1887

Abstract

Recovery from primary cytomegalovirus (CMV) infection is associated with resolution of the productive infection without clearance of the virus genome from affected organs. The presence of latent CMV genome in multiple organs provides the molecular basis for recurrence of CMV within multiple organs, and explains the diversity in the organ manifestations of recrudescent CMV disease during states of immunodeficiency. As a part of a unifying concept of multifocal CMV latency and recurrence, previous work has demonstrated the importance of primary virus replication for the overall load of latent CMV in organs and the risk of recurrence. In the present report, the establishment of CMV latency was studied in a murine model in which the course of primaiy infection in the immunocompromised host after syngeneic bone marrow transplantation was modulated by a CD8 T cell immunotherapy. The antiviral CD8effector cells limited virus replication in all organs and protected the recipients from lethal CMV disease, but after resolution of the productive infection virus DNA remained. Interestingly, the copy number of latent virus DNA in tissue did not quantitatively reflect the preceding virus production in the respective organ. Specifically, in contrast to the case in the lungs and the salivary glands, virus replication in the spleen was suppressed by CD8 T cells to below the limit of detection; yet, virus DNA was also detected in the spleen during latency and accordingly, virus recurrence in the spleen could be induced. These findings demonstrate that the control of virus replication in a particular organ does not prevent the establishment of latency in that organ.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-75-9-2329
1994-09-01
2021-10-20
Loading full text...

Full text loading...

/deliver/fulltext/jgv/75/9/JV0750092329.html?itemId=/content/journal/jgv/10.1099/0022-1317-75-9-2329&mimeType=html&fmt=ahah

References

  1. Balthesen M., Messerle M., Reddehase M. J. 1993; Lungs are a major organ site of cytomegalovirus latency and recurrence. Journal of Virology 67:5360–5366
    [Google Scholar]
  2. Balthesen M., Susa M., Lučin P., Reddehase M. J. 1994; Cytomegalovirus DNA detected in blood leukocytes after resolution of productive infection does not originate from latently infected hematopoietic stem cells in the bone marrow. Croatian Medical Journal 35:19–25
    [Google Scholar]
  3. Cheever M. A., Britzman Thompson D., Klarnet J. P., Greenberg P. D. 1986; Antigen-driven long term-cultured T cells proliferate in vivo, distribute widely, mediate specific tumor therapy, and persist long-term as functional memory cells. Journal of Experimental Medicine 163:1100–1112
    [Google Scholar]
  4. Chou S. 1993; Molecular diagnostic techniques for CMV infection. Excerpta Medica International Congress Series 1032:183–194
    [Google Scholar]
  5. Collins T., Pomeroy C., Jordan M. C. 1993; Detection of latent cytomegalovirus DNA in diverse organs of mice. Journal of Infectious Diseases 168:725–729
    [Google Scholar]
  6. Del Val M., Hengel H., Häcker H., Hartlaub U., Ruppert T., Lučin P., Koszinowski U. H. 1992; Cytomegalovirus prevents antigen presentation by blocking the transport of peptide-loaded major histocompatibility complex class I molecules into the medial- Golgi compartment. Journal of Experimental Medicine 176:729–738
    [Google Scholar]
  7. Gilbert M. J., Riddell S. R., Li C. -R., Greenberg P. D. 1993; Selective interference with class I major histocompatibility complex presentation of the major immediate-early protein following infection with human cytomegalovirus. Journal of Virology 67:3461–3469
    [Google Scholar]
  8. Henson D., Strano A. J. 1972; Mouse cytomegalovirus: necrosis of infected and morphologically normal submaxillary gland acinar cells during termination of chronic infection. American Journal of Pathology 68:183–202
    [Google Scholar]
  9. Jamieson B. D., Ahmed R. 1989; T cell memory. Long-term persistence of virus-specific cytotoxic T cells. Journal of Experimental Medicine 169:1993–2005
    [Google Scholar]
  10. Jonjić S., Mutter W., Weiland F., Reddehase M. J., Koszinowski U. H. 1989; Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4-positive T lymphocytes. Journal of Experimental Medicine 169:1199–1212
    [Google Scholar]
  11. Jordan M. C. 1983; Latent infection and the elusive cytomegalovirus. Reviews of Infectious Diseases 5:205–215
    [Google Scholar]
  12. Kaufmann S. H. E., Reddehase M. J. 1994; T cell subsets and defense against bacteria and viruses. In Handbook of T and B lymphocytes pp. 237–267 Snow E. C. Edited by San Diego: Academic Press;
    [Google Scholar]
  13. Klein J., Figueroa F., David C. S. 1983; FI-2 haplotypes, genes and antigens: second listing. Immunogenetics 17:553–596
    [Google Scholar]
  14. Klotman M. E., Henry S. C., Greene R. C., Brazy P. C., Klotman P. E., Hamilton J. H. 1990; Detection of mouse cytomegalovirus nucleic acid in infected mice. Journal of Infectious Diseases 161:220–225
    [Google Scholar]
  15. Koszinowski U. H., Del Val M., Reddehase M. J. 1990; Cellular and molecular basis of the protective immune response to cytomegalovirus infection. Current Topics in Microbiology and Immunology 154:189–220
    [Google Scholar]
  16. Koszinowski U. H., Reddehase M. J., Del Val M. 1992; Principles of cytomegalovirus antigen presentation in vitro and in vivo. Seminars in Immunology 4:71–79
    [Google Scholar]
  17. Koszinowski U. H., Reddehase M. J., Jonjić S. 1993; The role of T-lymphocyte subsets in the control of cytomegalovirus infection. In Viruses and the Cellular Immune Response pp. 429–445 Thomas D. B. Edited by New York: Marcel Dekker;
    [Google Scholar]
  18. Mercer J. A., Wiley C. A., Spector D. H. 1988; Pathogenesis of murine cytomegalovirus infection: identification of infected cells in the spleen during acute and latent infections. Journal of Virology 62:987–997
    [Google Scholar]
  19. Mocarski E. S., Abenes G. B., Manning W. C., Sambucetti L. C., Cherrington J. M. 1990; Molecular genetic analysis of cytomegalovirus gene regulation in growth, persistence, and latency. Current Topics in Microbiology and Immunology 154:47–74
    [Google Scholar]
  20. Mutter W., Reddehase M. J., Busch F. W., Bühring H. -J., Koszinowski U. H. 1988; Failure in generating hemopoietic stem cells is the primary cause of death from cytomegalovirus disease in the immunocompromised host. Journal of Experimental Medicine 167:1645–1658
    [Google Scholar]
  21. Oldstone M. B. A., Blount P., Southern P. J. 1986; Cytoim- munotherapy for persistent virus infection reveals a unique clearance pattern from the central nervous system. Nature; London: 321239–243
    [Google Scholar]
  22. Pomeroy C., Hilleren P. J., Jordan M. C. 1991; Latent murine cytomegalovirus DNA in splenic stromal cells of mice. Journal of Virology 65:3330–3334
    [Google Scholar]
  23. Quinnan G. V., Kirmani N., Rook A. H., Manischewitz J. F., Jackson L., Moreschi G., Santos G. W., Saral R., Burns W. H. 1982; Cytotoxic T cells in cytomegalovirus infection.HLA-restricted T-lymphocyte and non T-lymphocyte cytotoxic responsescorrelate with recovery from cytomegalovirus infection in bone-marrow-transplant recipients. New England Journal of Medicine 307:7–13
    [Google Scholar]
  24. Reddehase M. J., Weiland F., Münch K., Jonjić S., Lüske A., Koszinowski U. H. 1985; Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs. Journal of Virology 55:264–273
    [Google Scholar]
  25. Reddehase M. J., Mutter W., Koszinowski U. H. 1987a; In vivo application of recombinant interleukin 2 in the immunotherapy of established cytomegalovirus infection. Journal of Experimental Medicine 165:650–656
    [Google Scholar]
  26. Reddehase M. J., Mutter W., Münch K., Bühring H. -J., Koszinowski U. H. 1987b; CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity. Journal of Virology 61:3102–3108
    [Google Scholar]
  27. Reddehase M. J., Jonjić S., Weiland F., Mutter W., Koszinowski U. H. 1988; Adoptive immunotherapy of murine cytomegalovirus adrenalitis in the immunocompromised host: CD4 helper-independent antiviral function of CD8-positive memory T lymphocytes derived from latently infected donors. Journal of Virology 62:1061–1065
    [Google Scholar]
  28. Reddehase M. J., Balthesen M., Rapp M., Jonjić S., Pavić I., Koszinowski U. H. 1994; The conditions of primary infection define the load of latent viral genome in organs and the risk of recurrent cytomegalovirus disease. Journal of Experimental Medicine 179:185–193
    [Google Scholar]
  29. Reusser P., Riddell S. R., Meyers J., Greenberg P. D. 1991; Cytotoxic T lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 78:1373–1380
    [Google Scholar]
  30. Riddell S. R., Watanabe K., Goodrich J., Li C. -R., Agha M., Greenberg P. D. 1992; Restoration of viral immunity in immuno- deficient humans by adoptive transfer of T cell clones. Science 257:238–241
    [Google Scholar]
  31. Roizman B., Sears A. E. 1987; An inquiry into the mechanisms of herpes simplex virus latency. Annual Review of Microbiology 41:543–571
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-75-9-2329
Loading
/content/journal/jgv/10.1099/0022-1317-75-9-2329
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error