Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1976 Oct 1;144(4):970–984. doi: 10.1084/jem.144.4.970

Lysis of RNA tumor viruses by human serum: direct antibody-independent triggering of the classical complement pathway

PMCID: PMC2190433  PMID: 62019

Abstract

In earlier studies we found that human serum, but not serum from multiple other species, inactivated and lysed oncornaviruses from a number of diverse sources in the apparent absence of antibody. A detailed analysis of the role of the human complement (C) system in mediating this lytic process indicates that human C1q interacts directly, in the absence of immunoglobulin, with oncornaviruses. Binding of C1 via C1q in this manner leads to activation of C1r, C1s, and thus of the classical C pathway. Integrity of the classical pathway is an absolute requirement for lysis although activation of the alternative pathway considerably amplifies the amount of lysis obtained, possibly through involvement of the C3b-dependent feedback mechanism. Activation of C is accompanied by deposition of C components on the viral surface and lysis on completion of the C reaction sequence. Thus in this system, the C1q subunit of C1 subserves a specific recognition function normally associated with antibody. This ability of human serum to inactivate oncornaviruses may represent a natural defense mechanism operative in vivo which deters expression of intact oncornaviruses in human malignancies.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Aaronson S. A., Todaro G. J. Transformation and virus growth by murine sarcoma viruses in human cells. Nature. 1970 Jan 31;225(5231):458–459. doi: 10.1038/225458a0. [DOI] [PubMed] [Google Scholar]
  2. Baxt W. G., Spiegelman S. Nuclear DNA sequences present in human leukemic cells and absent in normal leukocytes. Proc Natl Acad Sci U S A. 1972 Dec;69(12):3737–3741. doi: 10.1073/pnas.69.12.3737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baxt W., Hehlmann R., Spiegelman S. Human leukaemic cells contain reverse transcriptase associated with a high molecular weight virus-related RNA. Nat New Biol. 1972 Nov 15;240(98):72–75. doi: 10.1038/newbio240072a0. [DOI] [PubMed] [Google Scholar]
  4. Charman H. P., Kim N., White M., Gilden R. V. Failure to detect, in human sera, antibodies cross-reactive with group-specific antigens of murine leukemia virus. J Natl Cancer Inst. 1974 May;52(5):1409–1413. doi: 10.1093/jnci/52.5.1409. [DOI] [PubMed] [Google Scholar]
  5. Cooper N. R., Müller-Eberhard H. J. A comparison of methods for the molecular quantitation of the fourth component of human complement. Immunochemistry. 1968 Mar;5(2):155–169. doi: 10.1016/0019-2791(68)90100-6. [DOI] [PubMed] [Google Scholar]
  6. Cooper N. R., Müller-Eberhard H. J. The reaction mechanism of human C5 in immune hemolysis. J Exp Med. 1970 Oct 1;132(4):775–793. doi: 10.1084/jem.132.4.775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cooper N. R., Polley M. J., Müller-Eberhard H. J. The second component of human complement (C2): quantitative molecular analysis of its reactions in immune hemolysis. Immunochemistry. 1970 Apr;7(4):341–356. doi: 10.1016/0019-2791(70)90237-5. [DOI] [PubMed] [Google Scholar]
  8. Cooper N. R., ten Bensel R., Kohler P. F. Studies of an additional kindred with hereditary deficiency of the second component of human complement (C2) and description of a new method for the quantitation of C2. J Immunol. 1968 Dec;101(6):1176–1182. [PubMed] [Google Scholar]
  9. Essex M. Horizontally and vertically transmitted oncornaviruses of cats. Adv Cancer Res. 1975;21:175–248. doi: 10.1016/s0065-230x(08)60973-2. [DOI] [PubMed] [Google Scholar]
  10. Gallagher R. E., Gallo R. C. Type C RNA tumor virus isolated from cultured human acute myelogenous leukemia cells. Science. 1975 Jan 31;187(4174):350–353. doi: 10.1126/science.46123. [DOI] [PubMed] [Google Scholar]
  11. Gallo R. C., Miller N. R., Saxinger W. C., Gillespie D. Primate RNA tumor virus-like DNA synthesized endogenously by RNA-dependent DNA polymerase in virus-like particles from fresh human acute leukemic blood cells. Proc Natl Acad Sci U S A. 1973 Nov;70(11):3219–3224. doi: 10.1073/pnas.70.11.3219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Götze O., Müller-Eberhard H. J. The C3-activator system: an alternate pathway of complement activation. J Exp Med. 1971 Sep 1;134(3 Pt 2):90s–108s. [PubMed] [Google Scholar]
  13. Hersh E. M., Hanna M. G., Jr, Gutterman J. U., Mavligit G., Yurconic M., Jr, Gschwind C. R. Human immune response to active immunization with Rauscher leukemia virus. II. Humoral immunity. J Natl Cancer Inst. 1974 Aug;53(2):327–333. doi: 10.1093/jnci/53.2.327. [DOI] [PubMed] [Google Scholar]
  14. Hirshaut Y., Reagan R. L., Perry S., De Vita V., Jr, Barile M. F. The search for a viral agent in Hodgkin's disease. Cancer. 1974 Oct;34(4):1080–1089. doi: 10.1002/1097-0142(197410)34:4<1080::aid-cncr2820340418>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  15. Huebner R. J., Todaro G. J. Oncogenes of RNA tumor viruses as determinants of cancer. Proc Natl Acad Sci U S A. 1969 Nov;64(3):1087–1094. doi: 10.1073/pnas.64.3.1087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ihle J. N., Hanna M. G., Jr, Roberson L. E., Kenney F. T. Autogenous immunity to endogenous RNA tumor virus. Identification of antibody reactivity to select viral antigens. J Exp Med. 1974 Jun 1;139(6):1568–1581. doi: 10.1084/jem.139.6.1568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. JENSEN F. C., GIRARDI A. J., GILDEN R. V., KOPROWSKI H. INFECTION OF HUMAN AND SIMIAN TISSUE CULTURES WITH ROUS SARCOMA VIRUS. Proc Natl Acad Sci U S A. 1964 Jul;52:53–59. doi: 10.1073/pnas.52.1.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kalter S. S., Helmke R. J., Heberling R. L., Panigel M., Fowler A. K., Strickland J. E., Hellman A. Brief communication: C-type particles in normal human placentas. J Natl Cancer Inst. 1973 Apr;50(4):1081–1084. doi: 10.1093/jnci/50.4.1081. [DOI] [PubMed] [Google Scholar]
  19. Kim B. S. Presence of antibody to a primate RNA virus in human plasma. Nature. 1975 Oct 16;257(5527):614–616. doi: 10.1038/257614a0. [DOI] [PubMed] [Google Scholar]
  20. Kolb W. P., Müller-Eberhard H. J. Mode of action of human C9: adsorption of multiple C9 molecules to cell-bound C8. J Immunol. 1974 Aug;113(2):479–488. [PubMed] [Google Scholar]
  21. Mak T. W., Kurtz S., Manaster J., Housman D. Viral-related information in oncornavirus-lik particles isolated from cultures of marrow cells from leukemic patients in relapse and remission. Proc Natl Acad Sci U S A. 1975 Feb;72(2):623–627. doi: 10.1073/pnas.72.2.623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. McAllister R. M. Viruses in human carcinogenesis. Prog Med Virol. 1973;16:48–85. [PubMed] [Google Scholar]
  23. McConahey P. J., Dixon F. J. A method of trace iodination of proteins for immunologic studies. Int Arch Allergy Appl Immunol. 1966;29(2):185–189. doi: 10.1159/000229699. [DOI] [PubMed] [Google Scholar]
  24. Natali P. G., Tan E. M. Precipitin reactions between polyribonucleotides and heat labile serum factors. J Immunol. 1972 Feb;108(2):318–324. [PubMed] [Google Scholar]
  25. Nooter K., Aarssen A. M., Bentvelzen P., De Groot F. G., Van Pelt F. G. Isolation of infectious C-type oncornavirus from human leukaemic bone marrow cells. Nature. 1975 Aug 14;256(5518):595–597. doi: 10.1038/256595a0. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Panem S., Prochownik E. V., Reale F. R., Kirsten W. H. Isolation of type C virions from a normal human fibroblast strain. Science. 1975 Jul 25;189(4199):297–299. doi: 10.1126/science.49927. [DOI] [PubMed] [Google Scholar]
  28. Pinckard R. N., Olson M. S., Kelley R. E., DeHeer D. H., Palmer J. D., O'Rourke R. A., Goldfein S. Antibody-independent activation of human C1 after interaction with heart subcellular membranes. J Immunol. 1973 May;110(5):1376–1382. [PubMed] [Google Scholar]
  29. Rent R., Ertel N., Eisenstein R., Gewurz H. Complement activation by interaction of polyanions and polycations. I. Heparin-protamine induced consumption of complement. J Immunol. 1975 Jan;114(1 Pt 1):120–124. [PubMed] [Google Scholar]
  30. Sarma P. S., Sharar A., Walters V., Gardner M. A survey of cats and humans for prevalence of feline leukemia-sarcoma virus neutralizing serum antibodies. Proc Soc Exp Biol Med. 1974 Feb;145(2):560–564. doi: 10.3181/00379727-145-37851. [DOI] [PubMed] [Google Scholar]
  31. Sarngadharan M. G., Sarin P. S., Reitz M. S., Gallo R. C. Reverse transcriptase activity of human acute leukaemic cells: purification of the enzyme, response to AMV 70S RNA, and characterization of the DNA product. Nat New Biol. 1972 Nov 15;240(98):67–72. doi: 10.1038/newbio240067a0. [DOI] [PubMed] [Google Scholar]
  32. Schreiber R. D., Müller-Eberhard H. J. Fourth component of human complement: description of a three polypeptide chain structure. J Exp Med. 1974 Nov 1;140(5):1324–1335. doi: 10.1084/jem.140.5.1324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sherr C. J., Todaro G. J. Primate type C virus p30 antigen in cells from humans with acute leukemia. Science. 1975 Mar 7;187(4179):855–857. doi: 10.1126/science.163489. [DOI] [PubMed] [Google Scholar]
  34. Sobel A. T., Bokisch V. A., Müller-Eberhard H. J. C1q deviation test for the detection of immune complexes, aggregates of IgG, and bacterial products in human serum. J Exp Med. 1975 Jul 1;142(1):139–150. doi: 10.1084/jem.142.1.139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Strand M., August J. T. Type-C RNA virus gene expression in human tissue. J Virol. 1974 Dec;14(6):1584–1596. doi: 10.1128/jvi.14.6.1584-1596.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Teich N. M., Weiss R. A., Salahuddin S. Z., Gallagher R. E., Gillespie D. H., Gallo R. C. Infective transmission and characterisation of a C-type virus released by cultured human myeloid leukaemia cells. Nature. 1975 Aug 14;256(5518):551–555. doi: 10.1038/256551a0. [DOI] [PubMed] [Google Scholar]
  37. Theofilopoulos A. N., Perrin L. H. Binding of components of the properdin system to cultured human lymphoblastoid cells and B lymphocytes. J Exp Med. 1976 Feb 1;143(2):271–289. doi: 10.1084/jem.143.2.271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Todaro G. J., Gallo R. C. Immunological relationship of DNA polymerase from human acute leukaemia cells and primate and mouse leukaemia virus reverse transcriptase. Nature. 1973 Jul 27;244(5413):206–209. doi: 10.1038/244206a0. [DOI] [PubMed] [Google Scholar]
  39. Valet G., Cooper N. R. Isolation and characterization of the proenzyme form of the C1s subunit of the first complement component. J Immunol. 1974 Jan;112(1):339–350. [PubMed] [Google Scholar]
  40. Volanakis J. E., Kaplan M. H. Interaction of C-reactive protein complexes with the complement system. II. Consumption of guinea pig complement by CRP complexes: requirement for human C1q. J Immunol. 1974 Jul;113(1):9–17. [PubMed] [Google Scholar]
  41. Weber K., Osborn M. The reliability of molecular weight determinations by dodecyl sulfate-polyacrylamide gel electrophoresis. J Biol Chem. 1969 Aug 25;244(16):4406–4412. [PubMed] [Google Scholar]
  42. 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]
  43. Yeh J., Ahmed M., Mayyasi S. A., Alessi A. A. Detection of an antigen related to Mason-Pfizer virus in malignant human breast tumors. Science. 1975 Nov 7;190(4214):583–584. doi: 10.1126/science.810888. [DOI] [PubMed] [Google Scholar]
  44. Yonemasu K., Stroud R. M. Clq: rapid purification method for preparation of monospecific antisera and for biochemical studies. J Immunol. 1971 Feb;106(2):304–313. [PubMed] [Google Scholar]
  45. Ziccardi R. J., Cooper N. R. Physicochemical and functional characterization of the C1r subunit of the first complement component. J Immunol. 1976 Feb;116(2):496–503. [PubMed] [Google Scholar]
  46. Zurcher C., Brinkhof J., Bentvelzen P., De Man J. C. C-type virus antigens detected by immunofluorescence in human bone tumour cultures. Nature. 1975 Apr 3;254(5499):457–459. doi: 10.1038/254457a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES