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. 1994 Apr;68(4):2735–2740. doi: 10.1128/jvi.68.4.2735-2740.1994

Murine retrovirus-induced depletion of T cells is mediated through activation-induced death by apoptosis.

K Saha 1, P H Yuen 1, P K Wong 1
PMCID: PMC236752  PMID: 8139049

Abstract

ts1, a mutant of Moloney murine leukemia virus, causes neurologic disorders and acute immunodeficiency associated with the destruction of thymocytes and helper T cells. In this study, we examined whether apoptosis was involved in ts1-induced killings of T cells. Neonatal mice were inoculated with ts1, and 20 to 23 days postinoculation, when cytopathic effects on T cells normally appear, thymocytes and splenic lymphocytes were isolated and examined. Our results showed that several features of apoptosis were present in ts1-infected thymocytes and splenic lymphocytes. Apoptotic fragmented DNA, condensation of the chromatin, and enhanced cell death after stimulation with mitogens which was preventable with protein synthesis inhibitors, all of which are common features of apoptotic cell death, were observed in ts1-infected cells. Several other viruses, including human immunodeficiency virus, have been shown to cause apoptotic death of T cells. Here we show for the first time that a murine retrovirus which also induces immunodeficiency can cause apoptotic T-cell death. Future studies with this murine retrovirus may provide important results to help us better understand the mechanisms of retrovirus-induced apoptosis of T cells.

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Selected References

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  1. Ameisen J. C., Capron A. Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. Immunol Today. 1991 Apr;12(4):102–105. doi: 10.1016/0167-5699(91)90092-8. [DOI] [PubMed] [Google Scholar]
  2. BALL J. K., HUH T. Y., MCCARTER J. A. ON THE STATISTICAL DISTRIBUTION OF EPIDERMAL PAPILLOMATA IN MICE. Br J Cancer. 1964 Mar;18:120–123. doi: 10.1038/bjc.1964.12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Banda N. K., Bernier J., Kurahara D. K., Kurrle R., Haigwood N., Sekaly R. P., Finkel T. H. Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med. 1992 Oct 1;176(4):1099–1106. doi: 10.1084/jem.176.4.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blackman M., Kappler J., Marrack P. The role of the T cell receptor in positive and negative selection of developing T cells. Science. 1990 Jun 15;248(4961):1335–1341. doi: 10.1126/science.1972592. [DOI] [PubMed] [Google Scholar]
  5. Brinchmann J. E., Gaudernack G., Thorsby E., Vartdal F. Staphylococcal exotoxin superantigens induce human immunodeficiency virus type 1 expression in naturally infected CD4+ T cells. J Virol. 1992 Oct;66(10):5924–5928. doi: 10.1128/jvi.66.10.5924-5928.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cohen J. J. Programmed cell death in the immune system. Adv Immunol. 1991;50:55–85. doi: 10.1016/s0065-2776(08)60822-6. [DOI] [PubMed] [Google Scholar]
  7. Crise B., Rose J. K. Human immunodeficiency virus type 1 glycoprotein precursor retains a CD4-p56lck complex in the endoplasmic reticulum. J Virol. 1992 Apr;66(4):2296–2301. doi: 10.1128/jvi.66.4.2296-2301.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Deng G., Podack E. R. Suppression of apoptosis in a cytotoxic T-cell line by interleukin 2-mediated gene transcription and deregulated expression of the protooncogene bcl-2. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2189–2193. doi: 10.1073/pnas.90.6.2189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dipasquale B., Youle R. J. Programmed cell death in heterokaryons. A study of the transfer of apoptosis between nuclei. Am J Pathol. 1992 Dec;141(6):1471–1479. [PMC free article] [PubMed] [Google Scholar]
  10. Greenfield I., Nickerson J., Penman S., Stanley M. Human papillomavirus 16 E7 protein is associated with the nuclear matrix. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11217–11221. doi: 10.1073/pnas.88.24.11217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Groux H., Torpier G., Monté D., Mouton Y., Capron A., Ameisen J. C. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med. 1992 Feb 1;175(2):331–340. doi: 10.1084/jem.175.2.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jeurissen S. H., Wagenaar F., Pol J. M., van der Eb A. J., Noteborn M. H. Chicken anemia virus causes apoptosis of thymocytes after in vivo infection and of cell lines after in vitro infection. J Virol. 1992 Dec;66(12):7383–7388. doi: 10.1128/jvi.66.12.7383-7388.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Koga Y., Sasaki M., Nakamura K., Kimura G., Nomoto K. Intracellular distribution of the envelope glycoprotein of human immunodeficiency virus and its role in the production of cytopathic effect in CD4+ and CD4- human cell lines. J Virol. 1990 Oct;64(10):4661–4671. doi: 10.1128/jvi.64.10.4661-4671.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Marrack P., Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990 May 11;248(4956):705–711. doi: 10.1126/science.2185544. [DOI] [PubMed] [Google Scholar]
  15. McCabe M. J., Jr, Orrenius S. Deletion and depletion: the involvement of viruses and environmental factors in T-lymphocyte apoptosis. Lab Invest. 1992 Apr;66(4):403–406. [PubMed] [Google Scholar]
  16. McConkey D. J., Hartzell P., Chow S. C., Orrenius S., Jondal M. Interleukin 1 inhibits T cell receptor-mediated apoptosis in immature thymocytes. J Biol Chem. 1990 Feb 25;265(6):3009–3011. [PubMed] [Google Scholar]
  17. McConkey D. J., Hartzell P., Duddy S. K., Håkansson H., Orrenius S. 2,3,7,8-Tetrachlorodibenzo-p-dioxin kills immature thymocytes by Ca2+-mediated endonuclease activation. Science. 1988 Oct 14;242(4876):256–259. doi: 10.1126/science.3262923. [DOI] [PubMed] [Google Scholar]
  18. McConkey D. J., Hartzell P., Jondal M., Orrenius S. Inhibition of DNA fragmentation in thymocytes and isolated thymocyte nuclei by agents that stimulate protein kinase C. J Biol Chem. 1989 Aug 15;264(23):13399–13402. [PubMed] [Google Scholar]
  19. McConkey D. J., Nicotera P., Hartzell P., Bellomo G., Wyllie A. H., Orrenius S. Glucocorticoids activate a suicide process in thymocytes through an elevation of cytosolic Ca2+ concentration. Arch Biochem Biophys. 1989 Feb 15;269(1):365–370. doi: 10.1016/0003-9861(89)90119-7. [DOI] [PubMed] [Google Scholar]
  20. Meyaard L., Otto S. A., Jonker R. R., Mijnster M. J., Keet R. P., Miedema F. Programmed death of T cells in HIV-1 infection. Science. 1992 Jul 10;257(5067):217–219. doi: 10.1126/science.1352911. [DOI] [PubMed] [Google Scholar]
  21. Newell M. K., Haughn L. J., Maroun C. R., Julius M. H. Death of mature T cells by separate ligation of CD4 and the T-cell receptor for antigen. Nature. 1990 Sep 20;347(6290):286–289. doi: 10.1038/347286a0. [DOI] [PubMed] [Google Scholar]
  22. Ohno K., Nakano T., Matsumoto Y., Watari T., Goitsuka R., Nakayama H., Tsujimoto H., Hasegawa A. Apoptosis induced by tumor necrosis factor in cells chronically infected with feline immunodeficiency virus. J Virol. 1993 May;67(5):2429–2433. doi: 10.1128/jvi.67.5.2429-2433.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pantaleo G., Graziosi C., Fauci A. S. New concepts in the immunopathogenesis of human immunodeficiency virus infection. N Engl J Med. 1993 Feb 4;328(5):327–335. doi: 10.1056/NEJM199302043280508. [DOI] [PubMed] [Google Scholar]
  24. Pinching A. J., Nye K. E. Defective signal transduction--a common pathway for cellular dysfunction in HIV infection? Immunol Today. 1990 Jul;11(7):256–259. doi: 10.1016/0167-5699(90)90100-n. [DOI] [PubMed] [Google Scholar]
  25. Poli G., Fauci A. S. Cytokine modulation of HIV expression. Semin Immunol. 1993 Jun;5(3):165–173. doi: 10.1006/smim.1993.1020. [DOI] [PubMed] [Google Scholar]
  26. Prasad G., Stoica G., Wong P. K. The role of the thymus in the pathogenesis of hind-limb paralysis induced by ts1, a mutant of Moloney murine leukemia virus-TB. Virology. 1989 Apr;169(2):332–340. doi: 10.1016/0042-6822(89)90158-x. [DOI] [PubMed] [Google Scholar]
  27. Rojko J. L., Fulton R. M., Rezanka L. J., Williams L. L., Copelan E., Cheney C. M., Reichel G. S., Neil J. C., Mathes L. E., Fisher T. G. Lymphocytotoxic strains of feline leukemia virus induce apoptosis in feline T4-thymic lymphoma cells. Lab Invest. 1992 Apr;66(4):418–426. [PubMed] [Google Scholar]
  28. Saha K., Wong P. K. Protective role of cytotoxic lymphocytes against murine leukemia virus-induced neurologic disease and immunodeficiency is enhanced by the presence of helper T cells. Virology. 1992 Jun;188(2):921–925. doi: 10.1016/0042-6822(92)90554-3. [DOI] [PubMed] [Google Scholar]
  29. Saha K., Wong P. K. Rudimentary thymus of SCID mouse plays an important role in the development of retrovirus-induced neurologic disorders. Virology. 1993 Jul;195(1):211–218. doi: 10.1006/viro.1993.1362. [DOI] [PubMed] [Google Scholar]
  30. Saha K., Wong P. K. T, not B, lymphocytes are required for immunodeficiency and paralysis induced by ts1, a mutant of Moloney murine leukemia virus-TB. Virology. 1991 Aug;183(2):815–820. doi: 10.1016/0042-6822(91)91017-b. [DOI] [PubMed] [Google Scholar]
  31. Saha K., Wong P. K. ts1, a temperature-sensitive mutant of Moloney murine leukemia virus TB, can infect both CD4+ and CD8+ T cells but requires CD4+ T cells in order to cause paralysis and immunodeficiency. J Virol. 1992 May;66(5):2639–2646. doi: 10.1128/jvi.66.5.2639-2646.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Schnittman S. M., Lane H. C., Greenhouse J., Justement J. S., Baseler M., Fauci A. S. Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6058–6062. doi: 10.1073/pnas.87.16.6058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schnittman S. M., Psallidopoulos M. C., Lane H. C., Thompson L., Baseler M., Massari F., Fox C. H., Salzman N. P., Fauci A. S. The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science. 1989 Jul 21;245(4915):305–308. doi: 10.1126/science.2665081. [DOI] [PubMed] [Google Scholar]
  34. Sellins K. S., Cohen J. J. Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes. J Immunol. 1987 Nov 15;139(10):3199–3206. [PubMed] [Google Scholar]
  35. Shi Y. F., Sahai B. M., Green D. R. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature. 1989 Jun 22;339(6226):625–626. doi: 10.1038/339625a0. [DOI] [PubMed] [Google Scholar]
  36. Shikova E., Lin Y. C., Saha K., Brooks B. R., Wong P. K. Correlation of specific virus-astrocyte interactions and cytopathic effects induced by ts1, a neurovirulent mutant of Moloney murine leukemia virus. J Virol. 1993 Mar;67(3):1137–1147. doi: 10.1128/jvi.67.3.1137-1147.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Smith C. A., Williams G. T., Kingston R., Jenkinson E. J., Owen J. J. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. doi: 10.1038/337181a0. [DOI] [PubMed] [Google Scholar]
  38. Stoica G., Floyd E., Illanes O., Wong P. K. Temporal lymphoreticular changes caused by ts1, a paralytogenic mutant of Moloney murine leukemia virus TB. Lab Invest. 1992 Apr;66(4):427–436. [PubMed] [Google Scholar]
  39. Szurek P. F., Yuen P. H., Ball J. K., Wong P. K. A Val-25-to-Ile substitution in the envelope precursor polyprotein, gPr80env, is responsible for the temperature sensitivity, inefficient processing of gPr80env, and neurovirulence of ts1, a mutant of Moloney murine leukemia virus TB. J Virol. 1990 Feb;64(2):467–475. doi: 10.1128/jvi.64.2.467-475.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Taylor M. V., Metcalfe J. C., Hesketh T. R., Smith G. A., Moore J. P. Mitogens increase phosphorylation of phosphoinositides in thymocytes. 1984 Nov 29-Dec 5Nature. 312(5993):462–465. doi: 10.1038/312462a0. [DOI] [PubMed] [Google Scholar]
  41. Terai C., Kornbluth R. S., Pauza C. D., Richman D. D., Carson D. A. Apoptosis as a mechanism of cell death in cultured T lymphoblasts acutely infected with HIV-1. J Clin Invest. 1991 May;87(5):1710–1715. doi: 10.1172/JCI115188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Thomas N., Bell P. A. Glucocorticoid-induced cell-size changes and nuclear fragility in rat thymocytes. Mol Cell Endocrinol. 1981 Apr;22(1):71–84. doi: 10.1016/0303-7207(81)90103-9. [DOI] [PubMed] [Google Scholar]
  43. Tsien R. Y., Pozzan T., Rink T. J. T-cell mitogens cause early changes in cytoplasmic free Ca2+ and membrane potential in lymphocytes. Nature. 1982 Jan 7;295(5844):68–71. doi: 10.1038/295068a0. [DOI] [PubMed] [Google Scholar]
  44. Ucker D. S., Ashwell J. D., Nickas G. Activation-driven T cell death. I. Requirements for de novo transcription and translation and association with genome fragmentation. J Immunol. 1989 Dec 1;143(11):3461–3469. [PubMed] [Google Scholar]
  45. Williams G. T., Smith C. A., Spooncer E., Dexter T. M., Taylor D. R. Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis. Nature. 1990 Jan 4;343(6253):76–79. doi: 10.1038/343076a0. [DOI] [PubMed] [Google Scholar]
  46. Wong P. K., Floyd E., Szurek P. F. High susceptibility of FVB/N mice to the paralytic disease induced by ts1, a mutant of Moloney murine leukemia virus TB. Virology. 1991 Jan;180(1):365–371. doi: 10.1016/0042-6822(91)90041-9. [DOI] [PubMed] [Google Scholar]
  47. Wong P. K. Moloney murine leukemia virus temperature-sensitive mutants: a model for retrovirus-induced neurologic disorders. Curr Top Microbiol Immunol. 1990;160:29–60. doi: 10.1007/978-3-642-75267-4_3. [DOI] [PubMed] [Google Scholar]
  48. Wong P. K., Prasad G., Hansen J., Yuen P. H. ts1, a mutant of Moloney murine leukemia virus-TB, causes both immunodeficiency and neurologic disorders in BALB/c mice. Virology. 1989 Jun;170(2):450–459. doi: 10.1016/0042-6822(89)90436-4. [DOI] [PubMed] [Google Scholar]
  49. Wong P. K., Soong M. M., Yuen P. H. Replication of murine leukemia virus in heterologous cells: interaction between ecotropic and xenotropic viruses. Virology. 1981 Mar;109(2):366–378. doi: 10.1016/0042-6822(81)90507-9. [DOI] [PubMed] [Google Scholar]
  50. Wong P. K., Szurek P. F., Floyd E., Saha K., Brooks B. R. Alteration from T- to B-cell tropism reduces thymic atrophy and cytocidal effects in thymocytes but not neurovirulence induced by ts1, a mutant of Moloney murine leukemia virus TB. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8991–8995. doi: 10.1073/pnas.88.20.8991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wyllie A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980 Apr 10;284(5756):555–556. doi: 10.1038/284555a0. [DOI] [PubMed] [Google Scholar]
  52. Yuen P. H., Malehorn D., Nau C., Soong M. M., Wong P. K. Molecular cloning of two paralytogenic, temperature-sensitive mutants, ts1 and ts7, and the parental wild-type Moloney murine leukemia virus. J Virol. 1985 Apr;54(1):178–185. doi: 10.1128/jvi.54.1.178-185.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Zhong L. T., Sarafian T., Kane D. J., Charles A. C., Mah S. P., Edwards R. H., Bredesen D. E. bcl-2 inhibits death of central neural cells induced by multiple agents. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4533–4537. doi: 10.1073/pnas.90.10.4533. [DOI] [PMC free article] [PubMed] [Google Scholar]

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