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. 1996 Apr 1;183(4):1669–1679. doi: 10.1084/jem.183.4.1669

T cell receptor usage and fine specificity of human immunodeficiency virus 1-specific cytotoxic T lymphocyte clones: analysis of quasispecies recognition reveals a dominant response directed against a minor in vivo variant

PMCID: PMC2192525  PMID: 8666925

Abstract

Numerous virus-specific, class I-restricted cytotoxic T lymphocyte (CTL) epitopes have been identified, yet little information is available regarding the specificity of the CTL response in persons of the same human histocompatibility leukocyte antigen (HLA) type. In this study, the human immunodeficiency virus (HIV) 1 envelope-specific CTL response was evaluated in five HLA-B14-positive persons. CTL responses specific for a previously described nine-amino acid epitope in gp41 (aa 584-592, ERYLKDQQL) could be identified in all subjects, and CTL clones specific for this epitope could be isolated from four persons. Despite heterogeneous T cell receptor usage, the fine specificity of the clones was similar, as defined by recognition of alanine-substituted peptides as well as peptides representing natural HIV-1 sequence variants. Correlation with in vivo virus sequences revealed that the dominant species in two of the subjects represented poorly recognized variants, with a K-->Q substitution at amino acid 588, whereas no variants were observed in the other two subjects. Although clonal type-specific responses to these dominant variants could be identified, the magnitude of these responses remained small, and the dominant CTL response was directed at the minor in vivo variant. These studies indicate that despite similar epitope-specific immunologic pressure in persons of the same HLA type, the in vivo quasispecies may differ, and that the major in vivo immune response to a given CTL epitope can be directed at a minor variant.

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Selected References

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

  1. Akella R., Porter R. Rapid isolation and sequencing of double-stranded plasmid DNA. Biotechniques. 1993 May;14(5):726-8, 730. [PubMed] [Google Scholar]
  2. Argaet V. P., Schmidt C. W., Burrows S. R., Silins S. L., Kurilla M. G., Doolan D. L., Suhrbier A., Moss D. J., Kieff E., Sculley T. B. Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus. J Exp Med. 1994 Dec 1;180(6):2335–2340. doi: 10.1084/jem.180.6.2335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bergmann C. C., Tong L., Cua R., Sensintaffar J., Stohlman S. Differential effects of flanking residues on presentation of epitopes from chimeric peptides. J Virol. 1994 Aug;68(8):5306–5310. doi: 10.1128/jvi.68.8.5306-5310.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bertoletti A., Sette A., Chisari F. V., Penna A., Levrero M., De Carli M., Fiaccadori F., Ferrari C. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature. 1994 Jun 2;369(6479):407–410. doi: 10.1038/369407a0. [DOI] [PubMed] [Google Scholar]
  5. Borrow P., Lewicki H., Hahn B. H., Shaw G. M., Oldstone M. B. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol. 1994 Sep;68(9):6103–6110. doi: 10.1128/jvi.68.9.6103-6110.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bowness P., Moss P. A., Rowland-Jones S., Bell J. I., McMichael A. J. Conservation of T cell receptor usage by HLA B27-restricted influenza-specific cytotoxic T lymphocytes suggests a general pattern for antigen-specific major histocompatibility complex class I-restricted responses. Eur J Immunol. 1993 Jul;23(7):1417–1421. doi: 10.1002/eji.1830230702. [DOI] [PubMed] [Google Scholar]
  7. Carmichael A., Jin X., Sissons P., Borysiewicz L. Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease. J Exp Med. 1993 Feb 1;177(2):249–256. doi: 10.1084/jem.177.2.249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Del Val M., Schlicht H. J., Ruppert T., Reddehase M. J., Koszinowski U. H. Efficient processing of an antigenic sequence for presentation by MHC class I molecules depends on its neighboring residues in the protein. Cell. 1991 Sep 20;66(6):1145–1153. doi: 10.1016/0092-8674(91)90037-y. [DOI] [PubMed] [Google Scholar]
  9. DiBrino M., Parker K. C., Margulies D. H., Shiloach J., Turner R. V., Biddison W. E., Coligan J. E. The HLA-B14 peptide binding site can accommodate peptides with different combinations of anchor residues. J Biol Chem. 1994 Dec 23;269(51):32426–32434. [PubMed] [Google Scholar]
  10. Eisenlohr L. C., Yewdell J. W., Bennink J. R. Flanking sequences influence the presentation of an endogenously synthesized peptide to cytotoxic T lymphocytes. J Exp Med. 1992 Feb 1;175(2):481–487. doi: 10.1084/jem.175.2.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jassoy C., Johnson R. P., Navia B. A., Worth J., Walker B. D. Detection of a vigorous HIV-1-specific cytotoxic T lymphocyte response in cerebrospinal fluid from infected persons with AIDS dementia complex. J Immunol. 1992 Nov 1;149(9):3113–3119. [PubMed] [Google Scholar]
  12. Johnson R. P., Trocha A., Buchanan T. M., Walker B. D. Identification of overlapping HLA class I-restricted cytotoxic T cell epitopes in a conserved region of the human immunodeficiency virus type 1 envelope glycoprotein: definition of minimum epitopes and analysis of the effects of sequence variation. J Exp Med. 1992 Apr 1;175(4):961–971. doi: 10.1084/jem.175.4.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kalams S. A., Johnson R. P., Trocha A. K., Dynan M. J., Ngo H. S., D'Aquila R. T., Kurnick J. T., Walker B. D. Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire. J Exp Med. 1994 Apr 1;179(4):1261–1271. doi: 10.1084/jem.179.4.1261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Klein M. R., van Baalen C. A., Holwerda A. M., Kerkhof Garde S. R., Bende R. J., Keet I. P., Eeftinck-Schattenkerk J. K., Osterhaus A. D., Schuitemaker H., Miedema F. Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. J Exp Med. 1995 Apr 1;181(4):1365–1372. doi: 10.1084/jem.181.4.1365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Klenerman P., Rowland-Jones S., McAdam S., Edwards J., Daenke S., Lalloo D., Köppe B., Rosenberg W., Boyd D., Edwards A. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature. 1994 Jun 2;369(6479):403–407. doi: 10.1038/369403a0. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Lehner P. J., Wang E. C., Moss P. A., Williams S., Platt K., Friedman S. M., Bell J. I., Borysiewicz L. K. Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the V beta 17 gene segment. J Exp Med. 1995 Jan 1;181(1):79–91. doi: 10.1084/jem.181.1.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lifson A. R., Buchbinder S. P., Sheppard H. W., Mawle A. C., Wilber J. C., Stanley M., Hart C. E., Hessol N. A., Holmberg S. D. Long-term human immunodeficiency virus infection in asymptomatic homosexual and bisexual men with normal CD4+ lymphocyte counts: immunologic and virologic characteristics. J Infect Dis. 1991 May;163(5):959–965. doi: 10.1093/infdis/163.5.959. [DOI] [PubMed] [Google Scholar]
  19. Martin R., Utz U., Coligan J. E., Richert J. R., Flerlage M., Robinson E., Stone R., Biddison W. E., McFarlin D. E., McFarland H. F. Diversity in fine specificity and T cell receptor usage of the human CD4+ cytotoxic T cell response specific for the immunodominant myelin basic protein peptide 87-106. J Immunol. 1992 Mar 1;148(5):1359–1366. [PubMed] [Google Scholar]
  20. Moss P. A., Moots R. J., Rosenberg W. M., Rowland-Jones S. J., Bodmer H. C., McMichael A. J., Bell J. I. Extensive conservation of alpha and beta chains of the human T-cell antigen receptor recognizing HLA-A2 and influenza A matrix peptide. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8987–8990. doi: 10.1073/pnas.88.20.8987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Moss P. A., Rosenberg W. M., Zintzaras E., Bell J. I. Characterization of the human T cell receptor alpha-chain repertoire and demonstration of a genetic influence on V alpha usage. Eur J Immunol. 1993 May;23(5):1153–1159. doi: 10.1002/eji.1830230526. [DOI] [PubMed] [Google Scholar]
  22. Moss P. A., Rowland-Jones S. L., Frodsham P. M., McAdam S., Giangrande P., McMichael A. J., Bell J. I. Persistent high frequency of human immunodeficiency virus-specific cytotoxic T cells in peripheral blood of infected donors. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):5773–5777. doi: 10.1073/pnas.92.13.5773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nowak M. A., May R. M., Phillips R. E., Rowland-Jones S., Lalloo D. G., McAdam S., Klenerman P., Köppe B., Sigmund K., Bangham C. R. Antigenic oscillations and shifting immunodominance in HIV-1 infections. Nature. 1995 Jun 15;375(6532):606–611. doi: 10.1038/375606a0. [DOI] [PubMed] [Google Scholar]
  24. Padovan E., Casorati G., Dellabona P., Meyer S., Brockhaus M., Lanzavecchia A. Expression of two T cell receptor alpha chains: dual receptor T cells. Science. 1993 Oct 15;262(5132):422–424. doi: 10.1126/science.8211163. [DOI] [PubMed] [Google Scholar]
  25. Rowley D. A., Stach R. M. A first or dominant immunization. I. Suppression of simultaneous cytolytic T cell responses to unrelated alloantigens. J Exp Med. 1993 Sep 1;178(3):835–840. doi: 10.1084/jem.178.3.835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Stach R. M., Rowley D. A. A first or dominant immunization. II. Induced immunoglobulin carries transforming growth factor beta and suppresses cytolytic T cell responses to unrelated alloantigens. J Exp Med. 1993 Sep 1;178(3):841–852. doi: 10.1084/jem.178.3.841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Walker B. D., Flexner C., Paradis T. J., Fuller T. C., Hirsch M. S., Schooley R. T., Moss B. HIV-1 reverse transcriptase is a target for cytotoxic T lymphocytes in infected individuals. Science. 1988 Apr 1;240(4848):64–66. doi: 10.1126/science.2451288. [DOI] [PubMed] [Google Scholar]
  29. Wei X., Ghosh S. K., Taylor M. E., Johnson V. A., Emini E. A., Deutsch P., Lifson J. D., Bonhoeffer S., Nowak M. A., Hahn B. H. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117–122. doi: 10.1038/373117a0. [DOI] [PubMed] [Google Scholar]

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