Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1993 Feb;67(2):801–806. doi: 10.1128/jvi.67.2.801-806.1993

Dengue virus protein recognition by virus-specific murine CD8+ cytotoxic T lymphocytes.

A L Rothman 1, I Kurane 1, C J Lai 1, M Bray 1, B Falgout 1, R Men 1, F A Ennis 1
PMCID: PMC237433  PMID: 7678307

Abstract

The identification of the protein targets for dengue virus-specific T lymphocytes may be useful for planning the development of subunit vaccines against dengue. We studied the recognition by murine dengue virus-specific major histocompatibility complex class I-restricted, CD8+ cytotoxic T lymphocytes (CTL) of dengue virus proteins using recombinant vaccinia viruses containing segments of the dengue virus genome. CTL from H-2k mice recognized a single serotype-cross-reactive epitope on the nonstructural (NS) protein NS3. CTL from H-2b mice recognized a serotype-cross-reactive epitope that was localized to NS4a or NS4b. CTL from H-2d mice recognized at least three epitopes: a serotype-specific epitope on one of the structural proteins, a serotype-cross-reactive epitope on NS3, and a serotype-cross-reactive epitope on NS1 or NS2a. Our findings demonstrate the limited recognition of dengue virus proteins by CTL from three inbred mouse strains and the predominance of CTL epitopes on dengue virus nonstructural proteins, particularly NS3. Since human dengue virus-specific CTL show similar patterns of recognition, these findings suggest that nonstructural proteins should be considered in designing vaccines against dengue.

Full text

PDF
801

Selected References

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

  1. Bennink J. R., Yewdell J. W., Smith G. L., Moss B. Anti-influenza virus cytotoxic T lymphocytes recognize the three viral polymerases and a nonstructural protein: responsiveness to individual viral antigens is major histocompatibility complex controlled. J Virol. 1987 Apr;61(4):1098–1102. doi: 10.1128/jvi.61.4.1098-1102.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brandt W. E. From the World Health Organization. Development of dengue and Japanese encephalitis vaccines. J Infect Dis. 1990 Sep;162(3):577–583. doi: 10.1093/infdis/162.3.577. [DOI] [PubMed] [Google Scholar]
  3. Bray M., Lai C. J. Dengue virus premembrane and membrane proteins elicit a protective immune response. Virology. 1991 Nov;185(1):505–508. doi: 10.1016/0042-6822(91)90809-p. [DOI] [PubMed] [Google Scholar]
  4. Bray M., Zhao B. T., Markoff L., Eckels K. H., Chanock R. M., Lai C. J. Mice immunized with recombinant vaccinia virus expressing dengue 4 virus structural proteins with or without nonstructural protein NS1 are protected against fatal dengue virus encephalitis. J Virol. 1989 Jun;63(6):2853–2856. doi: 10.1128/jvi.63.6.2853-2856.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bukowski J. F., Kurane I., Lai C. J., Bray M., Falgout B., Ennis F. A. Dengue virus-specific cross-reactive CD8+ human cytotoxic T lymphocytes. J Virol. 1989 Dec;63(12):5086–5091. doi: 10.1128/jvi.63.12.5086-5091.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Burke D. S., Nisalak A., Johnson D. E., Scott R. M. A prospective study of dengue infections in Bangkok. Am J Trop Med Hyg. 1988 Jan;38(1):172–180. doi: 10.4269/ajtmh.1988.38.172. [DOI] [PubMed] [Google Scholar]
  7. Chakrabarti S., Brechling K., Moss B. Vaccinia virus expression vector: coexpression of beta-galactosidase provides visual screening of recombinant virus plaques. Mol Cell Biol. 1985 Dec;5(12):3403–3409. doi: 10.1128/mcb.5.12.3403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Falgout B., Bray M., Schlesinger J. J., Lai C. J. Immunization of mice with recombinant vaccinia virus expressing authentic dengue virus nonstructural protein NS1 protects against lethal dengue virus encephalitis. J Virol. 1990 Sep;64(9):4356–4363. doi: 10.1128/jvi.64.9.4356-4363.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Falgout B., Pethel M., Zhang Y. M., Lai C. J. Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins. J Virol. 1991 May;65(5):2467–2475. doi: 10.1128/jvi.65.5.2467-2475.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gajdosová E., Oravec C., Mayer V. Cell-mediated immunity in flavivirus infections. I. Induction of cytotoxic T lymphocytes in mice by an attenuated virus from the tick-borne encephalitis complex and its group-reactive character. Acta Virol. 1981 Jan;25(1):10–18. [PubMed] [Google Scholar]
  11. Halstead S. B., Nimmannitya S., Cohen S. N. Observations related to pathogenesis of dengue hemorrhagic fever. IV. Relation of disease severity to antibody response and virus recovered. Yale J Biol Med. 1970 Apr;42(5):311–328. [PMC free article] [PubMed] [Google Scholar]
  12. Hill A. B., Müllbacher A., Parrish C., Coia G., Westaway E. G., Blanden R. V. Broad cross-reactivity with marked fine specificity in the cytotoxic T cell response to flaviviruses. J Gen Virol. 1992 May;73(Pt 5):1115–1123. doi: 10.1099/0022-1317-73-5-1115. [DOI] [PubMed] [Google Scholar]
  13. Hosmalin A., Clerici M., Houghten R., Pendleton C. D., Flexner C., Lucey D. R., Moss B., Germain R. N., Shearer G. M., Berzofsky J. A. An epitope in human immunodeficiency virus 1 reverse transcriptase recognized by both mouse and human cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2344–2348. doi: 10.1073/pnas.87.6.2344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Klavinskis L. S., Whitton J. L., Joly E., Oldstone M. B. Vaccination and protection from a lethal viral infection: identification, incorporation, and use of a cytotoxic T lymphocyte glycoprotein epitope. Virology. 1990 Oct;178(2):393–400. doi: 10.1016/0042-6822(90)90336-p. [DOI] [PubMed] [Google Scholar]
  15. Kurane I., Brinton M. A., Samson A. L., Ennis F. A. Dengue virus-specific, human CD4+ CD8- cytotoxic T-cell clones: multiple patterns of virus cross-reactivity recognized by NS3-specific T-cell clones. J Virol. 1991 Apr;65(4):1823–1828. doi: 10.1128/jvi.65.4.1823-1828.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kurane I., Hebblewaite D., Brandt W. E., Ennis F. A. Lysis of dengue virus-infected cells by natural cell-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity. J Virol. 1984 Oct;52(1):223–230. doi: 10.1128/jvi.52.1.223-230.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kurane I., Innis B. L., Nimmannitya S., Nisalak A., Meager A., Janus J., Ennis F. A. Activation of T lymphocytes in dengue virus infections. High levels of soluble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon-gamma in sera of children with dengue. J Clin Invest. 1991 Nov;88(5):1473–1480. doi: 10.1172/JCI115457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kurane I., Innis B. L., Nimmannitya S., Nisalak A., Rothman A. L., Livingston P. G., Janus J., Ennis F. A. Human immune responses to dengue viruses. Southeast Asian J Trop Med Public Health. 1990 Dec;21(4):658–662. [PubMed] [Google Scholar]
  19. Kuwano K., Scott M., Young J. F., Ennis F. A. Active immunization against virus infections due to antigenic drift by induction of crossreactive cytotoxic T lymphocytes. J Exp Med. 1989 Apr 1;169(4):1361–1371. doi: 10.1084/jem.169.4.1361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mackow E., Makino Y., Zhao B. T., Zhang Y. M., Markoff L., Buckler-White A., Guiler M., Chanock R., Lai C. J. The nucleotide sequence of dengue type 4 virus: analysis of genes coding for nonstructural proteins. Virology. 1987 Aug;159(2):217–228. doi: 10.1016/0042-6822(87)90458-2. [DOI] [PubMed] [Google Scholar]
  21. Margulies D. H., Evans G. A., Ozato K., Camerini-Otero R. D., Tanaka K., Appella E., Seidman J. G. Expression of H-2Dd and H-2Ld mouse major histocompatibility antigen genes in L cells after DNA-mediated gene transfer. J Immunol. 1983 Jan;130(1):463–470. [PubMed] [Google Scholar]
  22. Martin S., Courtney R. J., Fowler G., Rouse B. T. Herpes simplex virus type 1-specific cytotoxic T lymphocytes recognize virus nonstructural proteins. J Virol. 1988 Jul;62(7):2265–2273. doi: 10.1128/jvi.62.7.2265-2273.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Oehen S., Hengartner H., Zinkernagel R. M. Vaccination for disease. Science. 1991 Jan 11;251(4990):195–198. doi: 10.1126/science.1824801. [DOI] [PubMed] [Google Scholar]
  24. Pang T., Devi S., Blanden R. V., Lam S. K. T cell-mediated cytotoxicity against dengue-infected target cells. Microbiol Immunol. 1988;32(5):511–518. doi: 10.1111/j.1348-0421.1988.tb01411.x. [DOI] [PubMed] [Google Scholar]
  25. Rothman A. L., Kurane I., Zhang Y. M., Lai C. J., Ennis F. A. Dengue virus-specific murine T-lymphocyte proliferation: serotype specificity and response to recombinant viral proteins. J Virol. 1989 Jun;63(6):2486–2491. doi: 10.1128/jvi.63.6.2486-2491.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sangkawibha N., Rojanasuphot S., Ahandrik S., Viriyapongse S., Jatanasen S., Salitul V., Phanthumachinda B., Halstead S. B. Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am J Epidemiol. 1984 Nov;120(5):653–669. doi: 10.1093/oxfordjournals.aje.a113932. [DOI] [PubMed] [Google Scholar]
  27. Zhao B. T., Prince G., Horswood R., Eckels K., Summers P., Chanock R., Lai C. J. Expression of dengue virus structural proteins and nonstructural protein NS1 by a recombinant vaccinia virus. J Virol. 1987 Dec;61(12):4019–4022. doi: 10.1128/jvi.61.12.4019-4022.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Zhao B., Mackow E., Buckler-White A., Markoff L., Chanock R. M., Lai C. J., Makino Y. Cloning full-length dengue type 4 viral DNA sequences: analysis of genes coding for structural proteins. Virology. 1986 Nov;155(1):77–88. doi: 10.1016/0042-6822(86)90169-8. [DOI] [PubMed] [Google Scholar]

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

RESOURCES