Scholar
  72. Sethna, B. P., Hung, S.-L., and Brian, D. A., 1989, Coronavirus subgenomic minus-strand RNAs and the potential for mRNA replicons, Proc. Natl. Acad. Sci. USA 86:5626.PubMedCrossRefGoogle Scholar
  73. Sethna, P. B., Hofmann, M. A., and Brian, D. A., 1991, Minus-strand copies of replicating coronavirus messenger RNAs contain antileaders, J. Virol. 65:320.PubMedGoogle Scholar
  74. Shieh, C. K., Soe, L. H., Makino, S., Chang, M. F., Stohlman, S. A., and Lai, M. M., 1987, The 5’-end sequence of the murine coronavirus genome: Implications for multiple fusion sites in leader- primed transcription, Virology 156:321.PubMedCrossRefGoogle Scholar
  75. Shieh, C. K., Lee, H. J., Yokomori, K., La Monica, N., Makino, S., and Lai, M. M., 1989, Identification of a new transcriptional initiation site and the corresponding functional gene 2b in the murine coronavirus RNA genome, J. Virol. 63:3729.PubMedGoogle Scholar
  76. Spaan, W., Delius, H., Skinner, M., Armstrong, J., Rottier, P., Smeekens, S., van der Zeijst, B. A. M., and Siddell, S. G., 1983, Coronavirus mRNA synthesis involves fusion of non-contiguous sequences, EMBO J. 2:1839.PubMedGoogle Scholar
  77. Spaan, W., Cavanagh, D., and Horzinek, M. C., 1988, coronaviruses: Structure and genome expression, J. Gen. Virol. 69:2939.PubMedCrossRefGoogle Scholar
  78. Stern, D. F., and Sefton, B. M., 1982, Synthesis of coronavirus mRNAs: Kinetics of inactivation of infectious bronchitis virus RNA synthesis by UV light, J. Virol. 42:755.PubMedGoogle Scholar
  79. van der Most, R. G., Bredenbeek, P. J., and Spaan, W. J., 1991, A domain at the 3’ end of the polymerase gene is essential for encapsidation of coronavirus defective interfering RNAs, J. Virol. 65:3219.PubMedGoogle Scholar
  80. van der Most, R. G., Heijnen, L., Spaan, W. J. M., and de Groot, R. J., 1992, Homologous RNA recombination allows efficient introduction of site-specific mutations into the genome of coronavirus MHV-A59 via synthetic co-replicating RNAs, Nucleic Acids Res. 20:3375.PubMedCrossRefGoogle Scholar
  81. van der Most, R. G., de Groot, R. J., and Spaan, W. J. M., 1994, Subgenomic RNA synthesis directed by a synthetic defective interfering RNA of mouse hepatitis virus: A study of coronavirus transcription initiation, J. Virol. 68:3656–3666.PubMedGoogle Scholar
  82. Weiss, S. R., Hughes, S. A., Bonilla, P. J., Turner, J. D., Leibowitz, J. L., and Denison, M. R., 1994, coronavirus polyprotein processing, Arch. Virol. (Suppl.) 9:349.Google Scholar
  83. Zhang, X., Liao, C.-L. and Lai, M. M.C. , 1994, coronavirus leader RNA regulates and initiates subgenomic mRNA transcription both in trans and in cis, J. Virol. 68:4738.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Robbert G. van der Most
    • 1
  • Willy J. M. Spaan
    • 1
  1. 1.Department of Virology, Institute of Medical MicrobiologyLeiden UniversityLeidenThe Netherlands

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