Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1996 Nov;70(11):7725–7733. doi: 10.1128/jvi.70.11.7725-7733.1996

Cytotoxic T-lymphocyte responses to cytomegalovirus in normal and simian immunodeficiency virus-infected rhesus macaques.

A Kaur 1, M D Daniel 1, D Hempel 1, D Lee-Parritz 1, M S Hirsch 1, R P Johnson 1
PMCID: PMC190842  PMID: 8892893

Abstract

Disseminated cytomegalovirus (CMV) infection is a frequent occurrence in human immunodeficiency virus-infected humans and in simian immunodeficiency virus (SIV)-infected rhesus macaques. Rhesus macaques are a suitable animal model with which to study in vivo interactions between CMV and AIDS-associated retroviruses. Since cytotoxic T lymphocytes (CTL) play a major role in control of viral infections, we have characterized CMV-specific CTL responses in SIV-infected and uninfected rhesus macaques. Autologous fibroblasts infected with rhesus CMV were used to stimulate freshly isolated peripheral blood mononuclear cells from CMV-seropositive animals. Following in vitro stimulation, specific CTL activity against CMV-infected autologous fibroblasts was detected in CMV-seropositive but not in CMV-seronegative normal macaques. CMV-specific CTL activity comparable to that in normal animals was also detected in two CMV-seropositive macaques infected with a live attenuated SIV strain (SIVdelta3) and in two of three macaques infected with pathogenic SIV strains. The CMV-specific CTL response was class I major histocompatibility complex restricted and mediated by CD8+ cells. An early CMV protein(s) was the dominant target recognized by bulk CTL, although the pattern of CTL recognition of CMV proteins varied among animals. Analysis of CMV-specific CTL responses in macaques should serve as a valuable model for CMV immunopathogenesis and will facilitate prospective in vivo studies of immune interactions between CMV and SIV in AIDS.

Full Text

The Full Text of this article is available as a PDF (448.0 KB).

Selected References

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

  1. Asher D. M., Gibbs C. J., Jr, Lang D. J., Gajdusek D. C., Chanock R. M. Persistent shedding of cytomegalovirus in the urine of healthy Rhesus monkeys. Proc Soc Exp Biol Med. 1974 Mar;145(3):794–801. doi: 10.3181/00379727-145-37897. [DOI] [PubMed] [Google Scholar]
  2. Barry P. A., Pratt-Lowe E., Alcendor D. J., Unger R. E., Luciw P. A. Molecular interactions between human immunodeficiency virus type 1 and human cytomegalovirus. Ann N Y Acad Sci. 1990;616:54–63. doi: 10.1111/j.1749-6632.1990.tb17827.x. [DOI] [PubMed] [Google Scholar]
  3. Barry P. A., Pratt-Lowe E., Unger R. E., Marthas M., Alcendor D. J., Luciw P. A. Molecular interactions of cytomegalovirus and the human and simian immunodeficiency viruses. J Med Primatol. 1990;19(3-4):327–337. [PubMed] [Google Scholar]
  4. Baskin G. B. Disseminated cytomegalovirus infection in immunodeficient rhesus monkeys. Am J Pathol. 1987 Nov;129(2):345–352. [PMC free article] [PubMed] [Google Scholar]
  5. Baskin G. B., Murphey-Corb M., Watson E. A., Martin L. N. Necropsy findings in rhesus monkeys experimentally infected with cultured simian immunodeficiency virus (SIV)/delta. Vet Pathol. 1988 Nov;25(6):456–467. doi: 10.1177/030098588802500609. [DOI] [PubMed] [Google Scholar]
  6. Borysiewicz L. K., Morris S., Page J. D., Sissons J. G. Human cytomegalovirus-specific cytotoxic T lymphocytes: requirements for in vitro generation and specificity. Eur J Immunol. 1983 Oct;13(10):804–809. doi: 10.1002/eji.1830131005. [DOI] [PubMed] [Google Scholar]
  7. Clerici M., Stocks N. I., Zajac R. A., Boswell R. N., Lucey D. R., Via C. S., Shearer G. M. Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging. J Clin Invest. 1989 Dec;84(6):1892–1899. doi: 10.1172/JCI114376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Converse P. J., Fehniger T. E., Ehrnst A., Strannegård O., Britton S. Immune responses to fractionated cytomegalovirus (CMV) antigens after HIV infection. Loss of cellular and humoral reactivity to antigens recognized by HIV-, CMV+ individuals. Clin Exp Immunol. 1990 Dec;82(3):559–566. doi: 10.1111/j.1365-2249.1990.tb05490.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Del Val M., Schlicht H. J., Volkmer H., Messerle M., Reddehase M. J., Koszinowski U. H. Protection against lethal cytomegalovirus infection by a recombinant vaccine containing a single nonameric T-cell epitope. J Virol. 1991 Jul;65(7):3641–3646. doi: 10.1128/jvi.65.7.3641-3646.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dobrescu D., Ursea B., Pope M., Asch A. S., Posnett D. N. Enhanced HIV-1 replication in V beta 12 T cells due to human cytomegalovirus in monocytes: evidence for a putative herpesvirus superantigen. Cell. 1995 Sep 8;82(5):753–763. doi: 10.1016/0092-8674(95)90472-7. [DOI] [PubMed] [Google Scholar]
  11. Fiala M., Mosca J. D., Barry P., Luciw P. A., Vinters H. V. Multi-step pathogenesis of AIDS--role of cytomegalovirus. Res Immunol. 1991 Feb;142(2):87–95. doi: 10.1016/0923-2494(91)90016-c. [DOI] [PubMed] [Google Scholar]
  12. Flø R. W., Haukenes G., Nilsen A., Skjaerven R., Forsgren M., Fehniger T. E. Longitudinal study of cytomegalovirus antibodies in individuals infected with the human immunodeficiency virus. Eur J Clin Microbiol Infect Dis. 1995 Jun;14(6):504–511. doi: 10.1007/BF02113428. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Hanson C. V., Riggs J. L., Lennette E. H. Photochemical inactivation of DNA and RNA viruses by psoralen derivatives. J Gen Virol. 1978 Aug;40(2):345–358. doi: 10.1099/0022-1317-40-2-345. [DOI] [PubMed] [Google Scholar]
  15. Ho W. Z., Ayyavoo V., Srinivasan A., Stinski M. F., Plotkin S. A., Gönczöl E. Human immunodeficiency virus type 1 tat gene enhances human cytomegalovirus gene expression and viral replication. AIDS Res Hum Retroviruses. 1991 Aug;7(8):689–695. doi: 10.1089/aid.1991.7.689. [DOI] [PubMed] [Google Scholar]
  16. Jahn G., Mach M. Human cytomegalovirus phosphoproteins and glycoproteins and their coding regions. Curr Top Microbiol Immunol. 1990;154:171–185. doi: 10.1007/978-3-642-74980-3_7. [DOI] [PubMed] [Google Scholar]
  17. Jonjić S., Pavić I., Polić B., Crnković I., Lucin P., Koszinowski U. H. Antibodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus. J Exp Med. 1994 May 1;179(5):1713–1717. doi: 10.1084/jem.179.5.1713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jonjić S., del Val M., Keil G. M., Reddehase M. J., Koszinowski U. H. A nonstructural viral protein expressed by a recombinant vaccinia virus protects against lethal cytomegalovirus infection. J Virol. 1988 May;62(5):1653–1658. doi: 10.1128/jvi.62.5.1653-1658.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lackner A. A. Pathology of simian immunodeficiency virus induced disease. Curr Top Microbiol Immunol. 1994;188:35–64. doi: 10.1007/978-3-642-78536-8_3. [DOI] [PubMed] [Google Scholar]
  20. Li C. R., Greenberg P. D., Gilbert M. J., Goodrich J. M., Riddell S. R. Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood. 1994 Apr 1;83(7):1971–1979. [PubMed] [Google Scholar]
  21. Margalith M., D'Aquila R. T., Manion D. J., Basgoz N., Bechtel L. J., Smith B. R., Kaplan J. C., Hirsch M. S. HIV-1 DNA in fibroblast cultures infected with urine from HIV-seropositive cytomegalovirus (CMV) excretors. Arch Virol. 1995;140(5):927–935. doi: 10.1007/BF01314968. [DOI] [PubMed] [Google Scholar]
  22. McLaughlin-Taylor E., Pande H., Forman S. J., Tanamachi B., Li C. R., Zaia J. A., Greenberg P. D., Riddell S. R. Identification of the major late human cytomegalovirus matrix protein pp65 as a target antigen for CD8+ virus-specific cytotoxic T lymphocytes. J Med Virol. 1994 May;43(1):103–110. doi: 10.1002/jmv.1890430119. [DOI] [PubMed] [Google Scholar]
  23. Nuchtern J. G., Bonifacino J. S., Biddison W. E., Klausner R. D. Brefeldin A implicates egress from endoplasmic reticulum in class I restricted antigen presentation. Nature. 1989 May 18;339(6221):223–226. doi: 10.1038/339223a0. [DOI] [PubMed] [Google Scholar]
  24. Ohtaki S., Kodama H., Hondo R., Kurata T. Activation of cytomegalovirus infection in immunosuppressed cynomolgus monkeys inoculated with varicella-zoster virus. Acta Pathol Jpn. 1986 Oct;36(10):1537–1552. doi: 10.1111/j.1440-1827.1986.tb02825.x. [DOI] [PubMed] [Google Scholar]
  25. Osborn K. G., Prahalada S., Lowenstine L. J., Gardner M. B., Maul D. H., Henrickson R. V. The pathology of an epizootic of acquired immunodeficiency in rhesus macaques. Am J Pathol. 1984 Jan;114(1):94–103. [PMC free article] [PubMed] [Google Scholar]
  26. Quinnan G. V., Jr, Burns W. H., Kirmani N., Rook A. H., Manischewitz J., Jackson L., Santos G. W., Saral R. HLA-restricted cytotoxic T lymphocytes are an early immune response and important defense mechanism in cytomegalovirus infections. Rev Infect Dis. 1984 Mar-Apr;6(2):156–163. doi: 10.1093/clinids/6.2.156. [DOI] [PubMed] [Google Scholar]
  27. Reddehase M. J., Mutter W., Münch K., Bühring H. J., Koszinowski U. H. CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity. J Virol. 1987 Oct;61(10):3102–3108. doi: 10.1128/jvi.61.10.3102-3108.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Reusser P., Riddell S. R., Meyers J. D., Greenberg P. D. Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood. 1991 Sep 1;78(5):1373–1380. [PubMed] [Google Scholar]
  29. Riddell S. R., Greenberg P. D. Therapeutic reconstitution of human viral immunity by adoptive transfer of cytotoxic T lymphocyte clones. Curr Top Microbiol Immunol. 1994;189:9–34. doi: 10.1007/978-3-642-78530-6_2. [DOI] [PubMed] [Google Scholar]
  30. Riddell S. R., Rabin M., Geballe A. P., Britt W. J., Greenberg P. D. Class I MHC-restricted cytotoxic T lymphocyte recognition of cells infected with human cytomegalovirus does not require endogenous viral gene expression. J Immunol. 1991 Apr 15;146(8):2795–2804. [PubMed] [Google Scholar]
  31. Riddell S. R., Walter B. A., Gilbert M. J., Greenberg P. D. Selective reconstitution of CD8+ cytotoxic T lymphocyte responses in immunodeficient bone marrow transplant recipients by the adoptive transfer of T cell clones. Bone Marrow Transplant. 1994;14 (Suppl 4):S78–S84. [PubMed] [Google Scholar]
  32. Rook A. H., Manischewitz J. F., Frederick W. R., Epstein J. S., Jackson L., Gelmann E., Steis R., Masur H., Quinnan G. V., Jr Deficient, HLA-restricted, cytomegalovirus-specific cytotoxic T cells and natural killer cells in patients with the acquired immunodeficiency syndrome. J Infect Dis. 1985 Sep;152(3):627–630. doi: 10.1093/infdis/152.3.627. [DOI] [PubMed] [Google Scholar]
  33. Rook A. H., Quinnan G. V., Jr, Frederick W. J., Manischewitz J. F., Kirmani N., Dantzler T., Lee B. B., Currier C. B., Jr Importance of cytotoxic lymphocytes during cytomegalovirus infection in renal transplant recipients. Am J Med. 1984 Mar;76(3):385–392. doi: 10.1016/0002-9343(84)90655-7. [DOI] [PubMed] [Google Scholar]
  34. Schrier R. D., Freeman W. R., Wiley C. A., McCutchan J. A. Immune predispositions for cytomegalovirus retinitis in AIDS. The HNRC Group. J Clin Invest. 1995 Apr;95(4):1741–1746. doi: 10.1172/JCI117851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Simon M. A., Chalifoux L. V., Ringler D. J. Pathologic features of SIV-induced disease and the association of macrophage infection with disease evolution. AIDS Res Hum Retroviruses. 1992 Mar;8(3):327–337. doi: 10.1089/aid.1992.8.327. [DOI] [PubMed] [Google Scholar]
  36. Skolnik P. R., Kosloff B. R., Hirsch M. S. Bidirectional interactions between human immunodeficiency virus type 1 and cytomegalovirus. J Infect Dis. 1988 Mar;157(3):508–514. doi: 10.1093/infdis/157.3.508. [DOI] [PubMed] [Google Scholar]
  37. Spaete R. R., Gehrz R. C., Landini M. P. Human cytomegalovirus structural proteins. J Gen Virol. 1994 Dec;75(Pt 12):3287–3308. doi: 10.1099/0022-1317-75-12-3287. [DOI] [PubMed] [Google Scholar]
  38. Swack N. S., Hsiung G. D. Natural and experimental simian cytomegalovirus infections at a primate center. J Med Primatol. 1982;11(3):169–177. [PubMed] [Google Scholar]
  39. Swack N. S., Liu O. C., Hsiung G. D. Cytomegalovirus infections of monkeys and baboons. Am J Epidemiol. 1971 Oct;94(4):397–402. doi: 10.1093/oxfordjournals.aje.a121334. [DOI] [PubMed] [Google Scholar]
  40. Vogel P., Weigler B. J., Kerr H., Hendrickx A. G., Barry P. A. Seroepidemiologic studies of cytomegalovirus infection in a breeding population of rhesus macaques. Lab Anim Sci. 1994 Feb;44(1):25–30. [PubMed] [Google Scholar]
  41. Walter E. A., Greenberg P. D., Gilbert M. J., Finch R. J., Watanabe K. S., Thomas E. D., Riddell S. R. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995 Oct 19;333(16):1038–1044. doi: 10.1056/NEJM199510193331603. [DOI] [PubMed] [Google Scholar]
  42. Watkins D. I., Kannagi M., Stone M. E., Letvin N. L. Major histocompatibility complex class I molecules of nonhuman primates. Eur J Immunol. 1988 Sep;18(9):1425–1432. doi: 10.1002/eji.1830180919. [DOI] [PubMed] [Google Scholar]
  43. Wyand M. S., Manson K. H., Garcia-Moll M., Montefiori D., Desrosiers R. C. Vaccine protection by a triple deletion mutant of simian immunodeficiency virus. J Virol. 1996 Jun;70(6):3724–3733. doi: 10.1128/jvi.70.6.3724-3733.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yewdell J. W., Bennink J. R. Brefeldin A specifically inhibits presentation of protein antigens to cytotoxic T lymphocytes. Science. 1989 Jun 2;244(4908):1072–1075. doi: 10.1126/science.2471266. [DOI] [PubMed] [Google Scholar]

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

RESOURCES