Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1994 Nov;68(11):6976–6984. doi: 10.1128/jvi.68.11.6976-6984.1994

Molecular cloning and characterization of an immunosuppressive and weakly oncogenic variant of Friend murine leukemia virus, FIS-2.

H Y Dai 1, A Faxvaag 1, G I Troseth 1, H Aarset 1, A Dalen 1
PMCID: PMC237134  PMID: 7933079

Abstract

The FIS variant is a weakly leukemogenic, relatively strong immunosuppressive murine retrovirus which was isolated from the T helper cells of adult NMRI mice infected with Friend murine leukemia virus (F-MuLV) complex (FV). Unlike FV, it does not induce acute erythroleukemia but retains the immunosuppressive property of FV and induces suppression of the primary antibody response rapidly and persistently in adult mice. A previous study showed that the FIS variant contains two viral components, a replication-competent virus and a defective virus. In this study, we have biologically purified the FIS variant by end point dilution and we show that the replication-competent virus FIS-2 alone can induce immunosuppression as the parental FIS variant. Most newborn mice infected with FIS-2 developed erythroleukemia, but with an increased latency period compared with that of F-MuLV clone 57. In contrast, FIS-2 induced suppression of the primary antibody response and disease more rapidly than F-MuLV clone 57 in immunocompetent, adult mice. FIS-2 was further molecularly cloned and characterized. Restriction mapping and nucleotide sequence analysis of FIS-2 showed a high degree of homology between FIS-2 and F-MuLV clone 57, suggesting that FIS-2 is a variant of F-MuLV. The striking difference is the deletion of one of the tandem repeats in the FIS-2 long terminal repeat and the single point mutation in the binding sites for core-binding protein and FVa compared with the long terminal repeat of F-MuLV clone 57. Two single point mutations led to the appearance of two extra potential N glycosylation sites in the FIS-2 gag-encoded glycoprotein. Together, the results suggest that FIS-2 represents an interesting murine model to study retrovirus-induced immunosuppression on the basis of its unique combined property of low leukemogenicity and relatively strong and persistent immunosuppressive activity in adult mice.

Full text

PDF
6976

Selected References

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

  1. Bendinelli M., Friedman H. B and T lymphocyte activation by murine leukemia virus infection. Adv Exp Med Biol. 1979;121B:91–97. doi: 10.1007/978-1-4684-8914-9_9. [DOI] [PubMed] [Google Scholar]
  2. Botarelli P., Houlden B. A., Haigwood N. L., Servis C., Montagna D., Abrignani S. N-glycosylation of HIV-gp120 may constrain recognition by T lymphocytes. J Immunol. 1991 Nov 1;147(9):3128–3132. [PubMed] [Google Scholar]
  3. Ceglowski W. S., Friedman H. Immunosuppression by leukemia viruses. IV. Effect of Friend leukemia virus on antibody-precursors as assessed by cell transfer studies. J Immunol. 1970 Dec;105(6):1406–1415. [PubMed] [Google Scholar]
  4. Chatis P. A., Holland C. A., Hartley J. W., Rowe W. P., Hopkins N. Role for the 3' end of the genome in determining disease specificity of Friend and Moloney murine leukemia viruses. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4408–4411. doi: 10.1073/pnas.80.14.4408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chinsky J., Soeiro R. Fv-1 host restriction of Friend leukemia virus: analysis of unintegrated proviral DNA. J Virol. 1981 Oct;40(1):45–55. doi: 10.1128/jvi.40.1.45-55.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chung C. T., Niemela S. L., Miller R. H. One-step preparation of competent Escherichia coli: transformation and storage of bacterial cells in the same solution. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2172–2175. doi: 10.1073/pnas.86.7.2172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cianciolo G. J., Copeland T. D., Oroszlan S., Snyderman R. Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope proteins. Science. 1985 Oct 25;230(4724):453–455. doi: 10.1126/science.2996136. [DOI] [PubMed] [Google Scholar]
  8. Cianciolo G. J., Matthews T. J., Bolognesi D. P., Snyderman R. Macrophage accumulation in mice is inhibited by low molecular weight products from murine leukemia viruses. J Immunol. 1980 Jun;124(6):2900–2905. [PubMed] [Google Scholar]
  9. Copelan E. A., Rinehart J. J., Lewis M., Mathes L., Olsen R., Sagone A. The mechanism of retrovirus suppression of human T cell proliferation in vitro. J Immunol. 1983 Oct;131(4):2017–2020. [PubMed] [Google Scholar]
  10. DeFranco D., Yamamoto K. R. Two different factors act separately or together to specify functionally distinct activities at a single transcriptional enhancer. Mol Cell Biol. 1986 Apr;6(4):993–1001. doi: 10.1128/mcb.6.4.993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. DesGroseillers L., Jolicoeur P. The tandem direct repeats within the long terminal repeat of murine leukemia viruses are the primary determinant of their leukemogenic potential. J Virol. 1984 Dec;52(3):945–952. doi: 10.1128/jvi.52.3.945-952.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. DesGroseillers L., Rassart E., Jolicoeur P. Thymotropism of murine leukemia virus is conferred by its long terminal repeat. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4203–4207. doi: 10.1073/pnas.80.14.4203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dracott B. N., Wedderburn N., Doenhoff M. J. The immunodepressive effect of Friend virus. IV. Effects on spleen B lymphocytes. Immunology. 1978 Apr;34(4):679–687. [PMC free article] [PubMed] [Google Scholar]
  14. Evans L. H., Morrey J. D. Tissue-specific replication of Friend and Moloney murine leukemia viruses in infected mice. J Virol. 1987 May;61(5):1350–1357. doi: 10.1128/jvi.61.5.1350-1357.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Faxvaag A., Dai H. Y., Aarseth H., Dalen A. B. A low oncogenic variant of Friend murine leukemia virus with strong immunosuppressive properties. Arch Virol. 1993;131(3-4):265–275. doi: 10.1007/BF01378631. [DOI] [PubMed] [Google Scholar]
  16. Faxvaag A., Espevik T., Dalen A. Multiple derangements of cytokine homeostasis in mice infected with immunosuppressive retrovirus. Cell Immunol. 1993 Sep;150(2):247–256. doi: 10.1006/cimm.1993.1194. [DOI] [PubMed] [Google Scholar]
  17. Faxvaag A., Moen T., Dalen A. B. Polyclonal activation of B-lymphocytes and induction of autoimmunity in retrovirus infected NMRI mice. Scand J Immunol. 1993 Nov;38(5):459–462. doi: 10.1111/j.1365-3083.1993.tb02588.x. [DOI] [PubMed] [Google Scholar]
  18. Garaci E., Migliorati G., Jezzi T., Bartocci A., Gioia L., Rinaldi C., Bonmassar E. Impairment of in vitro generation of cytotoxic or T suppressor lymphocytes by Friend leukemia virus infection in mice. Int J Cancer. 1981 Sep 15;28(3):367–373. doi: 10.1002/ijc.2910280317. [DOI] [PubMed] [Google Scholar]
  19. Goff S., Traktman P., Baltimore D. Isolation and properties of Moloney murine leukemia virus mutants: use of a rapid assay for release of virion reverse transcriptase. J Virol. 1981 Apr;38(1):239–248. doi: 10.1128/jvi.38.1.239-248.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Golemis E., Li Y., Fredrickson T. N., Hartley J. W., Hopkins N. Distinct segments within the enhancer region collaborate to specify the type of leukemia induced by nondefective Friend and Moloney viruses. J Virol. 1989 Jan;63(1):328–337. doi: 10.1128/jvi.63.1.328-337.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gottlieb R. A., Lennarz W. J., Knowles R. D., Cianciolo G. J., Dinarello C. A., Lachman L. B., Kleinerman E. S. Synthetic peptide corresponding to a conserved domain of the retroviral protein p15E blocks IL-1-mediated signal transduction. J Immunol. 1989 Jun 15;142(12):4321–4328. [PubMed] [Google Scholar]
  22. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  23. Herr W., Gilbert W. Somatically acquired recombinant murine leukemia proviruses in thymic leukemias of AKR/J mice. J Virol. 1983 Apr;46(1):70–82. doi: 10.1128/jvi.46.1.70-82.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Holland C. A., Thomas C. Y., Chattopadhyay S. K., Koehne C., O'Donnell P. V. Influence of enhancer sequences on thymotropism and leukemogenicity of mink cell focus-forming viruses. J Virol. 1989 Mar;63(3):1284–1292. doi: 10.1128/jvi.63.3.1284-1292.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Holt C. A., Osorio K., Lilly F. Friend virus-specific cytotoxic T lymphocytes recognize both gag and env gene-encoded specificities. J Exp Med. 1986 Jul 1;164(1):211–226. doi: 10.1084/jem.164.1.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hügin A. W., Vacchio M. S., Morse H. C., 3rd A virus-encoded "superantigen" in a retrovirus-induced immunodeficiency syndrome of mice. Science. 1991 Apr 19;252(5004):424–427. doi: 10.1126/science.1850169. [DOI] [PubMed] [Google Scholar]
  27. Kadota J., Cianciolo G. J., Snyderman R. A synthetic peptide homologous to retroviral transmembrane envelope proteins depresses protein kinase C mediated lymphocyte proliferation and directly inactivated protein kinase C: a potential mechanism for immunosuppression. Microbiol Immunol. 1991;35(6):443–459. doi: 10.1111/j.1348-0421.1991.tb01575.x. [DOI] [PubMed] [Google Scholar]
  28. Lenz J., Celander D., Crowther R. L., Patarca R., Perkins D. W., Haseltine W. A. Determination of the leukaemogenicity of a murine retrovirus by sequences within the long terminal repeat. 1984 Mar 29-Apr 4Nature. 308(5958):467–470. doi: 10.1038/308467a0. [DOI] [PubMed] [Google Scholar]
  29. Li J. P., Baltimore D. Mechanism of leukemogenesis induced by mink cell focus-forming murine leukemia viruses. J Virol. 1991 May;65(5):2408–2414. doi: 10.1128/jvi.65.5.2408-2414.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Li J. P., D'Andrea A. D., Lodish H. F., Baltimore D. Activation of cell growth by binding of Friend spleen focus-forming virus gp55 glycoprotein to the erythropoietin receptor. Nature. 1990 Feb 22;343(6260):762–764. doi: 10.1038/343762a0. [DOI] [PubMed] [Google Scholar]
  31. Li Y., Golemis E., Hartley J. W., Hopkins N. Disease specificity of nondefective Friend and Moloney murine leukemia viruses is controlled by a small number of nucleotides. J Virol. 1987 Mar;61(3):693–700. doi: 10.1128/jvi.61.3.693-700.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Luban J., Bossolt K. L., Franke E. K., Kalpana G. V., Goff S. P. Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell. 1993 Jun 18;73(6):1067–1078. doi: 10.1016/0092-8674(93)90637-6. [DOI] [PubMed] [Google Scholar]
  33. Manley N. R., O'Connell M. A., Sharp P. A., Hopkins N. Nuclear factors that bind to the enhancer region of nondefective Friend murine leukemia virus. J Virol. 1989 Oct;63(10):4210–4223. doi: 10.1128/jvi.63.10.4210-4223.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Miksicek R., Heber A., Schmid W., Danesch U., Posseckert G., Beato M., Schütz G. Glucocorticoid responsiveness of the transcriptional enhancer of Moloney murine sarcoma virus. Cell. 1986 Jul 18;46(2):283–290. doi: 10.1016/0092-8674(86)90745-2. [DOI] [PubMed] [Google Scholar]
  35. Morrison R. P., Nishio J., Chesebro B. Influence of the murine MHC (H-2) on Friend leukemia virus-induced immunosuppression. J Exp Med. 1986 Feb 1;163(2):301–314. doi: 10.1084/jem.163.2.301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mortensen R. F., Ceglowski W. S., Friedman H. Leukemia virus-induced immunosuppression. X. Depression of T cell-mediated cytotoxicity after infection of mice with Friend leukemia virus. J Immunol. 1974 Jun;112(6):2077–2086. [PubMed] [Google Scholar]
  37. Méric C., Goff S. P. Characterization of Moloney murine leukemia virus mutants with single-amino-acid substitutions in the Cys-His box of the nucleocapsid protein. J Virol. 1989 Apr;63(4):1558–1568. doi: 10.1128/jvi.63.4.1558-1568.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ogasawara M., Haraguchi S., Cianciolo G. J., Mitani M., Good R. A., Day N. K. Inhibition of murine cytotoxic T lymphocyte activity by a synthetic retroviral peptide and abrogation of this activity by IL. J Immunol. 1990 Jul 15;145(2):456–462. [PubMed] [Google Scholar]
  39. Overbaugh J., Rudensey L. M. Alterations in potential sites for glycosylation predominate during evolution of the simian immunodeficiency virus envelope gene in macaques. J Virol. 1992 Oct;66(10):5937–5948. doi: 10.1128/jvi.66.10.5937-5948.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Perryman S., Nishio J., Chesebro B. Complete nucleotide sequence of Friend murine leukemia virus, strain FB29. Nucleic Acids Res. 1991 Dec 25;19(24):6950–6950. doi: 10.1093/nar/19.24.6950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Pozsgay J. M., Beilharz M. W., Wines B. D., Hess A. D., Pitha P. M. The MA (p15) and p12 regions of the gag gene are sufficient for the pathogenicity of the murine AIDS virus. J Virol. 1993 Oct;67(10):5989–5999. doi: 10.1128/jvi.67.10.5989-5999.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Prats A. C., De Billy G., Wang P., Darlix J. L. CUG initiation codon used for the synthesis of a cell surface antigen coded by the murine leukemia virus. J Mol Biol. 1989 Jan 20;205(2):363–372. doi: 10.1016/0022-2836(89)90347-1. [DOI] [PubMed] [Google Scholar]
  43. Remington M. P., Hoffman P. M., Ruscetti S. K., Masuda M. Complete nucleotide sequence of a neuropathogenic variant of Friend murine leukemia virus PVC-211. Nucleic Acids Res. 1992 Jun 25;20(12):3249–3249. doi: 10.1093/nar/20.12.3249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Schmidt D. M., Sidhu N. K., Cianciolo G. J., Snyderman R. Recombinant hydrophilic region of murine retroviral protein p15E inhibits stimulated T-lymphocyte proliferation. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7290–7294. doi: 10.1073/pnas.84.20.7290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Troxler D. H., Ruscetti S. K., Scolnick E. M. The molecular biology of Friend virus. Biochim Biophys Acta. 1980 Sep 22;605(3):305–324. doi: 10.1016/0304-419x(80)90014-1. [DOI] [PubMed] [Google Scholar]
  46. Tsichlis P. N., Bear S. E. Infection by mink cell focus-forming viruses confers interleukin 2 (IL-2) independence to an IL-2-dependent rat T-cell lymphoma line. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4611–4615. doi: 10.1073/pnas.88.11.4611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Tumas K. M., Poszgay J. M., Avidan N., Ksiazek S. J., Overmoyer B., Blank K. J., Prystowsky M. B. Loss of antigenic epitopes as the result of env gene recombination in retrovirus-induced leukemia in immunocompetent mice. Virology. 1993 Feb;192(2):587–595. doi: 10.1006/viro.1993.1075. [DOI] [PubMed] [Google Scholar]

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

RESOURCES