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. 1993 Feb;67(2):694–702. doi: 10.1128/jvi.67.2.694-702.1993

Gag-specific cytotoxic T lymphocytes from human immunodeficiency virus type 1-infected individuals: Gag epitopes are clustered in three regions of the p24gag protein.

F Buseyne 1, M McChesney 1, F Porrot 1, S Kovarik 1, B Guy 1, Y Rivière 1
PMCID: PMC237420  PMID: 7678303

Abstract

Virus-specific cytotoxic T lymphocytes (CTL) may be an important host defense mechanism in the control of virus replication in persons infected with human immunodeficiency virus type 1 (HIV-1). Cytotoxic T-cell lines generated by nonspecific stimulation with anti-CD3 monoclonal antibodies and interleukin 2 were used to identify regions within the HIV-1 Gag protein that are the most frequently recognized. Using autologous Epstein-Barr virus-transformed target cells infected with recombinant vaccinia viruses encoding p18gag, p24gag, and p55gag proteins of HIV-1/Lai or selected truncations of p24gag, we show that within a group of 29 infected subjects, the p24gag protein is the target of Gag-specific CTL in most donors. Using autologous Epstein-Barr virus-transformed target cells coated with different synthetic peptides spanning the Gag amino acid sequence, we found clusters of partially overlapping peptides in three conserved regions of the p24 protein (amino acids [aa] 169 to 192, aa 219 to 304, and aa 335 to 372) that are frequently recognized by CTL and presented by a variety of human leukocyte antigen class I molecules. Since there are experiments both in vitro and in vivo showing the role of CTL in the control of virus replication in HIV and simian immunodeficiency virus infections, these results may be particularly important for vaccine development.

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Selected References

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  1. Achour A., Picard O., Zagury D., Sarin P. S., Gallo R. C., Naylor P. H., Goldstein A. L. HGP-30, a synthetic analogue of human immunodeficiency virus (HIV) p17, is a target for cytotoxic lymphocytes in HIV-infected individuals. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7045–7049. doi: 10.1073/pnas.87.18.7045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Claverie J. M., Kourilsky P., Langlade-Demoyen P., Chalufour-Prochnicka A., Dadaglio G., Tekaia F., Plata F., Bougueleret L. T-immunogenic peptides are constituted of rare sequence patterns. Use in the identification of T epitopes in the human immunodeficiency virus gag protein. Eur J Immunol. 1988 Oct;18(10):1547–1553. doi: 10.1002/eji.1830181012. [DOI] [PubMed] [Google Scholar]
  3. Clerici M., Lucey D. R., Zajac R. A., Boswell R. N., Gebel H. M., Takahashi H., Berzofsky J. A., Shearer G. M. Detection of cytotoxic T lymphocytes specific for synthetic peptides of gp160 in HIV-seropositive individuals. J Immunol. 1991 Apr 1;146(7):2214–2219. [PubMed] [Google Scholar]
  4. Culmann B., Gomard E., Kiény M. P., Guy B., Dreyfus F., Saimot A. G., Sereni D., Sicard D., Lévy J. P. Six epitopes reacting with human cytotoxic CD8+ T cells in the central region of the HIV-1 NEF protein. J Immunol. 1991 Mar 1;146(5):1560–1565. [PubMed] [Google Scholar]
  5. Gotch F. M., Nixon D. F., Alp N., McMichael A. J., Borysiewicz L. K. High frequency of memory and effector gag specific cytotoxic T lymphocytes in HIV seropositive individuals. Int Immunol. 1990;2(8):707–712. doi: 10.1093/intimm/2.8.707. [DOI] [PubMed] [Google Scholar]
  6. Hoffenbach A., Langlade-Demoyen P., Dadaglio G., Vilmer E., Michel F., Mayaud C., Autran B., Plata F. Unusually high frequencies of HIV-specific cytotoxic T lymphocytes in humans. J Immunol. 1989 Jan 15;142(2):452–462. [PubMed] [Google Scholar]
  7. Johnson R. P., Trocha A., Yang L., Mazzara G. P., Panicali D. L., Buchanan T. M., Walker B. D. HIV-1 gag-specific cytotoxic T lymphocytes recognize multiple highly conserved epitopes. Fine specificity of the gag-specific response defined by using unstimulated peripheral blood mononuclear cells and cloned effector cells. J Immunol. 1991 Sep 1;147(5):1512–1521. [PubMed] [Google Scholar]
  8. Joly P., Guillon J. M., Mayaud C., Plata F., Theodorou I., Denis M., Debre P., Autran B. Cell-mediated suppression of HIV-specific cytotoxic T lymphocytes. J Immunol. 1989 Oct 1;143(7):2193–2201. [PubMed] [Google Scholar]
  9. Koup R. A., Pikora C. A., Luzuriaga K., Brettler D. B., Day E. S., Mazzara G. P., Sullivan J. L. Limiting dilution analysis of cytotoxic T lymphocytes to human immunodeficiency virus gag antigens in infected persons: in vitro quantitation of effector cell populations with p17 and p24 specificities. J Exp Med. 1991 Dec 1;174(6):1593–1600. doi: 10.1084/jem.174.6.1593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Koup R. A., Sullivan J. L., Levine P. H., Brettler D., Mahr A., Mazzara G., McKenzie S., Panicali D. Detection of major histocompatibility complex class I-restricted, HIV-specific cytotoxic T lymphocytes in the blood of infected hemophiliacs. Blood. 1989 May 15;73(7):1909–1914. [PubMed] [Google Scholar]
  11. Lieberman J., Fabry J. A., Kuo M. C., Earl P., Moss B., Skolnik P. R. Cytotoxic T lymphocytes from HIV-1 seropositive individuals recognize immunodominant epitopes in Gp160 and reverse transcriptase. J Immunol. 1992 May 1;148(9):2738–2747. [PubMed] [Google Scholar]
  12. Littaua R. A., Oldstone M. B., Takeda A., Ennis F. A. A CD4+ cytotoxic T-lymphocyte clone to a conserved epitope on human immunodeficiency virus type 1 p24: cytotoxic activity and secretion of interleukin-2 and interleukin-6. J Virol. 1992 Jan;66(1):608–611. doi: 10.1128/jvi.66.1.608-611.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. McChesney M., Tanneau F., Regnault A., Sansonetti P., Montagnier L., Kieny M. P., Rivière Y. Detection of primary cytotoxic T lymphocytes specific for the envelope glycoprotein of HIV-1 by deletion of the env amino-terminal signal sequence. Eur J Immunol. 1990 Jan;20(1):215–220. doi: 10.1002/eji.1830200131. [DOI] [PubMed] [Google Scholar]
  14. Meyerhans A., Dadaglio G., Vartanian J. P., Langlade-Demoyen P., Frank R., Asjö B., Plata F., Wain-Hobson S. In vivo persistence of a HIV-1-encoded HLA-B27-restricted cytotoxic T lymphocyte epitope despite specific in vitro reactivity. Eur J Immunol. 1991 Oct;21(10):2637–2640. doi: 10.1002/eji.1830211051. [DOI] [PubMed] [Google Scholar]
  15. Miller M. D., Lord C. I., Stallard V., Mazzara G. P., Letvin N. L. The gag-specific cytotoxic T lymphocytes in rhesus monkeys infected with the simian immunodeficiency virus of macaques. J Immunol. 1990 Jan 1;144(1):122–128. [PubMed] [Google Scholar]
  16. Mills K. H., Nixon D. F., McMichael A. J. T-cell strategies in AIDS vaccines: MHC-restricted T-cell responses to HIV proteins. AIDS. 1989;3 (Suppl 1):S101–S110. [PubMed] [Google Scholar]
  17. Miyazawa M., Nishio J., Chesebro B. Protection against Friend retrovirus-induced leukemia by recombinant vaccinia viruses expressing the gag gene. J Virol. 1992 Jul;66(7):4497–4507. doi: 10.1128/jvi.66.7.4497-4507.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nixon D. F., McMichael A. J. Cytotoxic T-cell recognition of HIV proteins and peptides. AIDS. 1991 Sep;5(9):1049–1059. [PubMed] [Google Scholar]
  19. Nixon D. F., Townsend A. R., Elvin J. G., Rizza C. R., Gallwey J., McMichael A. J. HIV-1 gag-specific cytotoxic T lymphocytes defined with recombinant vaccinia virus and synthetic peptides. Nature. 1988 Dec 1;336(6198):484–487. doi: 10.1038/336484a0. [DOI] [PubMed] [Google Scholar]
  20. Oldstone M. B. Molecular anatomy of viral persistence. J Virol. 1991 Dec;65(12):6381–6386. doi: 10.1128/jvi.65.12.6381-6386.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Phillips R. E., Rowland-Jones S., Nixon D. F., Gotch F. M., Edwards J. P., Ogunlesi A. O., Elvin J. G., Rothbard J. A., Bangham C. R., Rizza C. R. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature. 1991 Dec 12;354(6353):453–459. doi: 10.1038/354453a0. [DOI] [PubMed] [Google Scholar]
  22. Rautmann G., Kieny M. P., Brandely R., Dott K., Girard M., Montagnier L., Lecocq J. P. HIV-1 core proteins expressed from recombinant vaccinia viruses. AIDS Res Hum Retroviruses. 1989 Apr;5(2):147–157. doi: 10.1089/aid.1989.5.147. [DOI] [PubMed] [Google Scholar]
  23. Riviere Y., Tanneau-Salvadori F., Regnault A., Lopez O., Sansonetti P., Guy B., Kieny M. P., Fournel J. J., Montagnier L. Human immunodeficiency virus-specific cytotoxic responses of seropositive individuals: distinct types of effector cells mediate killing of targets expressing gag and env proteins. J Virol. 1989 May;63(5):2270–2277. doi: 10.1128/jvi.63.5.2270-2277.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rivière Y. The cellular immune response to the human immunodeficiency virus. Curr Opin Immunol. 1989;2(3):424–427. doi: 10.1016/0952-7915(89)90154-4. [DOI] [PubMed] [Google Scholar]
  25. Rötzschke O., Falk K., Deres K., Schild H., Norda M., Metzger J., Jung G., Rammensee H. G. Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature. 1990 Nov 15;348(6298):252–254. doi: 10.1038/348252a0. [DOI] [PubMed] [Google Scholar]
  26. Salmon P., Olivier R., Riviere Y., Brisson E., Gluckman J. C., Kieny M. P., Montagnier L., Klatzmann D. Loss of CD4 membrane expression and CD4 mRNA during acute human immunodeficiency virus replication. J Exp Med. 1988 Dec 1;168(6):1953–1969. doi: 10.1084/jem.168.6.1953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Townsend A. R., Rothbard J., Gotch F. M., Bahadur G., Wraith D., McMichael A. J. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986 Mar 28;44(6):959–968. doi: 10.1016/0092-8674(86)90019-x. [DOI] [PubMed] [Google Scholar]
  28. Tsubota H., Lord C. I., Watkins D. I., Morimoto C., Letvin N. L. A cytotoxic T lymphocyte inhibits acquired immunodeficiency syndrome virus replication in peripheral blood lymphocytes. J Exp Med. 1989 Apr 1;169(4):1421–1434. doi: 10.1084/jem.169.4.1421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Van Bleek G. M., Nathenson S. G. Isolation of an endogenously processed immunodominant viral peptide from the class I H-2Kb molecule. Nature. 1990 Nov 15;348(6298):213–216. doi: 10.1038/348213a0. [DOI] [PubMed] [Google Scholar]
  30. Wain-Hobson S., Vartanian J. P., Henry M., Chenciner N., Cheynier R., Delassus S., Martins L. P., Sala M., Nugeyre M. T., Guétard D. LAV revisited: origins of the early HIV-1 isolates from Institut Pasteur. Science. 1991 May 17;252(5008):961–965. doi: 10.1126/science.2035026. [DOI] [PubMed] [Google Scholar]
  31. Walker B. D., Chakrabarti S., Moss B., Paradis T. J., Flynn T., Durno A. G., Blumberg R. S., Kaplan J. C., Hirsch M. S., Schooley R. T. HIV-specific cytotoxic T lymphocytes in seropositive individuals. Nature. 1987 Jul 23;328(6128):345–348. doi: 10.1038/328345a0. [DOI] [PubMed] [Google Scholar]
  32. Walker B. D., Flexner C., Birch-Limberger K., Fisher L., Paradis T. J., Aldovini A., Young R., Moss B., Schooley R. T. Long-term culture and fine specificity of human cytotoxic T-lymphocyte clones reactive with human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9514–9518. doi: 10.1073/pnas.86.23.9514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Walker B. D., Plata F. Cytotoxic T lymphocytes against HIV. AIDS. 1990 Mar;4(3):177–184. doi: 10.1097/00002030-199003000-00001. [DOI] [PubMed] [Google Scholar]
  34. Walker C. M., Erickson A. L., Hsueh F. C., Levy J. A. Inhibition of human immunodeficiency virus replication in acutely infected CD4+ cells by CD8+ cells involves a noncytotoxic mechanism. J Virol. 1991 Nov;65(11):5921–5927. doi: 10.1128/jvi.65.11.5921-5927.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Walker C. M., Moody D. J., Stites D. P., Levy J. A. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science. 1986 Dec 19;234(4783):1563–1566. doi: 10.1126/science.2431484. [DOI] [PubMed] [Google Scholar]
  36. Whitton J. L., Oldstone M. B. Class I MHC can present an endogenous peptide to cytotoxic T lymphocytes. J Exp Med. 1989 Sep 1;170(3):1033–1038. doi: 10.1084/jem.170.3.1033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Yamamoto H., Miller M. D., Tsubota H., Watkins D. I., Mazzara G. P., Stallard V., Panicali D. L., Aldovini A., Young R. A., Letvin N. L. Studies of cloned simian immunodeficiency virus-specific T lymphocytes. gag-specific cytotoxic T lymphocytes exhibit a restricted epitope specificity. J Immunol. 1990 May 1;144(9):3385–3391. [PubMed] [Google Scholar]

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