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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Dec 15;89(24):12008–12012. doi: 10.1073/pnas.89.24.12008

Human immunodeficiency virus gp120 binding C'C" ridge of CD4 domain 1 is also involved in interaction with class II major histocompatibility complex molecules.

U Moebius 1, L K Clayton 1, S Abraham 1, A Diener 1, J J Yunis 1, S C Harrison 1, E L Reinherz 1
PMCID: PMC50687  PMID: 1465431

Abstract

Using site-directed mutagenesis informed by high-resolution CD4 structural data, we have investigated the role of residues of the C'C'' ridge region of human CD4 on class II major histocompatibility complex (MHC) binding. This C'C'' ridge is homologous to the CDR2 loop of an immunoglobulin variable domain and is known to contain the binding site for human immunodeficiency virus (HIV) coat glycoprotein gp120. Here we report that this region is also involved in interaction with class II MHC. Exposed positively charged residues Lys-35, Lys-46, and Arg-59 and the exposed hydrophobic residue Phe-43 contribute significantly to class II MHC binding. Moreover, mutations in the buried residues Trp-62 and Ser-49, which support the top and bottom of the C'C'' ridge, respectively, disrupt class II MHC interaction. The HIV binding region appears to involve a restricted area of the larger class II MHC binding site on CD4. Strategies of drug design aimed at interrupting CD4-HIV interaction will need to consider the extensive overlap between class II MHC and HIV gp120 binding surfaces in this region of CD4.

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Selected References

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  1. Arthos J., Deen K. C., Chaikin M. A., Fornwald J. A., Sathe G., Sattentau Q. J., Clapham P. R., Weiss R. A., McDougal J. S., Pietropaolo C. Identification of the residues in human CD4 critical for the binding of HIV. Cell. 1989 May 5;57(3):469–481. doi: 10.1016/0092-8674(89)90922-7. [DOI] [PubMed] [Google Scholar]
  2. Ashkenazi A., Presta L. G., Marsters S. A., Camerato T. R., Rosenthal K. A., Fendly B. M., Capon D. J. Mapping the CD4 binding site for human immunodeficiency virus by alanine-scanning mutagenesis. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7150–7154. doi: 10.1073/pnas.87.18.7150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Biddison W. E., Rao P. E., Talle M. A., Goldstein G., Shaw S. Possible involvement of the OKT4 molecule in T cell recognition of class II HLA antigens. Evidence from studies of cytotoxic T lymphocytes specific for SB antigens. J Exp Med. 1982 Oct 1;156(4):1065–1076. doi: 10.1084/jem.156.4.1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Bowman M. R., MacFerrin K. D., Schreiber S. L., Burakoff S. J. Identification and structural analysis of residues in the V1 region of CD4 involved in interaction with human immunodeficiency virus envelope glycoprotein gp120 and class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A. 1990 Nov;87(22):9052–9056. doi: 10.1073/pnas.87.22.9052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brodsky M. H., Warton M., Myers R. M., Littman D. R. Analysis of the site in CD4 that binds to the HIV envelope glycoprotein. J Immunol. 1990 Apr 15;144(8):3078–3086. [PubMed] [Google Scholar]
  7. Brown J. H., Jardetzky T., Saper M. A., Samraoui B., Bjorkman P. J., Wiley D. C. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature. 1988 Apr 28;332(6167):845–850. doi: 10.1038/332845a0. [DOI] [PubMed] [Google Scholar]
  8. Bugawan T. L., Erlich H. A. Rapid typing of HLA-DQB1 DNA polymorphism using nonradioactive oligonucleotide probes and amplified DNA. Immunogenetics. 1991;33(3):163–170. doi: 10.1007/BF01719235. [DOI] [PubMed] [Google Scholar]
  9. Clayton L. K., Hussey R. E., Steinbrich R., Ramachandran H., Husain Y., Reinherz E. L. Substitution of murine for human CD4 residues identifies amino acids critical for HIV-gp120 binding. Nature. 1988 Sep 22;335(6188):363–366. doi: 10.1038/335363a0. [DOI] [PubMed] [Google Scholar]
  10. Clayton L. K., Sieh M., Pious D. A., Reinherz E. L. Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding. Nature. 1989 Jun 15;339(6225):548–551. doi: 10.1038/339548a0. [DOI] [PubMed] [Google Scholar]
  11. Cosgrove D., Gray D., Dierich A., Kaufman J., Lemeur M., Benoist C., Mathis D. Mice lacking MHC class II molecules. Cell. 1991 Sep 6;66(5):1051–1066. doi: 10.1016/0092-8674(91)90448-8. [DOI] [PubMed] [Google Scholar]
  12. Dalgleish A. G., Beverley P. C., Clapham P. R., Crawford D. H., Greaves M. F., Weiss R. A. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984 Dec 20;312(5996):763–767. doi: 10.1038/312763a0. [DOI] [PubMed] [Google Scholar]
  13. Doyle C., Strominger J. L. Interaction between CD4 and class II MHC molecules mediates cell adhesion. Nature. 1987 Nov 19;330(6145):256–259. doi: 10.1038/330256a0. [DOI] [PubMed] [Google Scholar]
  14. Eichmann K., Jönsson J. I., Falk I., Emmrich F. Effective activation of resting mouse T lymphocytes by cross-linking submitogenic concentrations of the T cell antigen receptor with either Lyt-2 or L3T4. Eur J Immunol. 1987 May;17(5):643–650. doi: 10.1002/eji.1830170510. [DOI] [PubMed] [Google Scholar]
  15. Engleman E. G., Benike C. J., Grumet F. C., Evans R. L. Activation of human T lymphocyte subsets: helper and suppressor/cytotoxic T cells recognize and respond to distinct histocompatibility antigens. J Immunol. 1981 Nov;127(5):2124–2129. [PubMed] [Google Scholar]
  16. Fleury S., Lamarre D., Meloche S., Ryu S. E., Cantin C., Hendrickson W. A., Sekaly R. P. Mutational analysis of the interaction between CD4 and class II MHC: class II antigens contact CD4 on a surface opposite the gp120-binding site. Cell. 1991 Sep 6;66(5):1037–1049. doi: 10.1016/0092-8674(91)90447-7. [DOI] [PubMed] [Google Scholar]
  17. Grusby M. J., Johnson R. S., Papaioannou V. E., Glimcher L. H. Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice. Science. 1991 Sep 20;253(5026):1417–1420. doi: 10.1126/science.1910207. [DOI] [PubMed] [Google Scholar]
  18. Healey D. G., Dianda L., Buck D., Schroeder K., Truneh A., Sattentau Q. J., Beverley P. C. A highly selected panel of anti-CD4 antibodies fails to induce anti-idiotypic antisera mediating human immunodeficiency virus neutralization. Eur J Immunol. 1991 Jun;21(6):1491–1498. doi: 10.1002/eji.1830210624. [DOI] [PubMed] [Google Scholar]
  19. Klatzmann D., Champagne E., Chamaret S., Gruest J., Guetard D., Hercend T., Gluckman J. C., Montagnier L. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature. 1984 Dec 20;312(5996):767–768. doi: 10.1038/312767a0. [DOI] [PubMed] [Google Scholar]
  20. Krensky A. M., Reiss C. S., Mier J. W., Strominger J. L., Burakoff S. J. Long-term human cytolytic T-cell lines allospecific for HLA-DR6 antigen are OKT4+. Proc Natl Acad Sci U S A. 1982 Apr;79(7):2365–2369. doi: 10.1073/pnas.79.7.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kruisbeek A. M., Mond J. J., Fowlkes B. J., Carmen J. A., Bridges S., Longo D. L. Absence of the Lyt-2-,L3T4+ lineage of T cells in mice treated neonatally with anti-I-A correlates with absence of intrathymic I-A-bearing antigen-presenting cell function. J Exp Med. 1985 May 1;161(5):1029–1047. doi: 10.1084/jem.161.5.1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kupfer A., Singer S. J., Janeway C. A., Jr, Swain S. L. Coclustering of CD4 (L3T4) molecule with the T-cell receptor is induced by specific direct interaction of helper T cells and antigen-presenting cells. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5888–5892. doi: 10.1073/pnas.84.16.5888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lamarre D., Ashkenazi A., Fleury S., Smith D. H., Sekaly R. P., Capon D. J. The MHC-binding and gp120-binding functions of CD4 are separable. Science. 1989 Aug 18;245(4919):743–746. doi: 10.1126/science.2549633. [DOI] [PubMed] [Google Scholar]
  24. Levine F., Erlich H. A., Mach B., Pious D. Transcriptional regulation of HLA class II and invariant chain genes. J Immunol. 1985 Jan;134(1):637–640. [PubMed] [Google Scholar]
  25. Levine F., Erlich H., Mach B., Leach R., White R., Pious D. Deletion mapping of HLA and chromosome 6p genes. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3741–3745. doi: 10.1073/pnas.82.11.3741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Maddon P. J., Dalgleish A. G., McDougal J. S., Clapham P. R., Weiss R. A., Axel R. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell. 1986 Nov 7;47(3):333–348. doi: 10.1016/0092-8674(86)90590-8. [DOI] [PubMed] [Google Scholar]
  27. Maddon P. J., Littman D. R., Godfrey M., Maddon D. E., Chess L., Axel R. The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a new member of the immunoglobulin gene family. Cell. 1985 Aug;42(1):93–104. doi: 10.1016/s0092-8674(85)80105-7. [DOI] [PubMed] [Google Scholar]
  28. McDougal J. S., Mawle A., Cort S. P., Nicholson J. K., Cross G. D., Scheppler-Campbell J. A., Hicks D., Sligh J. Cellular tropism of the human retrovirus HTLV-III/LAV. I. Role of T cell activation and expression of the T4 antigen. J Immunol. 1985 Nov;135(5):3151–3162. [PubMed] [Google Scholar]
  29. Meuer S. C., Hussey R. E., Hodgdon J. C., Hercend T., Schlossman S. F., Reinherz E. L. Surface structures involved in target recognition by human cytotoxic T lymphocytes. Science. 1982 Oct 29;218(4571):471–473. doi: 10.1126/science.6981845. [DOI] [PubMed] [Google Scholar]
  30. Meuer S. C., Schlossman S. F., Reinherz E. L. Clonal analysis of human cytotoxic T lymphocytes: T4+ and T8+ effector T cells recognize products of different major histocompatibility complex regions. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4395–4399. doi: 10.1073/pnas.79.14.4395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mizukami T., Fuerst T. R., Berger E. A., Moss B. Binding region for human immunodeficiency virus (HIV) and epitopes for HIV-blocking monoclonal antibodies of the CD4 molecule defined by site-directed mutagenesis. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9273–9277. doi: 10.1073/pnas.85.23.9273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Moebius U., Clayton L. K., Abraham S., Harrison S. C., Reinherz E. L. The human immunodeficiency virus gp120 binding site on CD4: delineation by quantitative equilibrium and kinetic binding studies of mutants in conjunction with a high-resolution CD4 atomic structure. J Exp Med. 1992 Aug 1;176(2):507–517. doi: 10.1084/jem.176.2.507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Owens T., Fazekas de St Groth B., Miller J. F. Coaggregation of the T-cell receptor with CD4 and other T-cell surface molecules enhances T-cell activation. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9209–9213. doi: 10.1073/pnas.84.24.9209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Peterson A., Seed B. Genetic analysis of monoclonal antibody and HIV binding sites on the human lymphocyte antigen CD4. Cell. 1988 Jul 1;54(1):65–72. doi: 10.1016/0092-8674(88)90180-8. [DOI] [PubMed] [Google Scholar]
  35. Reinherz E. L., Kung P. C., Goldstein G., Levey R. H., Schlossman S. F. Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1588–1592. doi: 10.1073/pnas.77.3.1588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Reinherz E. L., Kung P. C., Goldstein G., Schlossman S. F. Separation of functional subsets of human T cells by a monoclonal antibody. Proc Natl Acad Sci U S A. 1979 Aug;76(8):4061–4065. doi: 10.1073/pnas.76.8.4061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Reinherz E. L., Morimoto C., Penta A. C., Schlossman S. F. Regulation of B cell immunoglobulin secretion by functional subsets of T lymphocytes in man. Eur J Immunol. 1980 Jul;10(7):570–572. doi: 10.1002/eji.1830100715. [DOI] [PubMed] [Google Scholar]
  38. Rudd C. E., Trevillyan J. M., Dasgupta J. D., Wong L. L., Schlossman S. F. The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5190–5194. doi: 10.1073/pnas.85.14.5190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ryu S. E., Kwong P. D., Truneh A., Porter T. G., Arthos J., Rosenberg M., Dai X. P., Xuong N. H., Axel R., Sweet R. W. Crystal structure of an HIV-binding recombinant fragment of human CD4. Nature. 1990 Nov 29;348(6300):419–426. doi: 10.1038/348419a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Saizawa K., Rojo J., Janeway C. A., Jr Evidence for a physical association of CD4 and the CD3:alpha:beta T-cell receptor. Nature. 1987 Jul 16;328(6127):260–263. doi: 10.1038/328260a0. [DOI] [PubMed] [Google Scholar]
  41. Sattentau Q. J., Arthos J., Deen K., Hanna N., Healey D., Beverley P. C., Sweet R., Truneh A. Structural analysis of the human immunodeficiency virus-binding domain of CD4. Epitope mapping with site-directed mutants and anti-idiotypes. J Exp Med. 1989 Oct 1;170(4):1319–1334. doi: 10.1084/jem.170.4.1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Seed B., Aruffo A. Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure. Proc Natl Acad Sci U S A. 1987 May;84(10):3365–3369. doi: 10.1073/pnas.84.10.3365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Veillette A., Bookman M. A., Horak E. M., Bolen J. B. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell. 1988 Oct 21;55(2):301–308. doi: 10.1016/0092-8674(88)90053-0. [DOI] [PubMed] [Google Scholar]
  44. Wang J. H., Yan Y. W., Garrett T. P., Liu J. H., Rodgers D. W., Garlick R. L., Tarr G. E., Husain Y., Reinherz E. L., Harrison S. C. Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains. Nature. 1990 Nov 29;348(6300):411–418. doi: 10.1038/348411a0. [DOI] [PubMed] [Google Scholar]
  45. Zuñiga-Pflücker J. C., McCarthy S. A., Weston M., Longo D. L., Singer A., Kruisbeek A. M. Role of CD4 in thymocyte selection and maturation. J Exp Med. 1989 Jun 1;169(6):2085–2096. doi: 10.1084/jem.169.6.2085. [DOI] [PMC free article] [PubMed] [Google Scholar]

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