Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1997 Apr;71(4):3013–3022. doi: 10.1128/jvi.71.4.3013-3022.1997

Studies of the susceptibility of nude, CD4 knockout, and SCID mutant mice to the disease induced by the murine AIDS defective virus.

C Simard 1, S J Klein 1, T Mak 1, P Jolicoeur 1
PMCID: PMC191430  PMID: 9060661

Abstract

Murine AIDS (MAIDS) is induced by a defective retrovirus that infects lymphocyte cells of the B lineage. To determine whether functional T cells are required for the infection of B cells, T-cell-deficient mice (nude, CD4 knockout, and SCII)) were infected with helper-free stocks of the MAIDS defective virus. Infection of B cells was monitored by Northern blot analysis and in situ hybridization. The C57BL/6 nude mice contained clusters of infected B cells, but less so than did the euthymic mice. In contrast, the (C57BL/6 x BALB/c)F1 nude mice harbored more infected B cells than did their euthymic littermates when maintained in a pathogen-free environment. Clusters of infected B cells were also detected in the MAIDS virus-infected CD4-/- knockout mice despite the total absence of CD4+ T cells in these mice. However, infected cells were not detected in SCID mice (deficient in mature T and B cells) inoculated with the same virus, indicating that precursor B cells are not a target of the virus in the absence of mature CD4+ T cells. These data confirm that the primary event in the development of MAIDS is the infection of relatively mature peripheral B cells and that CD4+ T cells are required to promote the expansion of these infected B cells.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. Aziz D. C., Hanna Z., Jolicoeur P. Severe immunodeficiency disease induced by a defective murine leukaemia virus. Nature. 1989 Apr 6;338(6215):505–508. doi: 10.1038/338505a0. [DOI] [PubMed] [Google Scholar]
  2. Bancroft G. J., Schreiber R. D., Unanue E. R. T cell-independent macrophage activation in scid mice. Curr Top Microbiol Immunol. 1989;152:235–242. doi: 10.1007/978-3-642-74974-2_28. [DOI] [PubMed] [Google Scholar]
  3. Bosma M. J., Carroll A. M. The SCID mouse mutant: definition, characterization, and potential uses. Annu Rev Immunol. 1991;9:323–350. doi: 10.1146/annurev.iy.09.040191.001543. [DOI] [PubMed] [Google Scholar]
  4. Cerny A., Hügin A. W., Hardy R. R., Hayakawa K., Zinkernagel R. M., Makino M., Morse H. C., 3rd B cells are required for induction of T cell abnormalities in a murine retrovirus-induced immunodeficiency syndrome. J Exp Med. 1990 Jan 1;171(1):315–320. doi: 10.1084/jem.171.1.315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cerny A., Hügin A. W., Holmes K. L., Morse H. C., 3rd CD4+ T cells in murine acquired immunodeficiency syndrome: evidence for an intrinsic defect in the proliferative response to soluble antigen. Eur J Immunol. 1990 Jul;20(7):1577–1581. doi: 10.1002/eji.1830200725. [DOI] [PubMed] [Google Scholar]
  6. Chattopadhyay S. K., Lander M. R., Rands E., Lowy D. R. Structure of endogenous murine leukemia virus DNA in mouse genomes. Proc Natl Acad Sci U S A. 1980 Oct;77(10):5774–5778. doi: 10.1073/pnas.77.10.5774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chattopadhyay S. K., Morse H. C., 3rd, Makino M., Ruscetti S. K., Hartley J. W. Defective virus is associated with induction of murine retrovirus-induced immunodeficiency syndrome. Proc Natl Acad Sci U S A. 1989 May;86(10):3862–3866. doi: 10.1073/pnas.86.10.3862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cheung S. C., Chattopadhyay S. K., Hartley J. W., Morse H. C., 3rd, Pitha P. M. Aberrant expression of cytokine genes in peritoneal macrophages from mice infected with LP-BM5 MuLV, a murine model of AIDS. J Immunol. 1991 Jan 1;146(1):121–127. [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Custer R. P., Bosma G. C., Bosma M. J. Severe combined immunodeficiency (SCID) in the mouse. Pathology, reconstitution, neoplasms. Am J Pathol. 1985 Sep;120(3):464–477. [PMC free article] [PubMed] [Google Scholar]
  11. Dorshkind K., Keller G. M., Phillips R. A., Miller R. G., Bosma G. C., O'Toole M., Bosma M. J. Functional status of cells from lymphoid and myeloid tissues in mice with severe combined immunodeficiency disease. J Immunol. 1984 Apr;132(4):1804–1808. [PubMed] [Google Scholar]
  12. Fitzpatrick E. A., Bryson J. S., Rhoads C., Kaplan A. M., Cohen D. A. T-deficient transmembrane signaling in CD4+ T cells of retroviral-induced immune-deficient mice. J Immunol. 1992 Jun 1;148(11):3377–3384. [PubMed] [Google Scholar]
  13. Fulop G. M., Bosma G. C., Bosma M. J., Phillips R. A. Early B-cell precursors in scid mice: normal numbers of cells transformable with Abelson murine leukemia virus (A-MuLV). Cell Immunol. 1988 Apr 15;113(1):192–201. doi: 10.1016/0008-8749(88)90017-2. [DOI] [PubMed] [Google Scholar]
  14. Giese N. A., Giese T., Morse H. C., 3rd Murine AIDS is an antigen-driven disease: requirements for major histocompatibility complex class II expression and CD4+ T cells. J Virol. 1994 Sep;68(9):5819–5824. doi: 10.1128/jvi.68.9.5819-5824.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hanna Z., Simard C., Laperrière A., Jolicoeur P. Specific expression of the human CD4 gene in mature CD4+ CD8- and immature CD4+ CD8+ T cells and in macrophages of transgenic mice. Mol Cell Biol. 1994 Feb;14(2):1084–1094. doi: 10.1128/mcb.14.2.1084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hardy R. R., Kemp J. D., Hayakawa K. Analysis of lymphoid population in scid mice; detection of a potential B lymphocyte progenitor population present at normal levels in scid mice by three color flow cytometry with B220 and S7. Curr Top Microbiol Immunol. 1989;152:19–25. doi: 10.1007/978-3-642-74974-2_3. [DOI] [PubMed] [Google Scholar]
  17. Huang M., Jolicoeur P. Characterization of the gag/fusion protein encoded by the defective Duplan retrovirus inducing murine acquired immunodeficiency syndrome. J Virol. 1990 Dec;64(12):5764–5772. doi: 10.1128/jvi.64.12.5764-5772.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Huang M., Simard C., Jolicoeur P. Immunodeficiency and clonal growth of target cells induced by helper-free defective retrovirus. Science. 1989 Dec 22;246(4937):1614–1617. doi: 10.1126/science.2480643. [DOI] [PubMed] [Google Scholar]
  19. Huang M., Simard C., Jolicoeur P. Susceptibility of inbred strains of mice to murine AIDS (MAIDS) correlates with target cell expansion and high expression of defective MAIDS virus. J Virol. 1992 Apr;66(4):2398–2406. doi: 10.1128/jvi.66.4.2398-2406.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Huang M., Simard C., Kay D. G., Jolicoeur P. The majority of cells infected with the defective murine AIDS virus belong to the B-cell lineage. J Virol. 1991 Dec;65(12):6562–6571. doi: 10.1128/jvi.65.12.6562-6571.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jacobson E. B., Caporale L. H., Thorbecke G. J. Effect of thymus cell injections on germinal center formation in lymphoid tissues of nude (thymusless) mice. Cell Immunol. 1974 Sep;13(3):416–430. doi: 10.1016/0008-8749(74)90261-5. [DOI] [PubMed] [Google Scholar]
  22. Jolicoeur P. Murine acquired immunodeficiency syndrome (MAIDS): an animal model to study the AIDS pathogenesis. FASEB J. 1991 Jul;5(10):2398–2405. doi: 10.1096/fasebj.5.10.2065888. [DOI] [PubMed] [Google Scholar]
  23. Kay D. G., Gravel C., Robitaille Y., Jolicoeur P. Retrovirus-induced spongiform myeloencephalopathy in mice: regional distribution of infected target cells and neuronal loss occurring in the absence of viral expression in neurons. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1281–1285. doi: 10.1073/pnas.88.4.1281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kim W. K., Tang Y., Kenny J. J., Longo D. L., Morse H. C., 3rd In murine AIDS, B cells are early targets of defective virus and are required for efficient infection and expression of defective virus in T cells and macrophages. J Virol. 1994 Oct;68(10):6767–6769. doi: 10.1128/jvi.68.10.6767-6769.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Locksley R. M., Reiner S. L., Hatam F., Littman D. R., Killeen N. Helper T cells without CD4: control of leishmaniasis in CD4-deficient mice. Science. 1993 Sep 10;261(5127):1448–1451. doi: 10.1126/science.8367726. [DOI] [PubMed] [Google Scholar]
  26. Makino M., Chattopadhyay S. K., Hartley J. W., Morse H. C., 3rd Analysis of role of CD8+ T cells in resistance to murine AIDS in A/J mice. J Immunol. 1992 Sep 1;149(5):1702–1706. [PubMed] [Google Scholar]
  27. Max E. E., Maizel J. V., Jr, Leder P. The nucleotide sequence of a 5.5-kilobase DNA segment containing the mouse kappa immunoglobulin J and C region genes. J Biol Chem. 1981 May 25;256(10):5116–5120. [PubMed] [Google Scholar]
  28. Morse H. C., 3rd, Chattopadhyay S. K., Makino M., Fredrickson T. N., Hügin A. W., Hartley J. W. Retrovirus-induced immunodeficiency in the mouse: MAIDS as a model for AIDS. AIDS. 1992 Jul;6(7):607–621. doi: 10.1097/00002030-199207000-00001. [DOI] [PubMed] [Google Scholar]
  29. Mosier D. E. Animal models for retrovirus-induced immunodeficiency disease. Immunol Invest. 1986 May;15(3):233–261. doi: 10.3109/08820138609026687. [DOI] [PubMed] [Google Scholar]
  30. Mosier D. E., Yetter R. A., Morse H. C., 3rd Functional T lymphocytes are required for a murine retrovirus-induced immunodeficiency disease (MAIDS). J Exp Med. 1987 Jun 1;165(6):1737–1742. doi: 10.1084/jem.165.6.1737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mosier D. E., Yetter R. A., Morse H. C., 3rd Retroviral induction of acute lymphoproliferative disease and profound immunosuppression in adult C57BL/6 mice. J Exp Med. 1985 Apr 1;161(4):766–784. doi: 10.1084/jem.161.4.766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Muralidhar G., Koch S., Haas M., Swain S. L. CD4 T cells in murine acquired immunodeficiency syndrome: polyclonal progression to anergy. J Exp Med. 1992 Jun 1;175(6):1589–1599. doi: 10.1084/jem.175.6.1589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Paquette Y., Doyon L., Laperrière A., Hanna Z., Ball J., Sekaly R. P., Jolicoeur P. A viral long terminal repeat expressed in CD4+CD8+ precursors is downregulated in mature peripheral CD4-CD8+ or CD4+CD8- T cells. Mol Cell Biol. 1992 Aug;12(8):3522–3530. doi: 10.1128/mcb.12.8.3522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Paquette Y., Kay D. G., Rassart E., Robitaille Y., Jolicoeur P. Substitution of the U3 long terminal repeat region of the neurotropic Cas-Br-E retrovirus affects its disease-inducing potential. J Virol. 1990 Aug;64(8):3742–3752. doi: 10.1128/jvi.64.8.3742-3752.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pelleitier M., Montplaisir S. The nude mouse: a model of deficient T-cell function. Methods Achiev Exp Pathol. 1975;7:149–166. [PubMed] [Google Scholar]
  36. Rahemtulla A., Fung-Leung W. P., Schilham M. W., Kündig T. M., Sambhara S. R., Narendran A., Arabian A., Wakeham A., Paige C. J., Zinkernagel R. M. Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature. 1991 Sep 12;353(6340):180–184. doi: 10.1038/353180a0. [DOI] [PubMed] [Google Scholar]
  37. Schuler W., Bosma M. J. Nature of the scid defect: a defective VDJ recombinase system. Curr Top Microbiol Immunol. 1989;152:55–62. doi: 10.1007/978-3-642-74974-2_8. [DOI] [PubMed] [Google Scholar]
  38. Simard C., Huang M., Jolicoeur P. Murine AIDS is initiated in the lymph nodes draining the site of inoculation, and the infected B cells influence T cells located at distance, in noninfected organs. J Virol. 1994 Mar;68(3):1903–1912. doi: 10.1128/jvi.68.3.1903-1912.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Simard C., Jolicoeur P. The effect of anti-neoplastic drugs on murine acquired immunodeficiency syndrome. Science. 1991 Jan 18;251(4991):305–308. doi: 10.1126/science.1987646. [DOI] [PubMed] [Google Scholar]
  40. Yetter R. A., Buller R. M., Lee J. S., Elkins K. L., Mosier D. E., Fredrickson T. N., Morse H. C., 3rd CD4+ T cells are required for development of a murine retrovirus-induced immunodeficiency syndrome (MAIDS). J Exp Med. 1988 Aug 1;168(2):623–635. doi: 10.1084/jem.168.2.623. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES