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. 1996 Jun;70(6):3947–3960. doi: 10.1128/jvi.70.6.3947-3960.1996

Molecular anatomy of mouse hepatitis virus persistence: coevolution of increased host cell resistance and virus virulence.

W Chen 1, R S Baric 1
PMCID: PMC190273  PMID: 8648732

Abstract

Persistent infection of murine astrocytoma (DBT) cells with mouse hepatitis virus (MHV) has been established. From this in vitro virus-host system, persistence is mediated at the level of cellular MHV receptor (MHVR) expression and increased virus virulence. MHV persistence selects for resistant host cell populations which abate virus replication. Reductions in MHVR expression were significantly associated with increased host resistance, and transfection of MHVR into resistant host cells completely restored the capacity of cells to support efficient replication of MHV strain A59. The emergence of resistant host cells coselected for variant viruses that had increased avidity for MHVR and also recognized different receptors for entry into resistant cells. These data illustrate that MHV persistence in vitro provides a model to identify critical sites of virus-host interaction at the cellular level which are altered during the evolution of host cell resistance to viral infection and the coevolution of virus virulence.

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Selected References

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  1. Ahmed R., Hahn C. S., Somasundaram T., Villarete L., Matloubian M., Strauss J. H. Molecular basis of organ-specific selection of viral variants during chronic infection. J Virol. 1991 Aug;65(8):4242–4247. doi: 10.1128/jvi.65.8.4242-4247.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Apple R. J., Erlich H. A., Klitz W., Manos M. M., Becker T. M., Wheeler C. M. HLA DR-DQ associations with cervical carcinoma show papillomavirus-type specificity. Nat Genet. 1994 Feb;6(2):157–162. doi: 10.1038/ng0294-157. [DOI] [PubMed] [Google Scholar]
  3. Baybutt H. N., Wege H., Carter M. J., ter Meulen V. Adaptation of coronavirus JHM to persistent infection of murine sac(-) cells. J Gen Virol. 1984 May;65(Pt 5):915–924. doi: 10.1099/0022-1317-65-5-915. [DOI] [PubMed] [Google Scholar]
  4. Black F. L. Why did they die? Science. 1992 Dec 11;258(5089):1739–1740. doi: 10.1126/science.1465610. [DOI] [PubMed] [Google Scholar]
  5. Borzakian S., Couderc T., Barbier Y., Attal G., Pelletier I., Colbère-Garapin F. Persistent poliovirus infection: establishment and maintenance involve distinct mechanisms. Virology. 1992 Feb;186(2):398–408. doi: 10.1016/0042-6822(92)90005-a. [DOI] [PubMed] [Google Scholar]
  6. Borzakian S., Pelletier I., Calvez V., Colbere-Garapin F. Precise missense and silent point mutations are fixed in the genomes of poliovirus mutants from persistently infected cells. J Virol. 1993 May;67(5):2914–2917. doi: 10.1128/jvi.67.5.2914-2917.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Boyle J. F., Weismiller D. G., Holmes K. V. Genetic resistance to mouse hepatitis virus correlates with absence of virus-binding activity on target tissues. J Virol. 1987 Jan;61(1):185–189. doi: 10.1128/jvi.61.1.185-189.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Burks J. S., DeVald B. L., Jankovsky L. D., Gerdes J. C. Two coronaviruses isolated from central nervous system tissue of two multiple sclerosis patients. Science. 1980 Aug 22;209(4459):933–934. doi: 10.1126/science.7403860. [DOI] [PubMed] [Google Scholar]
  9. Chen W., Baric R. S. Function of a 5'-end genomic RNA mutation that evolves during persistent mouse hepatitis virus infection in vitro. J Virol. 1995 Dec;69(12):7529–7540. doi: 10.1128/jvi.69.12.7529-7540.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Compton S. R. Enterotropic strains of mouse coronavirus differ in their use of murine carcinoembryonic antigen-related glycoprotein receptors. Virology. 1994 Aug 15;203(1):197–201. doi: 10.1006/viro.1994.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Delmas B., Gelfi J., L'Haridon R., Vogel L. K., Sjöström H., Norén O., Laude H. Aminopeptidase N is a major receptor for the entero-pathogenic coronavirus TGEV. Nature. 1992 Jun 4;357(6377):417–420. doi: 10.1038/357417a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dermody T. S., Chappell J. D., Hofler J. G., Kramp W., Tyler K. L. Eradication of persistent reovirus infection from a B-cell hybridoma. Virology. 1995 Sep 10;212(1):272–276. doi: 10.1006/viro.1995.1483. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Dveksler G. S., Basile A. A., Cardellichio C. B., Holmes K. V. Mouse hepatitis virus receptor activities of an MHVR/mph chimera and MHVR mutants lacking N-linked glycosylation of the N-terminal domain. J Virol. 1995 Jan;69(1):543–546. doi: 10.1128/jvi.69.1.543-546.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dveksler G. S., Dieffenbach C. W., Cardellichio C. B., McCuaig K., Pensiero M. N., Jiang G. S., Beauchemin N., Holmes K. V. Several members of the mouse carcinoembryonic antigen-related glycoprotein family are functional receptors for the coronavirus mouse hepatitis virus-A59. J Virol. 1993 Jan;67(1):1–8. doi: 10.1128/jvi.67.1.1-8.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dveksler G. S., Pensiero M. N., Cardellichio C. B., Williams R. K., Jiang G. S., Holmes K. V., Dieffenbach C. W. Cloning of the mouse hepatitis virus (MHV) receptor: expression in human and hamster cell lines confers susceptibility to MHV. J Virol. 1991 Dec;65(12):6881–6891. doi: 10.1128/jvi.65.12.6881-6891.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Dveksler G. S., Pensiero M. N., Dieffenbach C. W., Cardellichio C. B., Basile A. A., Elia P. E., Holmes K. V. Mouse hepatitis virus strain A59 and blocking antireceptor monoclonal antibody bind to the N-terminal domain of cellular receptor. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1716–1720. doi: 10.1073/pnas.90.5.1716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ewald P. W. The evolution of virulence. Sci Am. 1993 Apr;268(4):86–93. doi: 10.1038/scientificamerican0493-86. [DOI] [PubMed] [Google Scholar]
  19. Fantini J., Cook D. G., Nathanson N., Spitalnik S. L., Gonzalez-Scarano F. Infection of colonic epithelial cell lines by type 1 human immunodeficiency virus is associated with cell surface expression of galactosylceramide, a potential alternative gp120 receptor. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2700–2704. doi: 10.1073/pnas.90.7.2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Friedman M. J. Erythrocytic mechanism of sickle cell resistance to malaria. Proc Natl Acad Sci U S A. 1978 Apr;75(4):1994–1997. doi: 10.1073/pnas.75.4.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gabriel S. E., Brigman K. N., Koller B. H., Boucher R. C., Stutts M. J. Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science. 1994 Oct 7;266(5182):107–109. doi: 10.1126/science.7524148. [DOI] [PubMed] [Google Scholar]
  22. Gallagher T. M., Escarmis C., Buchmeier M. J. Alteration of the pH dependence of coronavirus-induced cell fusion: effect of mutations in the spike glycoprotein. J Virol. 1991 Apr;65(4):1916–1928. doi: 10.1128/jvi.65.4.1916-1928.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gombold J. L., Hingley S. T., Weiss S. R. Fusion-defective mutants of mouse hepatitis virus A59 contain a mutation in the spike protein cleavage signal. J Virol. 1993 Aug;67(8):4504–4512. doi: 10.1128/jvi.67.8.4504-4512.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hingley S. T., Gombold J. L., Lavi E., Weiss S. R. MHV-A59 fusion mutants are attenuated and display altered hepatotropism. Virology. 1994 Apr;200(1):1–10. doi: 10.1006/viro.1994.1156. [DOI] [PubMed] [Google Scholar]
  25. Hirano N., Fujiwara K., Hino S., Matumoto M. Replication and plaque formation of mouse hepatitis virus (MHV-2) in mouse cell line DBT culture. Arch Gesamte Virusforsch. 1974;44(3):298–302. doi: 10.1007/BF01240618. [DOI] [PubMed] [Google Scholar]
  26. Hirano N., Goto N., Makino S., Fujiwara K. Persistent infection with mouse hepatitis virus, JHM strain in DBT cell culture. Adv Exp Med Biol. 1981;142:301–308. doi: 10.1007/978-1-4757-0456-3_24. [DOI] [PubMed] [Google Scholar]
  27. Hofmann M. A., Chang R. Y., Ku S., Brian D. A. Leader-mRNA junction sequences are unique for each subgenomic mRNA species in the bovine coronavirus and remain so throughout persistent infection. Virology. 1993 Sep;196(1):163–171. doi: 10.1006/viro.1993.1464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hofmann M. A., Senanayake S. D., Brian D. A. A translation-attenuating intraleader open reading frame is selected on coronavirus mRNAs during persistent infection. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11733–11737. doi: 10.1073/pnas.90.24.11733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. Holmes K. V., Behnke J. N. Evolution of a coronavirus during persistent infection in vitro. Adv Exp Med Biol. 1981;142:287–299. doi: 10.1007/978-1-4757-0456-3_23. [DOI] [PubMed] [Google Scholar]
  31. Johnson R. B. Human disease and the evolution of pathogen virulence. J Theor Biol. 1986 Sep 7;122(1):19–24. doi: 10.1016/s0022-5193(86)80222-3. [DOI] [PubMed] [Google Scholar]
  32. Knobler R. L., Lampert P. W., Oldstone M. B. Virus persistence and recurring demyelination produced by a temperature-sensitive mutant of MHV-4. Nature. 1982 Jul 15;298(5871):279–280. doi: 10.1038/298279a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kumanishi T. Brain tumors induced with Rous sarcoma virus, Schmidt-Ruppin strain. I. Induction of brain tumors in adult mice with Rous chicken sarcoma cells. Jpn J Exp Med. 1967 Oct;37(5):461–474. [PubMed] [Google Scholar]
  34. Mahy B. W. Strategies of virus persistence. Br Med Bull. 1985 Jan;41(1):50–55. doi: 10.1093/oxfordjournals.bmb.a072024. [DOI] [PubMed] [Google Scholar]
  35. Malo D., Skamene E. Genetic control of host resistance to infection. Trends Genet. 1994 Oct;10(10):365–371. doi: 10.1016/0168-9525(94)90133-3. [DOI] [PubMed] [Google Scholar]
  36. Martín Hernández A. M., Carrillo E. C., Sevilla N., Domingo E. Rapid cell variation can determine the establishment of a persistent viral infection. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3705–3709. doi: 10.1073/pnas.91.9.3705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. McCuaig K., Rosenberg M., Nédellec P., Turbide C., Beauchemin N. Expression of the Bgp gene and characterization of mouse colon biliary glycoprotein isoforms. Gene. 1993 May 30;127(2):173–183. doi: 10.1016/0378-1119(93)90716-G. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Mizzen L., Cheley S., Rao M., Wolf R., Anderson R. Fusion resistance and decreased infectability as major host cell determinants of coronavirus persistence. Virology. 1983 Jul 30;128(2):407–417. doi: 10.1016/0042-6822(83)90266-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Murray R. S., Cai G. Y., Hoel K., Zhang J. Y., Soike K. F., Cabirac G. F. Coronavirus infects and causes demyelination in primate central nervous system. Virology. 1992 May;188(1):274–284. doi: 10.1016/0042-6822(92)90757-G. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Nicolson G. L. Tumor cell instability, diversification, and progression to the metastatic phenotype: from oncogene to oncofetal expression. Cancer Res. 1987 Mar 15;47(6):1473–1487. [PubMed] [Google Scholar]
  41. Nédellec P., Dveksler G. S., Daniels E., Turbide C., Chow B., Basile A. A., Holmes K. V., Beauchemin N. Bgp2, a new member of the carcinoembryonic antigen-related gene family, encodes an alternative receptor for mouse hepatitis viruses. J Virol. 1994 Jul;68(7):4525–4537. doi: 10.1128/jvi.68.7.4525-4537.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Pachuk C. J., Bredenbeek P. J., Zoltick P. W., Spaan W. J., Weiss S. R. Molecular cloning of the gene encoding the putative polymerase of mouse hepatitis coronavirus, strain A59. Virology. 1989 Jul;171(1):141–148. doi: 10.1016/0042-6822(89)90520-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pavlovic J., Haller O., Staeheli P. Human and mouse Mx proteins inhibit different steps of the influenza virus multiplication cycle. J Virol. 1992 Apr;66(4):2564–2569. doi: 10.1128/jvi.66.4.2564-2569.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Perlman S., Jacobsen G., Olson A. L., Afifi A. Identification of the spinal cord as a major site of persistence during chronic infection with a murine coronavirus. Virology. 1990 Apr;175(2):418–426. doi: 10.1016/0042-6822(90)90426-R. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Ron D., Tal J. Coevolution of cells and virus as a mechanism for the persistence of lymphotropic minute virus of mice in L-cells. J Virol. 1985 Aug;55(2):424–430. doi: 10.1128/jvi.55.2.424-430.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Rudert F., Saunders A. M., Rebstock S., Thompson J. A., Zimmermann W. Characterization of murine carcinoembryonic antigen gene family members. Mamm Genome. 1992;3(5):262–273. doi: 10.1007/BF00292154. [DOI] [PubMed] [Google Scholar]
  47. Sawicki S. G., Lu J. H., Holmes K. V. Persistent infection of cultured cells with mouse hepatitis virus (MHV) results from the epigenetic expression of the MHV receptor. J Virol. 1995 Sep;69(9):5535–5543. doi: 10.1128/jvi.69.9.5535-5543.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Schaad M. C., Baric R. S. Evidence for new transcriptional units encoded at the 3' end of the mouse hepatitis virus genome. Virology. 1993 Sep;196(1):190–198. doi: 10.1006/viro.1993.1467. [DOI] [PubMed] [Google Scholar]
  49. Schaad M. C., Stohlman S. A., Egbert J., Lum K., Fu K., Wei T., Jr, Baric R. S. Genetics of mouse hepatitis virus transcription: identification of cistrons which may function in positive and negative strand RNA synthesis. Virology. 1990 Aug;177(2):634–645. doi: 10.1016/0042-6822(90)90529-Z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Shively J. E., Beatty J. D. CEA-related antigens: molecular biology and clinical significance. Crit Rev Oncol Hematol. 1985;2(4):355–399. doi: 10.1016/s1040-8428(85)80008-1. [DOI] [PubMed] [Google Scholar]
  51. Skamene E. Population and molecular genetics of susceptibility to tuberculosis. Clin Invest Med. 1991 Apr;14(2):160–166. [PubMed] [Google Scholar]
  52. Stead W. W. Genetics and resistance to tuberculosis. Could resistance be enhanced by genetic engineering? Ann Intern Med. 1992 Jun 1;116(11):937–941. doi: 10.7326/0003-4819-116-11-937. [DOI] [PubMed] [Google Scholar]
  53. Stohlman S. A., Sakaguchi A. Y., Weiner L. P. Characterization of the cold-sensitive murine hepatitis virus mutants rescued from latently infected cells by cell fusion. Virology. 1979 Oct 30;98(2):448–455. doi: 10.1016/0042-6822(79)90567-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Stohlman S. A., Sakaguchi A. Y., Weiner L. P. Rescue of a positive stranded RNA virus from antigen negative neuroblastoma cells. Life Sci. 1979 Mar 12;24(11):1029–1035. doi: 10.1016/0024-3205(79)90323-0. [DOI] [PubMed] [Google Scholar]
  55. Stohlman S. A., Weiner L. P. Stability of neurotropic mouse hepatitis virus (JHM strain) during chronic infection of neuroblastoma cells. Arch Virol. 1978;57(1):53–61. doi: 10.1007/BF01315637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Vlasak R., Luytjes W., Spaan W., Palese P. Human and bovine coronaviruses recognize sialic acid-containing receptors similar to those of influenza C viruses. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4526–4529. doi: 10.1073/pnas.85.12.4526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Wang K. S., Kuhn R. J., Strauss E. G., Ou S., Strauss J. H. High-affinity laminin receptor is a receptor for Sindbis virus in mammalian cells. J Virol. 1992 Aug;66(8):4992–5001. doi: 10.1128/jvi.66.8.4992-5001.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Williams R. K., Jiang G. S., Snyder S. W., Frana M. F., Holmes K. V. Purification of the 110-kilodalton glycoprotein receptor for mouse hepatitis virus (MHV)-A59 from mouse liver and identification of a nonfunctional, homologous protein in MHV-resistant SJL/J mice. J Virol. 1990 Aug;64(8):3817–3823. doi: 10.1128/jvi.64.8.3817-3823.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Yeager C. L., Ashmun R. A., Williams R. K., Cardellichio C. B., Shapiro L. H., Look A. T., Holmes K. V. Human aminopeptidase N is a receptor for human coronavirus 229E. Nature. 1992 Jun 4;357(6377):420–422. doi: 10.1038/357420a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yokomori K., Asanaka M., Stohlman S. A., Lai M. M. A spike protein-dependent cellular factor other than the viral receptor is required for mouse hepatitis virus entry. Virology. 1993 Sep;196(1):45–56. doi: 10.1006/viro.1993.1453. [DOI] [PubMed] [Google Scholar]
  61. Yokomori K., Lai M. M. Mouse hepatitis virus utilizes two carcinoembryonic antigens as alternative receptors. J Virol. 1992 Oct;66(10):6194–6199. doi: 10.1128/jvi.66.10.6194-6199.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. de la Torre J. C., Martínez-Salas E., Diez J., Villaverde A., Gebauer F., Rocha E., Dávila M., Domingo E. Coevolution of cells and viruses in a persistent infection of foot-and-mouth disease virus in cell culture. J Virol. 1988 Jun;62(6):2050–2058. doi: 10.1128/jvi.62.6.2050-2058.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]

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