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. 1994 Jul 5;91(14):6594–6598. doi: 10.1073/pnas.91.14.6594

Human immunodeficiency virus 1 Tat binds to dipeptidyl aminopeptidase IV (CD26): a possible mechanism for Tat's immunosuppressive activity.

W G Gutheil 1, M Subramanyam 1, G R Flentke 1, D G Sanford 1, E Munoz 1, B T Huber 1, W W Bachovchin 1
PMCID: PMC44249  PMID: 7912830

Abstract

The human immunodeficiency virus 1 (HIV-1) Tat protein suppresses antigen-induced, but not mitogen-induced, activation of human T cells when added to T-cell cultures [Viscidi, R. P., Mayur, K., Lederman, H. M. & Frankel, A. D. (1989) Science 246, 1606-1608]. This activity is potentially pertinent to the development of AIDS because lymphocytes from HIV-infected individuals exhibit a similar antigen-specific dysfunction. Here we report that Tat binds with high affinity to the T-cell activation molecule dipeptidyl aminopeptidase IV (DP IV), also known as CD26. This molecule occurs on the surface of CD4+ cells responsible for the recall antigen response and appears to play an essential role in this response. Tat binds to both the cell surface and soluble forms of DP IV at physiological salt concentrations without inhibiting the protease activity of DP IV against small chromogenic substrates used to assay activity, but Tat markedly inhibits the activity of DP IV at lower salt concentrations. The kinetics of inhibition indicate the affinity of Tat for DP IV varies from 20 pM to 11 nM, and the activity of the Tat-DP IV complex varies from 13% to 100%, as the NaCl concentration varies from 0 to 140 mM. Cytofluorometry experiments demonstrate that Tat competes with anti-Ta1, a monoclonal antibody (mAb) specific for DP IV, for binding to cell surface DP IV, thus indicating that Tat binds DP IV at or near the Ta1 epitope. Moreover, the anti-Ta1 mAb blocks the immunosuppressive activity of Tat. The high affinity of Tat for DP IV, previous evidence implicating DP IV in antigen-specific T-cell activation events, and the ability of anti-Ta1 mAb to block the immunosuppressive effect of Tat make DP IV a plausible receptor for Tat's immunosuppressive activity.

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Selected References

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

  1. Barone A. D., Silva J. J., Ho D. D., Gallo R. C., Wong-Staal F. F., Chang N. T. Reactivity of E. coli-derived trans-activating protein of human T lymphotropic virus type III with sera from patients with acquired immune deficiency syndrome. J Immunol. 1986 Jul 15;137(2):669–673. [PubMed] [Google Scholar]
  2. Blazquez M. V., Madueño J. A., Gonzalez R., Jurado R., Bachovchin W. W., Peña J., Muñoz E. Selective decrease of CD26 expression in T cells from HIV-1-infected individuals. J Immunol. 1992 Nov 1;149(9):3073–3077. [PubMed] [Google Scholar]
  3. Brake D. A., Goudsmit J., Krone W. J., Schammel P., Appleby N., Meloen R. H., Debouck C. Characterization of murine monoclonal antibodies to the tat protein from human immunodeficiency virus type 1. J Virol. 1990 Feb;64(2):962–965. doi: 10.1128/jvi.64.2.962-965.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Callebaut C., Krust B., Jacotot E., Hovanessian A. G. T cell activation antigen, CD26, as a cofactor for entry of HIV in CD4+ cells. Science. 1993 Dec 24;262(5142):2045–2050. doi: 10.1126/science.7903479. [DOI] [PubMed] [Google Scholar]
  5. Dayton A. I., Sodroski J. G., Rosen C. A., Goh W. C., Haseltine W. A. The trans-activator gene of the human T cell lymphotropic virus type III is required for replication. Cell. 1986 Mar 28;44(6):941–947. doi: 10.1016/0092-8674(86)90017-6. [DOI] [PubMed] [Google Scholar]
  6. Ensoli B., Barillari G., Salahuddin S. Z., Gallo R. C., Wong-Staal F. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature. 1990 May 3;345(6270):84–86. doi: 10.1038/345084a0. [DOI] [PubMed] [Google Scholar]
  7. Etzkorn F. A., Chang Z. Y., Stolz L. A., Walsh C. T. Cyclophilin residues that affect noncompetitive inhibition of the protein serine phosphatase activity of calcineurin by the cyclophilin.cyclosporin A complex. Biochemistry. 1994 Mar 8;33(9):2380–2388. doi: 10.1021/bi00175a005. [DOI] [PubMed] [Google Scholar]
  8. Fauci A. S. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988 Feb 5;239(4840):617–622. doi: 10.1126/science.3277274. [DOI] [PubMed] [Google Scholar]
  9. Fiore M. M., Neuenschwander P. F., Morrissey J. H. An unusual antibody that blocks tissue factor/factor VIIa function by inhibiting cleavage only of macromolecular substrates. Blood. 1992 Dec 15;80(12):3127–3134. [PubMed] [Google Scholar]
  10. Flentke G. R., Munoz E., Huber B. T., Plaut A. G., Kettner C. A., Bachovchin W. W. Inhibition of dipeptidyl aminopeptidase IV (DP-IV) by Xaa-boroPro dipeptides and use of these inhibitors to examine the role of DP-IV in T-cell function. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1556–1559. doi: 10.1073/pnas.88.4.1556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gentz R., Chen C. H., Rosen C. A. Bioassay for trans-activation using purified human immunodeficiency virus tat-encoded protein: trans-activation requires mRNA synthesis. Proc Natl Acad Sci U S A. 1989 Feb;86(3):821–824. doi: 10.1073/pnas.86.3.821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gutheil W. G., Bachovchin W. W. Separation of L-Pro-DL-boroPro into its component diastereomers and kinetic analysis of their inhibition of dipeptidyl peptidase IV. A new method for the analysis of slow, tight-binding inhibition. Biochemistry. 1993 Aug 31;32(34):8723–8731. doi: 10.1021/bi00085a001. [DOI] [PubMed] [Google Scholar]
  13. Hafler D. A., Chofflon M., Benjamin D., Dang N. H., Breitmeyer J. Mechanisms of immune memory. T cell activation and CD3 phosphorylation correlates with Ta1 (CDw26) expression. J Immunol. 1989 Apr 15;142(8):2590–2596. [PubMed] [Google Scholar]
  14. Hafler D. A., Fox D. A., Benjamin D., Weiner H. L. Antigen reactive memory T cells are defined by Ta1. J Immunol. 1986 Jul 15;137(2):414–418. [PubMed] [Google Scholar]
  15. Harper J. W., Logsdon N. J. Refolded HIV-1 tat protein protects both bulge and loop nucleotides in TAR RNA from ribonucleolytic cleavage. Biochemistry. 1991 Aug 13;30(32):8060–8066. doi: 10.1021/bi00246a026. [DOI] [PubMed] [Google Scholar]
  16. Hegen M., Niedobitek G., Klein C. E., Stein H., Fleischer B. The T cell triggering molecule Tp103 is associated with dipeptidyl aminopeptidase IV activity. J Immunol. 1990 Apr 15;144(8):2908–2914. [PubMed] [Google Scholar]
  17. Helland D. E., Welles J. L., Caputo A., Haseltine W. A. Transcellular transactivation by the human immunodeficiency virus type 1 tat protein. J Virol. 1991 Aug;65(8):4547–4549. doi: 10.1128/jvi.65.8.4547-4549.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kameoka J., Tanaka T., Nojima Y., Schlossman S. F., Morimoto C. Direct association of adenosine deaminase with a T cell activation antigen, CD26. Science. 1993 Jul 23;261(5120):466–469. doi: 10.1126/science.8101391. [DOI] [PubMed] [Google Scholar]
  19. Lane H. C., Depper J. M., Greene W. C., Whalen G., Waldmann T. A., Fauci A. S. Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. Evidence for a selective defect in soluble antigen recognition. N Engl J Med. 1985 Jul 11;313(2):79–84. doi: 10.1056/NEJM198507113130204. [DOI] [PubMed] [Google Scholar]
  20. Marguet D., Bernard A. M., Vivier I., Darmoul D., Naquet P., Pierres M. cDNA cloning for mouse thymocyte-activating molecule. A multifunctional ecto-dipeptidyl peptidase IV (CD26) included in a subgroup of serine proteases. J Biol Chem. 1992 Feb 5;267(4):2200–2208. [PubMed] [Google Scholar]
  21. Morimoto C., Torimoto Y., Levinson G., Rudd C. E., Schrieber M., Dang N. H., Letvin N. L., Schlossman S. F. 1F7, a novel cell surface molecule, involved in helper function of CD4 cells. J Immunol. 1989 Dec 1;143(11):3430–3439. [PubMed] [Google Scholar]
  22. Morrison M. E., Vijayasaradhi S., Engelstein D., Albino A. P., Houghton A. N. A marker for neoplastic progression of human melanocytes is a cell surface ectopeptidase. J Exp Med. 1993 Apr 1;177(4):1135–1143. doi: 10.1084/jem.177.4.1135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Püschel G., Mentlein R., Heymann E. Isolation and characterization of dipeptidyl peptidase IV from human placenta. Eur J Biochem. 1982 Aug;126(2):359–365. doi: 10.1111/j.1432-1033.1982.tb06788.x. [DOI] [PubMed] [Google Scholar]
  24. Schnittman S. M., Lane H. C., Greenhouse J., Justement J. S., Baseler M., Fauci A. S. Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6058–6062. doi: 10.1073/pnas.87.16.6058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Seidl R., Schaefer W. Preparative purification of dipeptidyl peptidase IV. Prep Biochem. 1991;21(2-3):141–150. doi: 10.1080/10826069108018009. [DOI] [PubMed] [Google Scholar]
  26. Sodroski J., Rosen C., Goh W. C., Haseltine W. A transcriptional activator protein encoded by the x-lor region of the human T-cell leukemia virus. Science. 1985 Jun 21;228(4706):1430–1434. doi: 10.1126/science.2990028. [DOI] [PubMed] [Google Scholar]
  27. Subramanyam M., Gutheil W. G., Bachovchin W. W., Huber B. T. Mechanism of HIV-1 Tat induced inhibition of antigen-specific T cell responsiveness. J Immunol. 1993 Mar 15;150(6):2544–2553. [PubMed] [Google Scholar]
  28. Torimoto Y., Dang N. H., Vivier E., Tanaka T., Schlossman S. F., Morimoto C. Coassociation of CD26 (dipeptidyl peptidase IV) with CD45 on the surface of human T lymphocytes. J Immunol. 1991 Oct 15;147(8):2514–2517. [PubMed] [Google Scholar]
  29. Ulmer A. J., Mattern T., Flad H. D. Expression of CD26 (dipeptidyl peptidase IV) on memory and naive T lymphocytes. Scand J Immunol. 1992 May;35(5):551–559. doi: 10.1111/j.1365-3083.1992.tb03254.x. [DOI] [PubMed] [Google Scholar]
  30. Vanham G., Kestens L., De Meester I., Vingerhoets J., Penne G., Vanhoof G., Scharpé S., Heyligen H., Bosmans E., Ceuppens J. L. Decreased expression of the memory marker CD26 on both CD4+ and CD8+ T lymphocytes of HIV-infected subjects. J Acquir Immune Defic Syndr. 1993 Jul;6(7):749–757. [PubMed] [Google Scholar]
  31. Viscidi R. P., Mayur K., Lederman H. M., Frankel A. D. Inhibition of antigen-induced lymphocyte proliferation by Tat protein from HIV-1. Science. 1989 Dec 22;246(4937):1606–1608. doi: 10.1126/science.2556795. [DOI] [PubMed] [Google Scholar]
  32. Wolf G. B., Scherberich J. E., Fischer P., Schoeppe W. Isolation and characterization of dipeptidyl aminopeptidase IV from human kidney cortex. Clin Chim Acta. 1989 Jan 13;179(1):61–71. doi: 10.1016/0009-8981(89)90023-5. [DOI] [PubMed] [Google Scholar]

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