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. 1997 Mar;150(3):1089–1100.

Effect of a retroviral immunodeficiency syndrome on murine cytomegalovirus-induced hepatitis.

C D Peacock 1, S D Olver 1, P Price 1
PMCID: PMC1857883  PMID: 9060844

Abstract

We have studied the effects of LP-BM5 MuLV-induced murine acquired immunodeficiency syndrome (MAIDS) on concomitant murine cytomegalovirus (MCMV) infection in the livers of C57BL mice. A delayed inflammatory response in livers of mice with MAIDS (M+) on day 4 was associated with impaired clearance of MCMV-infected cells 6 days after infection. This correlated with increased levels of inflammation and serum alanine transaminase. The latter reflects enhanced hepatic necrosis, which was evident histologically. Delayed-type hypersensitivity responses to MCMV antigen were unimpaired in M+ mice and were mediated by CD8+ cells. Depletion of NK1.1+ cells from M+ mice increased MCMV replication and associated liver damage on day 6, whereas CD8+ depletion had little effect. In contrast, in the presence of CD8+ cells M- C57BL mice did not require NK1.1+ cells for control of hepatic MCMV infection, but dual NK1.1+ and CD8+ depletion dramatically potentiated hepatic MCMV replication. Our results suggest that M+ mice may acquire non-NK1.1+ and non-CD8+ cells that are able to partially control hepatic MCMV infection. These findings are discussed with reference to mortality in M+ mice after high-dose MCMV infection, as this is initially delayed but ultimately higher than in M- controls.

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Selected References

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

  1. Allan J. E., Shellam G. R. Genetic control of murine cytomegalovirus infection: virus titres in resistant and susceptible strains of mice. Arch Virol. 1984;81(1-2):139–150. doi: 10.1007/BF01309303. [DOI] [PubMed] [Google Scholar]
  2. Allcock R. J., Peacock C. D., Price P. The inflammatory macrophage response to MCMV in mice with a retroviral immunodeficiency syndrome (MAIDS). J Leukoc Biol. 1996 Jul;60(1):44–50. doi: 10.1002/jlb.60.1.44. [DOI] [PubMed] [Google Scholar]
  3. Bancroft G. J., Shellam G. R., Chalmer J. E. Genetic influences on the augmentation of natural killer (NK) cells during murine cytomegalovirus infection: correlation with patterns of resistance. J Immunol. 1981 Mar;126(3):988–994. [PubMed] [Google Scholar]
  4. Bonacini M. Hepatobiliary complications in patients with human immunodeficiency virus infection. Am J Med. 1992 Apr;92(4):404–411. doi: 10.1016/0002-9343(92)90271-c. [DOI] [PubMed] [Google Scholar]
  5. Bukowski J. F., Woda B. A., Habu S., Okumura K., Welsh R. M. Natural killer cell depletion enhances virus synthesis and virus-induced hepatitis in vivo. J Immunol. 1983 Sep;131(3):1531–1538. [PubMed] [Google Scholar]
  6. Bukowski J. F., Woda B. A., Welsh R. M. Pathogenesis of murine cytomegalovirus infection in natural killer cell-depleted mice. J Virol. 1984 Oct;52(1):119–128. doi: 10.1128/jvi.52.1.119-128.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Drew W. L. Cytomegalovirus infection in patients with AIDS. J Infect Dis. 1988 Aug;158(2):449–456. doi: 10.1093/infdis/158.2.449. [DOI] [PubMed] [Google Scholar]
  9. Erlich K. S., Mills J., Shanley J. D. Effects of L3T4+ lymphocyte depletion on acute murine cytomegalovirus infection. J Gen Virol. 1989 Jul;70(Pt 7):1765–1771. doi: 10.1099/0022-1317-70-7-1765. [DOI] [PubMed] [Google Scholar]
  10. Griffiths P. D., Grundy J. E. Molecular biology and immunology of cytomegalovirus. Biochem J. 1987 Jan 15;241(2):313–324. doi: 10.1042/bj2410313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Grundy J. E., Mackenzie J. S., Stanley N. F. Influence of H-2 and non-H-2 genes on resistance to murine cytomegalovirus infection. Infect Immun. 1981 Apr;32(1):277–286. doi: 10.1128/iai.32.1.277-286.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Grundy J. E., Melief C. J. Effect of Nu/Nu gene on genetically determined resistance to murine cytomegalovirus. J Gen Virol. 1982 Jul;61(Pt 50):133–136. doi: 10.1099/0022-1317-61-1-133. [DOI] [PubMed] [Google Scholar]
  13. Grundy J. E., Trapman J., Allan J. E., Shellam G. R., Melief C. J. Evidence for a protective role of interferon in resistance to murine cytomegalovirus and its control by non-H-2-linked genes. Infect Immun. 1982 Jul;37(1):143–150. doi: 10.1128/iai.37.1.143-150.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Harbison M. A., De Girolami P. C., Jenkins R. L., Hammer S. M. Ganciclovir therapy of severe cytomegalovirus infections in solid-organ transplant recipients. Transplantation. 1988 Jul;46(1):82–88. doi: 10.1097/00007890-198807000-00015. [DOI] [PubMed] [Google Scholar]
  15. Ho M. Role of specific cytotoxic lymphocytes in cellular immunity against murine cytomegalovirus. Infect Immun. 1980 Mar;27(3):767–776. doi: 10.1128/iai.27.3.767-776.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hudson J. B. The murine cytomegalovirus as a model for the study of viral pathogenesis and persistent infections. Arch Virol. 1979;62(1):1–29. doi: 10.1007/BF01314900. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Jonjić S., Mutter W., Weiland F., Reddehase M. J., Koszinowski U. H. Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes. J Exp Med. 1989 Apr 1;169(4):1199–1212. doi: 10.1084/jem.169.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lathbury L. J., Allan J. E., Shellam G. R., Scalzo A. A. Effect of host genotype in determining the relative roles of natural killer cells and T cells in mediating protection against murine cytomegalovirus infection. J Gen Virol. 1996 Oct;77(Pt 10):2605–2613. doi: 10.1099/0022-1317-77-10-2605. [DOI] [PubMed] [Google Scholar]
  20. Lawson C. M., Grundy J. E., Shellam G. R. Delayed-type hypersensitivity responses to murine cytomegalovirus in genetically resistant and susceptible strains of mice. J Gen Virol. 1987 Sep;68(Pt 9):2379–2388. doi: 10.1099/0022-1317-68-9-2379. [DOI] [PubMed] [Google Scholar]
  21. Lehmann-Grube F., Assmann U., Löliger C., Moskophidis D., Löhler J. Mechanism of recovery from acute virus infection. I. Role of T lymphocytes in the clearance of lymphocytic choriomeningitis virus from spleens of mice. J Immunol. 1985 Jan;134(1):608–615. [PubMed] [Google Scholar]
  22. Luby J. P., Burnett W., Hull A. R., Ware A. J., Shorey J. W., Peters P. C. Relationship between cytomegalovirus and hepatic function abnormalities in the period after renal transplant. J Infect Dis. 1974 May;129(5):511–518. doi: 10.1093/infdis/129.5.511. [DOI] [PubMed] [Google Scholar]
  23. Makino M., Morse H. C., 3rd, Fredrickson T. N., Hartley J. W. H-2-associated and background genes influence the development of a murine retrovirus-induced immunodeficiency syndrome. J Immunol. 1990 Jun 1;144(11):4347–4355. [PubMed] [Google Scholar]
  24. Mercer J. A., Spector D. H. Pathogenesis of acute murine cytomegalovirus infection in resistant and susceptible strains of mice. J Virol. 1986 Feb;57(2):497–504. doi: 10.1128/jvi.57.2.497-504.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Meyers J. D. Cytomegalovirus infection following marrow transplantation: risk, treatment, and prevention. Birth Defects Orig Artic Ser. 1984;20(1):101–117. [PubMed] [Google Scholar]
  26. 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]
  27. Morse H. C., 3rd, Yetter R. A., Via C. S., Hardy R. R., Cerny A., Hayakawa K., Hugin A. W., Miller M. W., Holmes K. L., Shearer G. M. Functional and phenotypic alterations in T cell subsets during the course of MAIDS, a murine retrovirus-induced immunodeficiency syndrome. J Immunol. 1989 Aug 1;143(3):844–850. [PubMed] [Google Scholar]
  28. 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]
  29. Olver S. D., Price P., Shellam G. R. Cytomegalovirus hepatitis: characterization of the inflammatory infiltrate in resistant and susceptible mice. Clin Exp Immunol. 1994 Dec;98(3):375–381. doi: 10.1111/j.1365-2249.1994.tb05500.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Papadimitriou J. M., Shellam G. R., Allan J. E. The effect of the beige mutation on infection with murine cytomegalovirus: histopathologic studies. Am J Pathol. 1982 Sep;108(3):299–309. [PMC free article] [PubMed] [Google Scholar]
  31. Peacock C. D., Price P. Effect of a retroviral immunodeficiency syndrome on resistance to MCMV: a role for natural killer cells. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Oct 1;10(2):120–128. doi: 10.1097/00042560-199510020-00003. [DOI] [PubMed] [Google Scholar]
  32. Price P., Eddy K. S., Papadimitriou J. M., Robertson T. A., Shellam G. R. Cytomegalovirus infection of adipose tissues induces steatitis in adult mice. Int J Exp Pathol. 1990 Aug;71(4):557–571. [PMC free article] [PubMed] [Google Scholar]
  33. Price P., Gibbons A. E., Shellam G. R. H-2 class I loci determine sensitivity to MCMV in macrophages and fibroblasts. Immunogenetics. 1990;32(1):20–26. doi: 10.1007/BF01787324. [DOI] [PubMed] [Google Scholar]
  34. Price P., Olver S. D., Silich M., Nador T. Z., Yerkovich S., Wilson S. G. Adrenalitis and the adrenocortical response of resistant and susceptible mice to acute murine cytomegalovirus infection. Eur J Clin Invest. 1996 Sep;26(9):811–819. doi: 10.1046/j.1365-2362.1996.2210562.x. [DOI] [PubMed] [Google Scholar]
  35. Quinnan G. V., Manischewitz J. E., Ennis F. A. Cytotoxic T lymphocyte response to murine cytomegalovirus infection. Nature. 1978 Jun 15;273(5663):541–543. doi: 10.1038/273541a0. [DOI] [PubMed] [Google Scholar]
  36. Reichert C. M., O'Leary T. J., Levens D. L., Simrell C. R., Macher A. M. Autopsy pathology in the acquired immune deficiency syndrome. Am J Pathol. 1983 Sep;112(3):357–382. [PMC free article] [PubMed] [Google Scholar]
  37. Scalzo A. A., Fitzgerald N. A., Simmons A., La Vista A. B., Shellam G. R. Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J Exp Med. 1990 May 1;171(5):1469–1483. doi: 10.1084/jem.171.5.1469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Scalzo A. A., Fitzgerald N. A., Wallace C. R., Gibbons A. E., Smart Y. C., Burton R. C., Shellam G. R. The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells. J Immunol. 1992 Jul 15;149(2):581–589. [PubMed] [Google Scholar]
  39. Shanley J. D., Biczak L., Forman S. J. Acute murine cytomegalovirus infection induces lethal hepatitis. J Infect Dis. 1993 Feb;167(2):264–269. doi: 10.1093/infdis/167.2.264. [DOI] [PubMed] [Google Scholar]
  40. Shanley J. D. In vivo administration of monoclonal antibody to the NK 1.1 antigen of natural killer cells: effect on acute murine cytomegalovirus infection. J Med Virol. 1990 Jan;30(1):58–60. doi: 10.1002/jmv.1890300113. [DOI] [PubMed] [Google Scholar]
  41. Shanley J. D., Pesanti E. L. Murine cytomegalovirus adrenalitis in athymic nude mice. Arch Virol. 1986;88(1-2):27–35. doi: 10.1007/BF01310887. [DOI] [PubMed] [Google Scholar]
  42. Shellam G. R., Allan J. E., Papadimitriou J. M., Bancroft G. J. Increased susceptibility to cytomegalovirus infection in beige mutant mice. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5104–5108. doi: 10.1073/pnas.78.8.5104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Shellam G. R., Flexman J. P., Farrell H. E., Papadimitriou J. M. The genetic background modulates the effect of the beige gene on susceptibility to cytomegalovirus infection in mice. Scand J Immunol. 1985 Aug;22(2):147–155. doi: 10.1111/j.1365-3083.1985.tb01867.x. [DOI] [PubMed] [Google Scholar]
  44. Shusterman N. H., Frauenhoffer C., Kinsey M. D. Fatal massive hepatic necrosis in cytomegalovirus mononucleosis. Ann Intern Med. 1978 Jun;88(6):810–812. doi: 10.7326/0003-4819-88-6-810. [DOI] [PubMed] [Google Scholar]
  45. Smyth R. L., Scott J. P., Borysiewicz L. K., Sharples L. D., Stewart S., Wreghitt T. G., Gray J. J., Higenbottam T. W., Wallwork J. Cytomegalovirus infection in heart-lung transplant recipients: risk factors, clinical associations, and response to treatment. J Infect Dis. 1991 Dec;164(6):1045–1050. doi: 10.1093/infdis/164.6.1045. [DOI] [PubMed] [Google Scholar]
  46. Ten Napel C. H., Houthoff H. J., The T. H. Cytomegalovirus hepatitis in normal and immune compromised hosts. Liver. 1984 Jun;4(3):184–194. doi: 10.1111/j.1600-0676.1984.tb00926.x. [DOI] [PubMed] [Google Scholar]
  47. Teo H. K., Price P., Papadimitriou J. M. The effects of protein malnutrition on the pathogenesis of murine cytomegalovirus disease. Int J Exp Pathol. 1991 Feb;72(1):67–82. [PMC free article] [PubMed] [Google Scholar]
  48. Welsh R. M., Dundon P. L., Eynon E. E., Brubaker J. O., Koo G. C., O'Donnell C. L. Demonstration of the antiviral role of natural killer cells in vivo with a natural killer cell-specific monoclonal antibody (NK 1.1). Nat Immun Cell Growth Regul. 1990;9(2):112–120. [PubMed] [Google Scholar]
  49. Zinkernagel R. M., Haenseler E., Leist T., Cerny A., Hengartner H., Althage A. T cell-mediated hepatitis in mice infected with lymphocytic choriomeningitis virus. Liver cell destruction by H-2 class I-restricted virus-specific cytotoxic T cells as a physiological correlate of the 51Cr-release assay? J Exp Med. 1986 Oct 1;164(4):1075–1092. doi: 10.1084/jem.164.4.1075. [DOI] [PMC free article] [PubMed] [Google Scholar]

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