Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1977 Jun 1;145(6):1449–1468. doi: 10.1084/jem.145.6.1449

Inhibition of immunologic injury of cultured cells infected with lymphocytic choriomeningitis virus: role of defective interfering virus in regulating viral antigenic expression

RM Welsh, MBA Oldstone
PMCID: PMC2180676  PMID: 301173

Abstract

The expression of viral antigens on the surfaces of lymphocytic choriomeningitis virus (LCMV)-infected L-929 cells peaked 2-4 days postinfection and thereafter precipitously declined. Little or no viral antigen was expressed on the plasma membrane surfaces of persistently infected cells, but LCMV antigens were clearly present in the cytoplasms of most of those cells. Cells early after acute infection (days 2-4) were lysed by both virus-specific antibody and complement (C) and immune T lymphocytes. To the contrary, antibody and C did not kill persistently infected cells, but T lymphocytes did kill such cells although at a lower efficiency than acutely infected cells. The expression of viral antigens on the surfaces of infected cells was regulated by the virus- cell interaction in the absence of immune reagents and was closely associated with defective interfering (DI) LCMV interference. DI LCMV, per se, blocked the synthesis and cell surface expression of LCMV antigens, and DI LCMV generation immediately preceded a precipitous reduction in cell surface antigenicity during the acute infection. Persistently infected cells produced DI LCMV but no detectable S LCMV. Peritoneal cells isolated from mice persistently infected with LCMV resembled cultured persistently infected cells in their reduced expression of cell surface antigens and their resistance to LCMV superinfection. It is proposed that DI virus-mediated interference with viral protein synthesis may allow cells to escape immune surveillance during persistent infections.

Full Text

The Full Text of this article is available as a PDF (1.7 MB).

Selected References

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

  1. Argyris B. F. Role of macrophages in antibody production. Immune response to sheep red blood cells. J Immunol. 1967 Oct;99(4):744–750. [PubMed] [Google Scholar]
  2. Cikes M. Antigenic expression of a murine lymphoma during growth in vitro. Nature. 1970 Feb 14;225(5233):645–647. doi: 10.1038/225645a0. [DOI] [PubMed] [Google Scholar]
  3. Cooper N. R., Jensen F. C., Welsh R. M., Jr, Oldstone M. B. Lysis of RNA tumor viruses by human serum: direct antibody-independent triggering of the classical complement pathway. J Exp Med. 1976 Oct 1;144(4):970–984. doi: 10.1084/jem.144.4.970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. De Maeyer E., De Maeyer-Guignard J., Vandeputte M. Inhibition by interferon of delayed-type hypersensitivity in the mouse. Proc Natl Acad Sci U S A. 1975 May;72(5):1753–1757. doi: 10.1073/pnas.72.5.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Doherty P. C., Zinkernagel R. M. T-cell-mediated immunopathology in viral infections. Transplant Rev. 1974;19(0):89–120. doi: 10.1111/j.1600-065x.1974.tb00129.x. [DOI] [PubMed] [Google Scholar]
  6. Doyle M., Holland J. J. Prophylaxis and immunization in mice by use of virus-free defective T particles to protect against intracerebral infection by vesicular stomatitis virus. Proc Natl Acad Sci U S A. 1973 Jul;70(7):2105–2108. doi: 10.1073/pnas.70.7.2105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dutko F. J., Wright E. A., Pfau C. J. The RNAs of the defective interfering Pichinide virus. J Gen Virol. 1976 Jun;31(3):417–427. doi: 10.1099/0022-1317-31-3-417. [DOI] [PubMed] [Google Scholar]
  8. Ekidin M., Henney C. S. The effect of capping H-2 antigens on the susceptibility of target cells to humoral and T cell-mediated lysis. Nat New Biol. 1973 Nov 14;246(150):47–49. doi: 10.1038/newbio246047a0. [DOI] [PubMed] [Google Scholar]
  9. GINSBERG H. S., PILLEMER L., WEDGWOOD R. J. The properdin system and immunity. VI. The inactivation of Newcastle disease virus by the properdin system. J Exp Med. 1956 Nov 1;104(5):707–725. doi: 10.1084/jem.104.5.707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. HOTCHIN J., BENSON L. THE PATHOGENESIS OF LYMPHOCYTIC CHORIOMENINGITIS IN MICE: THE EFFECTS OF DIFFERENT INOCULATION ROUTES AND THE FOOTPAD RESPONSE. J Immunol. 1963 Oct;91:460–468. [PubMed] [Google Scholar]
  11. HOTCHIN J. The biology of lymphocytic choriomeningitis infection: virus-induced immune disease. Cold Spring Harb Symp Quant Biol. 1962;27:479–499. doi: 10.1101/sqb.1962.027.001.046. [DOI] [PubMed] [Google Scholar]
  12. Holland J. J., Villarreal L. P. Purification of defective interfering T particles of vesicular stomatitis and rabies viruses generated in vivo in brains of newborn mice. Virology. 1975 Oct;67(2):438–449. doi: 10.1016/0042-6822(75)90445-6. [DOI] [PubMed] [Google Scholar]
  13. Holland J. J., Villarreal L. P., Welsh R. M., Oldstone M. B., Kohne D., Lazzarini R., Scolnick E. Long-term persistent vesicular stomatitis virus and rabies virus infection of cells in vitro. J Gen Virol. 1976 Nov;33(2):193–211. doi: 10.1099/0022-1317-33-2-193. [DOI] [PubMed] [Google Scholar]
  14. Hotchin J., Kinch W., Benson L. Lytic and turbid plaque-type mutants of lymphocytic choriomeningitis virus as a cause of neurological disease or persistent infection. Infect Immun. 1971 Sep;4(3):281–286. doi: 10.1128/iai.4.3.281-286.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Huang A. S. Defective interfering viruses. Annu Rev Microbiol. 1973;27:101–117. doi: 10.1146/annurev.mi.27.100173.000533. [DOI] [PubMed] [Google Scholar]
  16. Jondal M., Klein G., Oldstone M. B., Bokish V., Yefenof E. Surface markers on human B and T lymphocytes. VIII. Association between complement and Epstein-Barr virus receptors on human lymphoid cells. Scand J Immunol. 1976;5(4):401–410. doi: 10.1111/j.1365-3083.1976.tb00294.x. [DOI] [PubMed] [Google Scholar]
  17. Joseph B. S., Cooper N. R., Oldstone M. B. Immunologic injury of cultured cells infected with measles virus. I. role of IfG antibody and the alternative complement pathway. J Exp Med. 1975 Apr 1;141(4):761–774. [PMC free article] [PubMed] [Google Scholar]
  18. Joseph B. S., Oldstone M. B. Immunologic injury in measles virus infection. II. Suppression of immune injury through antigenic modulation. J Exp Med. 1975 Oct 1;142(4):864–876. doi: 10.1084/jem.142.4.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Joseph B. S., Perrin L. H., Oldstone M. B. Measurement of virus antigens on the surface of HeLa cells persistently infected with wild type and vaccine strains of measles virus by radioimmune assay. J Gen Virol. 1976 Mar;30(3):329–337. doi: 10.1099/0022-1317-30-3-329. [DOI] [PubMed] [Google Scholar]
  20. Lehmann-Grube F., Slenczka W., Tees R. A persistent and inapparent infection of L cells with the virus of lymphocytic choriomeningitis. J Gen Virol. 1969 Jul;5(1):63–81. doi: 10.1099/0022-1317-5-1-63. [DOI] [PubMed] [Google Scholar]
  21. Lerner R. A., Oldstone M. B., Cooper N. R. Cell cycle-dependent immune lysis of Moloney virus-transformed lymphocytes: presence of viral antigen, accessibility to antibody, and complement activation. Proc Natl Acad Sci U S A. 1971 Oct;68(10):2584–2588. doi: 10.1073/pnas.68.10.2584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mims C. A., Subrahmanyan T. P. Immunofluorescence study of the mechanism of resistance to superinfection in mice carrying the lymphocytic choriomeningitis virus. J Pathol Bacteriol. 1966 Apr;91(2):403–415. doi: 10.1002/path.1700910215. [DOI] [PubMed] [Google Scholar]
  23. Notkins A. L., Mergenhagen S. E., Howard R. J. Effect of virus infections on the function of the immune system. Annu Rev Microbiol. 1970;24:525–538. doi: 10.1146/annurev.mi.24.100170.002521. [DOI] [PubMed] [Google Scholar]
  24. Okada H., Baba T. Rosette formation of human erythrocytes on cultured cells of tumour origin and activation of complement by cell membrane. Nature. 1974 Apr 5;248(448):521–522. doi: 10.1038/248521a0. [DOI] [PubMed] [Google Scholar]
  25. Oldstone M. B., Dixon F. J. Acute viral infection: tissue injury mediated by anti-viral antibody through a complement effector system. J Immunol. 1971 Nov;107(5):1274–1280. [PubMed] [Google Scholar]
  26. Oldstone M. B., Dixon F. J. Pathogenesis of chronic disease associated with persistent lymphocytic choriomeningitis viral infection. I. Relationship of antibody production to disease in neonatally infected mice. J Exp Med. 1969 Mar 1;129(3):483–505. doi: 10.1084/jem.129.3.483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. PORTER R. R. The hydrolysis of rabbit y-globulin and antibodies with crystalline papain. Biochem J. 1959 Sep;73:119–126. doi: 10.1042/bj0730119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Perrin L. H., Joseph B. S., Cooper N. R., Oldstone M. B. Mechanism of injury of virus-infected cells by antiviral antibody and complement: participation of IgG, F(ab')2, and the alternative complement pathway. J Exp Med. 1976 May 1;143(5):1027–1041. doi: 10.1084/jem.143.5.1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Popescu M., Lehmann-Grube F. Diversity of lymphocytic choriomeningitis virus: variation due to replication of the virus in the mouse. J Gen Virol. 1976 Jan;30(1):113–122. doi: 10.1099/0022-1317-30-1-113. [DOI] [PubMed] [Google Scholar]
  30. Popescu M., Schaefer H., Lehmann-Grube F. Homologous interference of lymphocytic choriomeningitis virus: detection and measurement of interference focus-forming units. J Virol. 1976 Oct;20(1):1–8. doi: 10.1128/jvi.20.1.1-8.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Porter D. D., Porter H. G., Cox N. A. Failure to demonstrate a humoral immune response to scrapie infection in mice. J Immunol. 1973 Nov;111(5):1407–1410. [PubMed] [Google Scholar]
  32. Preble O. T., Youngner J. S. Temperature-sensitive viruses and the etiology of chronic and inapparent infections. J Infect Dis. 1975 Apr;131(4):467–473. doi: 10.1093/infdis/131.4.467. [DOI] [PubMed] [Google Scholar]
  33. Pulkkinen A. J., Pfau C. J. Plaque size heterogeneity: a genetic trait of lymphocytic choriomeningitis virus. Appl Microbiol. 1970 Jul;20(1):123–128. doi: 10.1128/am.20.1.123-128.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rajan T. V., Bloom B. R., Nathenson S. G. Regulatory variants for the expression of H-2 antigens. II. Level of discrimination of cell-mediated cytolysis. J Natl Cancer Inst. 1976 Jun;56(6):1229–1231. doi: 10.1093/jnci/56.6.1229. [DOI] [PubMed] [Google Scholar]
  35. Rajan T. V., Nathenson S. G., Scharff M. D. Regulatory variants for the expression of H-2 antigens. I. Isolation and characterization. J Natl Cancer Inst. 1976 Jun;56(6):1221–1227. doi: 10.1093/jnci/56.6.1221. [DOI] [PubMed] [Google Scholar]
  36. Simpson R. W., Iinuma M. Recovery of infectious proviral DNA from mammalian cells infected with respiratory syncytial virus. Proc Natl Acad Sci U S A. 1975 Aug;72(8):3230–3234. doi: 10.1073/pnas.72.8.3230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Spandidos D. A., Graham A. F. Generation of defective virus after infection of newborn rats with reovirus. J Virol. 1976 Oct;20(1):234–247. doi: 10.1128/jvi.20.1.234-247.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Staneck L. D., Trowbridge R. S., Welsh R. M., Wright E. A., Pfau C. J. Arenaviruses: cellular response to long-term in vitro infection with parana and lymphocytic choriomeningitis viruses. Infect Immun. 1972 Oct;6(4):444–450. doi: 10.1128/iai.6.4.444-450.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Theofilopoulos A. N., Bokisch V. A., Dixon F. J. Receptor for soluble C3 and C3b on human lymphoblastoid (RAJI) cells. Properties and biologocal significance. J Exp Med. 1974 Mar 1;139(3):696–711. doi: 10.1084/jem.139.3.696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Traub E. THE EPIDEMIOLOGY OF LYMPHOCYTIC CHORIOMENINGITIS IN WHITE MICE. J Exp Med. 1936 Jul 31;64(2):183–200. doi: 10.1084/jem.64.2.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Welsh R. M., Burner P. A., Holland J. J., Oldstone M. B., Thompson H. A., Villarreal L. P. A comparison of biochemical and biological properties of standard and defective lymphocytic choriomeningitis virus. Bull World Health Organ. 1975;52(4-6):403–408. [PMC free article] [PubMed] [Google Scholar]
  42. Welsh R. M. Host cell modification of lymphocytic choriomeningitis virus and Newcastle disease virus altering viral inactivation by human complement. J Immunol. 1977 Jan;118(1):348–354. [PubMed] [Google Scholar]
  43. Welsh R. M., Jr, Cooper N. R., Jensen F. C., Oldstone M. B. Human serum lyses RNA tumour viruses. Nature. 1975 Oct 16;257(5527):612–614. doi: 10.1038/257612a0. [DOI] [PubMed] [Google Scholar]
  44. Welsh R. M., Jr, Lampert P. W., Burner P. A., Oldstone M. B. Antibody-complement interactions with purified lymphocytic choriomeningitis virus. Virology. 1976 Aug;73(1):59–71. doi: 10.1016/0042-6822(76)90060-x. [DOI] [PubMed] [Google Scholar]
  45. Welsh R. M., O'Connell C. M., Pfau C. J. Properties of defective lymphocytic choriomeningitis virus. J Gen Virol. 1972 Dec;17(3):355–359. doi: 10.1099/0022-1317-17-3-355. [DOI] [PubMed] [Google Scholar]
  46. Welsh R. M., Pfau C. J. Determinants of lymphocytic choriomeningitis interference. J Gen Virol. 1972 Feb;14(2):177–187. doi: 10.1099/0022-1317-14-2-177. [DOI] [PubMed] [Google Scholar]
  47. Welsh R. M., Trowbridge R. S., Kowalski J. B., O'Connell C. M., Peau C. J. Amantadine hydrochloride inhibition of early and late stages of lymphocytic choriomenigitis virus-cell interactions. Virology. 1971 Sep;45(3):679–686. [PubMed] [Google Scholar]
  48. Zhdanov V. M. Integration of viral genomes. Nature. 1975 Aug 7;256(5517):471–473. doi: 10.1038/256471a0. [DOI] [PubMed] [Google Scholar]
  49. Zinkernagel R. M., Oldstone M. B. Cells that express viral antigens but lack H-2 determinants are not lysed by immune thymus-derived lymphocytes but are lysed by other antiviral immune attack mechanisms. Proc Natl Acad Sci U S A. 1976 Oct;73(10):3666–3670. doi: 10.1073/pnas.73.10.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES