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. 1989 Dec 1;170(6):2023–2035. doi: 10.1084/jem.170.6.2023

Structural requirements for class I MHC molecule-mediated antigen presentation and cytotoxic T cell recognition of an immunodominant determinant of the human immunodeficiency virus envelope protein

PMCID: PMC2189527  PMID: 2479705

Abstract

In H-2d mice, the immunodominant determinant of the HIV-1-IIIB gp160 envelope glycoprotein recognized by CD8+ CTL is represented by a 15- residue synthetic peptide (315-329: RIQRGPGRAFVTIGK). This peptide is seen in association with the Dd class I MHC molecule expressed on H-2k L cell fibroblast targets. We explored the structural requirements for CTL recognition of this peptide at the levels of both the peptide molecule and the class I MHC molecule. Using several transfectants expressing recombinant Dd/Ld molecules, we found that presentation of this epitope required both the alpha 1 and alpha 2 domains of the Dd molecule, in contrast to certain instances of allorecognition for which alpha 1 of Dd was sufficient in association with alpha 2 of Ld. Because this peptide derives from a hypervariable segment of the HIV envelope, substituted peptides could be used to define not only the structures affecting interaction of peptide with class I MHC molecule and with the TCR, but also the structural basis for the effect of naturally occurring viral variation on CTL recognition. The CTL-LINE specific for this HIV-1-IIIB-derived sequence could not recognize the HIV-1-RF variant-derived sequence from exactly the same site (315-329:-- HIGPGRVIYATGQ). Peptides with single amino acid substitutions from the HIV-1-IIIB sequence toward the HIV-1-RF sequence were made to test the effect of each residue significantly affected recognition, and only one, 324(F), was obligatory. Moreover, both 322(R) and 324(F) substituted peptides failed to inhibit the binding of the wild type peptide to the MHC molecule. Therefore, the amino-acids 322(R) and 324(F) seem to be involved in regulating peptide interaction with the Dd class I MHC molecule. In contrast, 325(V) appeared to affect interaction with the TCR. We suggest that sequence variations among known HIV-1 isolates that affect peptide binding to MHC such as those described here, if occurring during the course of infection of an individual, could result in failure of the MHC molecules of that individual to present the peptide. If the number of dominant HIV CTL epitopes is indeed very limited, such a blind spot could allow the virus to escape immune control, proliferate rapidly, and cause AIDS.

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Selected References

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  1. Ajitkumar P., Geier S. S., Kesari K. V., Borriello F., Nakagawa M., Bluestone J. A., Saper M. A., Wiley D. C., Nathenson S. G. Evidence that multiple residues on both the alpha-helices of the class I MHC molecule are simultaneously recognized by the T cell receptor. Cell. 1988 Jul 1;54(1):47–56. doi: 10.1016/0092-8674(88)90178-x. [DOI] [PubMed] [Google Scholar]
  2. Allen P. M., Matsueda G. R., Evans R. J., Dunbar J. B., Jr, Marshall G. R., Unanue E. R. Identification of the T-cell and Ia contact residues of a T-cell antigenic epitope. 1987 Jun 25-Jul 1Nature. 327(6124):713–715. doi: 10.1038/327713a0. [DOI] [PubMed] [Google Scholar]
  3. Babbitt B. P., Allen P. M., Matsueda G., Haber E., Unanue E. R. Binding of immunogenic peptides to Ia histocompatibility molecules. 1985 Sep 26-Oct 2Nature. 317(6035):359–361. doi: 10.1038/317359a0. [DOI] [PubMed] [Google Scholar]
  4. Bennink J. R., Yewdell J. W. Murine cytotoxic T lymphocyte recognition of individual influenza virus proteins. High frequency of nonresponder MHC class I alleles. J Exp Med. 1988 Nov 1;168(5):1935–1939. doi: 10.1084/jem.168.5.1935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Berzofsky J. A., Brett S. J., Streicher H. Z., Takahashi H. Antigen processing for presentation to T lymphocytes: function, mechanisms, and implications for the T-cell repertoire. Immunol Rev. 1988 Dec;106:5–31. doi: 10.1111/j.1600-065x.1988.tb00771.x. [DOI] [PubMed] [Google Scholar]
  6. Bjorkman P. J., Saper M. A., Samraoui B., Bennett W. S., Strominger J. L., Wiley D. C. Structure of the human class I histocompatibility antigen, HLA-A2. Nature. 1987 Oct 8;329(6139):506–512. doi: 10.1038/329506a0. [DOI] [PubMed] [Google Scholar]
  7. Bjorkman P. J., Saper M. A., Samraoui B., Bennett W. S., Strominger J. L., Wiley D. C. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. 1987 Oct 8;329(6139):512–518. doi: 10.1038/329512a0. [DOI] [PubMed] [Google Scholar]
  8. Braciale T. J., Sweetser M. T., Morrison L. A., Kittlesen D. J., Braciale V. L. Class I major histocompatibility complex-restricted cytolytic T lymphocytes recognize a limited number of sites on the influenza hemagglutinin. Proc Natl Acad Sci U S A. 1989 Jan;86(1):277–281. doi: 10.1073/pnas.86.1.277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Buus S., Sette A., Colon S. M., Jenis D. M., Grey H. M. Isolation and characterization of antigen-Ia complexes involved in T cell recognition. Cell. 1986 Dec 26;47(6):1071–1077. doi: 10.1016/0092-8674(86)90822-6. [DOI] [PubMed] [Google Scholar]
  10. Buus S., Sette A., Colon S. M., Miles C., Grey H. M. The relation between major histocompatibility complex (MHC) restriction and the capacity of Ia to bind immunogenic peptides. Science. 1987 Mar 13;235(4794):1353–1358. doi: 10.1126/science.2435001. [DOI] [PubMed] [Google Scholar]
  11. Chakrabarti S., Robert-Guroff M., Wong-Staal F., Gallo R. C., Moss B. Expression of the HTLV-III envelope gene by a recombinant vaccinia virus. Nature. 1986 Apr 10;320(6062):535–537. doi: 10.1038/320535a0. [DOI] [PubMed] [Google Scholar]
  12. DeLisi C., Berzofsky J. A. T-cell antigenic sites tend to be amphipathic structures. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7048–7052. doi: 10.1073/pnas.82.20.7048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Engelhard V. H., Le A. X., Holterman M. J. Species-specific structural differences in the alpha 1 + alpha 2 domains determine the frequency of murine cytotoxic T cell precursors stimulated by human and murine class I molecules. J Immunol. 1988 Sep 15;141(6):1835–1839. [PubMed] [Google Scholar]
  14. Evans G. A., Margulies D. H., Shykind B., Seidman J. G., Ozato K. Exon shuffling: mapping polymorphic determinants on hybrid mouse transplantation antigens. Nature. 1982 Dec 23;300(5894):755–757. doi: 10.1038/300755a0. [DOI] [PubMed] [Google Scholar]
  15. Fisher A. G., Ensoli B., Looney D., Rose A., Gallo R. C., Saag M. S., Shaw G. M., Hahn B. H., Wong-Staal F. Biologically diverse molecular variants within a single HIV-1 isolate. Nature. 1988 Aug 4;334(6181):444–447. doi: 10.1038/334444a0. [DOI] [PubMed] [Google Scholar]
  16. Gotch F., McMichael A., Rothbard J. Recognition of influenza A matrix protein by HLA-A2-restricted cytotoxic T lymphocytes. Use of analogues to orientate the matrix peptide in the HLA-A2 binding site. J Exp Med. 1988 Dec 1;168(6):2045–2057. doi: 10.1084/jem.168.6.2045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Houghten R. A. General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5131–5135. doi: 10.1073/pnas.82.15.5131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Maloy W. L. Comparison of the primary structure of class I molecules. Immunol Res. 1987;6(1-2):11–29. doi: 10.1007/BF02918101. [DOI] [PubMed] [Google Scholar]
  19. Margalit H., Spouge J. L., Cornette J. L., Cease K. B., Delisi C., Berzofsky J. A. Prediction of immunodominant helper T cell antigenic sites from the primary sequence. J Immunol. 1987 Apr 1;138(7):2213–2229. [PubMed] [Google Scholar]
  20. 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]
  21. Martinon F., Cornille F., Gomard E., Fournie-Zaluski M. C., Abastado J. P., Roques B. P., Levy J. P. Two epitopes and one agretope map to a single HLA-A2 peptide recognized by H-2-restricted T cells. J Immunol. 1989 May 15;142(10):3489–3494. [PubMed] [Google Scholar]
  22. Maryanski J. L., Pala P., Cerottini J. C., Corradin G. Synthetic peptides as antigens and competitors in recognition by H-2-restricted cytolytic T cells specific for HLA. J Exp Med. 1988 Apr 1;167(4):1391–1405. doi: 10.1084/jem.167.4.1391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. McCluskey J., Boyd L., Foo M., Forman J., Margulies D. H., Bluestone J. A. Analysis of hybrid H-2D and L antigens with reciprocally mismatched aminoterminal domains: functional T cell recognition requires preservation of fine structural determinants. J Immunol. 1986 Dec 15;137(12):3881–3890. [PubMed] [Google Scholar]
  24. McMichael A. J., Gotch F. M., Santos-Aguado J., Strominger J. L. Effect of mutations and variations of HLA-A2 on recognition of a virus peptide epitope by cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9194–9198. doi: 10.1073/pnas.85.23.9194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Murre C., Choi E., Weis J., Seidman J. G., Ozato K., Liu L., Burakoff S. J., Reiss C. S. Dissection of serological and cytolytic T lymphocyte epitopes on murine major histocompatibility antigens by a recombinant H-2 gene separating the first two external domains. J Exp Med. 1984 Jul 1;160(1):167–178. doi: 10.1084/jem.160.1.167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ogasawara K., Maloy W. L., Schwartz R. H. Failure to find holes in the T-cell repertoire. 1987 Jan 29-Feb 4Nature. 325(6103):450–452. doi: 10.1038/325450a0. [DOI] [PubMed] [Google Scholar]
  27. Oldstone M. B., Whitton J. L., Lewicki H., Tishon A. Fine dissection of a nine amino acid glycoprotein epitope, a major determinant recognized by lymphocytic choriomeningitis virus-specific class I-restricted H-2Db cytotoxic T lymphocytes. J Exp Med. 1988 Aug 1;168(2):559–570. doi: 10.1084/jem.168.2.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ozato K., Evans G. A., Shykind B., Margulies D. H., Seidman J. G. Hybrid H-2 histocompatibility gene products assign domains recognized by alloreactive T cells. Proc Natl Acad Sci U S A. 1983 Apr;80(7):2040–2043. doi: 10.1073/pnas.80.7.2040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Reiss C. S., Evans G. A., Margulies D. H., Seidman J. G., Burakoff S. J. Allospecific and virus-specific cytolytic T lymphocytes are restricted to the N or C1 domain of H-2 antigens expressed on L cells after DNA-mediated gene transfer. Proc Natl Acad Sci U S A. 1983 May;80(9):2709–2712. doi: 10.1073/pnas.80.9.2709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rosenthal A. S. Determinant selection and macrophage function in genetic control of the immune response. Immunol Rev. 1978;40:136–152. doi: 10.1111/j.1600-065x.1978.tb00404.x. [DOI] [PubMed] [Google Scholar]
  31. Saag M. S., Hahn B. H., Gibbons J., Li Y., Parks E. S., Parks W. P., Shaw G. M. Extensive variation of human immunodeficiency virus type-1 in vivo. Nature. 1988 Aug 4;334(6181):440–444. doi: 10.1038/334440a0. [DOI] [PubMed] [Google Scholar]
  32. Spouge J. L., Guy H. R., Cornette J. L., Margalit H., Cease K., Berzofsky J. A., DeLisi C. Strong conformational propensities enhance T cell antigenicity. J Immunol. 1987 Jan 1;138(1):204–212. [PubMed] [Google Scholar]
  33. Takahashi H., Cohen J., Hosmalin A., Cease K. B., Houghten R., Cornette J. L., DeLisi C., Moss B., Germain R. N., Berzofsky J. A. An immunodominant epitope of the human immunodeficiency virus envelope glycoprotein gp160 recognized by class I major histocompatibility complex molecule-restricted murine cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1988 May;85(9):3105–3109. doi: 10.1073/pnas.85.9.3105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. 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]
  36. Unanue E. R., Allen P. M. The basis for the immunoregulatory role of macrophages and other accessory cells. Science. 1987 May 1;236(4801):551–557. doi: 10.1126/science.2437650. [DOI] [PubMed] [Google Scholar]
  37. Watts T. H., Brian A. A., Kappler J. W., Marrack P., McConnell H. M. Antigen presentation by supported planar membranes containing affinity-purified I-Ad. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7564–7568. doi: 10.1073/pnas.81.23.7564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]

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