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. 1975 Oct 1;142(4):936–948. doi: 10.1084/jem.142.4.936

Continuous replication of Friend virus complex (spleen focus-forming virus-lymphatic leukemia-inducing virus) in mouse embryo fibroblasts. Retention of leukemogenicity and loss of immunosuppressive properties

PMCID: PMC2189940  PMID: 1176891

Abstract

Exposure of NIH Swiss mouse embryo fibroblasts (MEF) to infectious Friend virus (FV) complex [containing defective spleen focus-forming virus (SFFV) and endogenous NB-tropic leukemia-inducing helper virus (LLV-F)] resulted in the productive infection of these cells by both SFFV and LLV-F. Stocks of SFFV derived after extensive growth in this Swiss MEF cell culture system are fully leukemogenic in adult mice for the induction of erythroleukemia and spleen foci. In addition, in vitro- derived LLV-F, when isolated free of SFFV, is fully leukemogenic for the induction of lymphatic leukemia when inoculated into susceptible newborn BALB/c mice. The host range of in vitro-derived FV complex (i.e., FV-TC) for focus formation in vivo is NB-tropic. Unlike in vivo- derived FV complex, FV-TC does not suppress the responsiveness of murine thymocytes to concanavalin A (Con A) in vitro. Rather, FV-TC acts as a mitogen to nonspecifically stimulate the proliferation of BALB/c thymocytes. The mitogenicity of in vitro-derived FV complex is directly associated with the presence of type-C virus particles, is a heat-labile and UV-sensitive property of the virus, and may be primarily due to LLV since equivalent amounts of LLV with or without SFFV present are equally mitogenic. One in vivo passage of FV-TC resulted in the total loss of this mitogenic property with the reappearance of full immunosuppressive properties. This result demonstrates a clear association between in vivo growth of FV and its ability to suppress mouse thymocytes, and suggests that FV complex (SFFV-LLV) is not inherently immunosuppressive for these cells. While the mechanism of this interconversion between immunostimulatory and fully suppressive virus is unknown, both virus markers appear to be dependent upon the presence of infectious FV.

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Selected References

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  1. AXELRAD A. A., STEEVES R. A. ASSAY FOR FRIEND LEUKEMIA VIRUS: RAPID QUANTITATIVE METHOD BASED ON ENUMERATION OF MACROSCOPIC SPLEEN FOCI IN MICE. Virology. 1964 Nov;24:513–518. doi: 10.1016/0042-6822(64)90199-0. [DOI] [PubMed] [Google Scholar]
  2. Armstrong M. Y., Ruddle N. H., Lipman M. B., Richards F. F. Tumor induction by immunologically activated murine leukemia virus. J Exp Med. 1973 May 1;137(5):1163–1179. doi: 10.1084/jem.137.5.1163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barski G., Barbieri D., Youn J. K., Hue G. Low-leukemogenic variants of Rauscher leukemia virus obtained in long-term cultures at supra-optimal temperature. Int J Cancer. 1973 Jul 15;12(1):55–65. doi: 10.1002/ijc.2910120106. [DOI] [PubMed] [Google Scholar]
  4. Bentvelzen P., Aarssen A. M., Brinkhof J. Defectivity of Rauscher murine erythroblastosis virus. Nat New Biol. 1972 Sep 27;239(91):122–123. doi: 10.1038/newbio239122a0. [DOI] [PubMed] [Google Scholar]
  5. Eckner B. J., Steeves R. A. Defective Friend spleen focus-forming virus: pseudotype neutralization by helper-specific antisera. Nat New Biol. 1971 Feb 24;229(8):241–243. doi: 10.1038/newbio229241a0. [DOI] [PubMed] [Google Scholar]
  6. Eckner R. J. Helper-dependent properties of Friend spleen focus-forming virus: effect of the Fv-1 gene on the late stages in virus synthesis. J Virol. 1973 Sep;12(3):523–533. doi: 10.1128/jvi.12.3.523-533.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eckner R. J., Kumar V., Bennett M. Immunogenetic analysis of the mechanism of induction of Friend virus leukemia. Transplant Proc. 1975 Jun;7(2):173–184. [PubMed] [Google Scholar]
  8. Eckner R. J., Steeves R. A. A classification of the murine leukemia viruses. Neutralization of pseudotypes of Friend spleen focus-forming virus by type-specific murine antisera. J Exp Med. 1972 Oct 1;136(4):832–850. doi: 10.1084/jem.136.4.832. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Greenberger J. S., Stephenson J. R., Moloney W. C., Aaronson S. A. Different hematological diseases induced by type C viruses chemically activated from embryo cells of different mouse strains. Cancer Res. 1975 Jan;35(1):245–252. [PubMed] [Google Scholar]
  10. Hartley J. W., Rowe W. P., Huebner R. J. Host-range restrictions of murine leukemia viruses in mouse embryo cell cultures. J Virol. 1970 Feb;5(2):221–225. doi: 10.1128/jvi.5.2.221-225.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hirsch M. S., Ellis D. A., Black P. H., Monaco A. P., Wood M. L. Leukemia virus activation during homograft rejection. Science. 1973 May 4;180(4085):500–502. doi: 10.1126/science.180.4085.500. [DOI] [PubMed] [Google Scholar]
  12. Hirsch M. S., Phillips S. M., Solnik C., Black P. H., Schwartz R. S., Carpenter C. B. Activation of leukemia viruses by graft-versus-host and mixed lymphocyte reactions in vitro. Proc Natl Acad Sci U S A. 1972 May;69(5):1069–1072. doi: 10.1073/pnas.69.5.1069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Häyry P., Rago D., Defendi V. Inhibition of phytohemagglutinin- and alloantigen-induced lymphocyte stimulation by Rauscher leukemia virus. J Natl Cancer Inst. 1970 Jun;44(6):1311–1319. [PubMed] [Google Scholar]
  14. Ikawa Y., Ross J., Leder P. An association between globin messenger RNA and 60S RNA derived from Friend leukemia virus. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1154–1158. doi: 10.1073/pnas.71.4.1154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Levy J. A., Hartley J. W., Rowe W. P., Huebner R. J. Studies of FBJ osteosarcoma virus in tissue culture. II. Autoinhibition of focus formation. J Natl Cancer Inst. 1975 Mar;54(3):615–619. [PubMed] [Google Scholar]
  16. Lieberman M., Niwa O., Declève A., Kaplan H. S. Continuous propagation of radiation leukemia virus on a C57BL mouse-embryo fibroblast line, with attenuation of leukemogenic activity. Proc Natl Acad Sci U S A. 1973 Apr;70(4):1250–1253. doi: 10.1073/pnas.70.4.1250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lilly F. Mouse leukemia: a model of a multiple-gene disease. J Natl Cancer Inst. 1972 Oct;49(4):927–934. [PubMed] [Google Scholar]
  18. Machala O., Boyd R., Youn J., Barski G. Long-term in vitro culture of pathogenic Gross leukemia virus in mouse thymus cells. Eur J Cancer. 1974 Aug;10(8):467–472. doi: 10.1016/0014-2964(74)90067-x. [DOI] [PubMed] [Google Scholar]
  19. Ostertag W., Roesler G., Krieg C. J., Kind J., Cole T., Crozier T., Gaedicke G., Steinheider G., Kluge N., Dube S. Induction of endogenous virus and of thymidine kinase by bromodeoxyuridine in cell cultures transformed by Friend virus. Proc Natl Acad Sci U S A. 1974 Dec;71(12):4980–4985. doi: 10.1073/pnas.71.12.4980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Phillips S. M., Gleichmann H., Hirsch M. S., Black P., Merrill J. P., Schwartz R. S., Carpenter C. B. Cellular immunity in the mouse. IV. Altered thymic-dependent lymphocyte reactivity in the chronic graft vs host reaction and leukemia virus activation. Cell Immunol. 1975 Jan;15(1):152–168. doi: 10.1016/0008-8749(75)90172-0. [DOI] [PubMed] [Google Scholar]
  21. Rowe W. P., Pugh W. E., Hartley J. W. Plaque assay techniques for murine leukemia viruses. Virology. 1970 Dec;42(4):1136–1139. doi: 10.1016/0042-6822(70)90362-4. [DOI] [PubMed] [Google Scholar]
  22. Schlom J., Moloney J. B., Groupé V. Evidence for the rapid decrease in leukemogenic potential Rauscher leukemia virus in cell culture. Cancer Res. 1971 Mar;31(3):260–264. [PubMed] [Google Scholar]
  23. Steeves R. A., Eckner R. J., Mirand E. A., Priore R. L. Rapid assay of murine leukemia virus helper activity for Friend spleen focus-forming virus. J Natl Cancer Inst. 1971 Jun;46(6):1219–1228. [PubMed] [Google Scholar]
  24. Stefanski E., Kirsten W. H. In vitro growth of an attenuated mouse leukemia virus. Cancer Res. 1974 Dec;34(12):3456–3460. [PubMed] [Google Scholar]
  25. Swetly P., Ostertag W. Friend virus release and induction of haemoglobin synthesis in erythroleukaemic cells respond differently to interferon. Nature. 1974 Oct 18;251(5476):642–644. doi: 10.1038/251642a0. [DOI] [PubMed] [Google Scholar]
  26. Yoshikura H., Hirokawa Y., Ikawa Y., Sugano H. Infectious but non-leukemogenic Friend leukemia virus obtained after prolonged cultivation in vitro. Int J Cancer. 1969 Sep 15;4(5):636–640. doi: 10.1002/ijc.2910040508. [DOI] [PubMed] [Google Scholar]
  27. Youn J. K., Blanchard M. G., Barski G. Immunization against Gross malignant lymphoma with mouse cell lines chronically infected with non-oncogenic murine C-type viruses. Eur J Cancer. 1974 Aug;10(8):491–496. doi: 10.1016/0014-2964(74)90072-3. [DOI] [PubMed] [Google Scholar]

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