1887

Abstract

The Tat regulatory protein of human immunodeficiency virus type 1 (HIV-1) is secreted by infected cells and plays a key role in viral pathogenesis and replication. Tat protein has been proposed as a target antigen for vaccine design since anti-Tat antibodies may interfere with virus spread and disease progression. The aim of this study was to analyse the serum antibody response of mice, rabbits, macaques and humans immunized with recombinant Tat, synthetic Tat, Tat toxoid or Tat peptides and to examine the biological properties of these antibodies in terms of Tat-induced transactivation and HIV-1 replication. Only sera with antibody specificity to both N-terminal and basic functional domains were able to inhibit extracellular Tat-dependent transactivation significantly . Antibodies from a human subject immunized with Tat also reduced HIV-1 replication in acutely infected T cells and blocked reactivation of virus replicating low levels in chronically infected cells by exogenous Tat. These results demonstrate that immunization with Tat protein or a combination of synthetic Tat peptides elicits the production of Tat-neutralizing serum antibodies and suggest that Tat vaccination could be used to block extracellular Tat autocrine/paracrine transactivation of HIV-1 replication.

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2004-10-01
2024-03-29
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References

  1. Alape-Giron A., Miranda-Arrieta K., Cortes-Bratti X., Stiles B. G., Gutierrez J. M. 1997; A comparison of in vitro methods for assessing the potency of therapeutic antisera against the venom of the coral snake Micrurus nigrocinctus . Toxicon 35:573–581 [CrossRef]
    [Google Scholar]
  2. Albini A., Benelli R., Giunciuglio D., Cai T., Mariani G., Ferrini S., Noonan D. M. 1998; Identification of a novel domain of HIV tat involved in monocyte chemotaxis. J Biol Chem 273:15895–15900 [CrossRef]
    [Google Scholar]
  3. Bartz S. R., Emerman M. 1999; Human immunodeficiency virus type 1 Tat induces apoptosis and increases sensitivity to apoptotic signals by up-regulating FLICE/caspase-8. J Virol 73:1956–1963
    [Google Scholar]
  4. Belliard G., Romieu A., Zagury J. F. 8 other authors 2003; Specificity and effect on apoptosis of Tat antibodies from vaccinated and SHIV-infected rhesus macaques and HIV-infected individuals. Vaccine 21:3186–3199 [CrossRef]
    [Google Scholar]
  5. Bennasser Y., Badou A., Tkaczuk J., Bahraoui E. 2002; Signaling pathways triggered by HIV-1 Tat in human monocytes to induce TNF- α . . : Virology 303:174–180 [CrossRef]
    [Google Scholar]
  6. Borgatti P., Zauli G., Colamussi M. L., Gibellini D., Previati M., Cantley L. L., Capitani S. 1997; Extracellular HIV-1 Tat protein activates phosphatidylinositol 3- and Akt/PKB kinases in CD4+ T lymphoblastoid Jurkat cells. Eur J Immunol 27:2805–2811 [CrossRef]
    [Google Scholar]
  7. Boykins R. A., Ardans J. A., Wahl L. M., Lal R. B., Yamada K. M., Dhawan S. 2000; Immunization with a novel HIV-1-Tat multiple-peptide conjugate induces effective immune response in mice. Peptides 21:1839–1847 [CrossRef]
    [Google Scholar]
  8. Brake D. A., Debouck C., Biesecker G. 1990a; Identification of an Arg-Gly-Asp (RGD) cell adhesion site in human immunodeficiency virus type 1 transactivation protein, tat. J Cell Biol 111:1275–1281 [CrossRef]
    [Google Scholar]
  9. Brake D. A., Goudsmit J., Krone W. J., Schammel P., Appleby N., Meloen R. H., Debouck C. 1990b; Characterization of murine monoclonal antibodies to the tat protein from human immunodeficiency virus type 1. J Virol 64:962–965
    [Google Scholar]
  10. Cafaro A., Caputo A., Fracasso C. 16 other authors 1999; Control of SHIV-89.6P-infection of cynomolgus monkeys by HIV-1 Tat protein vaccine. Nat Med 5:643–650 [CrossRef]
    [Google Scholar]
  11. Cartier C., Sivard P., Tranchat C., Decimo D., Desgranges C., Boyer V. 1999; Identification of three major phosphorylation sites within HIV-1 capsid. Role of phosphorylation during the early steps of infection. J Biol Chem 274:19434–19440 [CrossRef]
    [Google Scholar]
  12. Chirmule N., Than S., Khan S. A., Pahwa S. 1995; Human immunodeficiency virus Tat induces functional unresponsiveness in T cells. J Virol 69:492–498
    [Google Scholar]
  13. Cornille F., Wecker K., Loffet A., Genet R., Roques B. 1999; Efficient solid-phase synthesis of Vpr from HIV-1 using low quantities of uniformly 13C-, 15N-labeled amino acids for NMR structural studies. J Pept Res 54:427–435 [CrossRef]
    [Google Scholar]
  14. Dayton A. I., Sodroski J. G., Rosen C. A., Goh W. C., Haseltine W. A. 1986; The trans -activator gene of the human T cell lymphotropic virus type III is required for replication. Cell 44:941–947 [CrossRef]
    [Google Scholar]
  15. Ensoli B., Barillari G., Salahuddin S. Z., Gallo R. C., Wong-Staal F. 1990; Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature 345:84–86 [CrossRef]
    [Google Scholar]
  16. Ensoli B., Buonaguro L., Barillari G., Fiorelli V., Gendelman R., Morgan R. A., Wingfield P., Gallo R. C. 1993; Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol 67:277–287
    [Google Scholar]
  17. Felber B. K., Pavlakis G. N. 1988; A quantitative bioassay for HIV-1 based on trans-activation. Science 239:184–187 [CrossRef]
    [Google Scholar]
  18. Frankel A. D., Pabo C. O. 1988; Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55:1189–1193 [CrossRef]
    [Google Scholar]
  19. Gallo R. C. 1999; Tat as one key to HIV-induced immune pathogenesis and Tat (correction of Pat) toxoid as an important component of a vaccine. Proc Natl Acad Sci U S A 96:8324–8326 [CrossRef]
    [Google Scholar]
  20. Ganju R. K., Munshi N., Nair B. C., Liu Z. Y., Gill P., Groopman J. E. 1998; Human immunodeficiency virus tat modulates the Flk-1/KDR receptor, mitogen-activated protein kinases, and components of focal adhesion in Kaposi's sarcoma cells. J Virol 72:6131–6137
    [Google Scholar]
  21. Gibellini D., Bassini A., Pierpaoli S., Bertolaso L., Milani D., Capitani S., La Placa M., Zauli G. 1998; Extracellular HIV-1 Tat protein induces the rapid Ser133 phosphorylation and activation of CREB transcription factor in both Jurkat lymphoblastoid T cells and primary peripheral blood mononuclear cells. J Immunol 160:3891–3898
    [Google Scholar]
  22. Goldstein G. 1996; HIV-1 Tat protein as a potential AIDS vaccine. Nat Med 2:960–964 [CrossRef]
    [Google Scholar]
  23. Goldstein G., Manson K., Tribbick G., Smith R. 2000; Minimization of chronic plasma viremia in rhesus macaques immunized with synthetic HIV-1 Tat peptides and infected with a chimeric simian/human immunodeficiency virus (SHIV33). . : Vaccine 18:2789–2795 [CrossRef]
    [Google Scholar]
  24. Goldstein G., Tribbick G., Manson K. 2001; Two B cell epitopes of HIV-1 Tat protein have limited antigenic polymorphism in geographically diverse HIV-1 strains. Vaccine 19:1738–1746 [CrossRef]
    [Google Scholar]
  25. Gringeri A., Santagostino E., Muca-Perja M. 8 other authors 1999; Tat toxoid as a component of a preventive vaccine in seronegative subjects. J Acquir Immune Defic Syndr Hum Retrovirol 20:371–375 [CrossRef]
    [Google Scholar]
  26. Hauber J., Perkins A., Heimer E. P., Cullen B. R. 1987; Trans-activation of human immunodeficiency virus gene expression is mediated by nuclear events. Proc Natl Acad Sci U S A 84:6364–6368 [CrossRef]
    [Google Scholar]
  27. Herrmann C. H., Rice A. P. 1995; Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor. J Virol 69:1612–1620
    [Google Scholar]
  28. Huang L., Bosch I., Hofmann W., Sodroski J., Pardee A. B. 1998; Tat protein induces human immunodeficiency virus type 1 (HIV-1) coreceptors and promotes infection with both macrophage-tropic and T-lymphotropic HIV-1 strains. J Virol 72:8952–8960
    [Google Scholar]
  29. Laemmli U. K. 1970; Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685 [CrossRef]
    [Google Scholar]
  30. Le Buanec H., Bizzini B. 2000; Procedures for preparing biologically inactive, but immunogenic HIV-1 Tat protein (Tat toxoid) for human use. Biomed Pharmacother 54:41–54 [CrossRef]
    [Google Scholar]
  31. Moreau E., Hoebeke J., Zagury D., Muller S., Desgranges C. 2004; Generation and characterization of neutralizing human monoclonal antibodies against human immunodeficiency virus type 1 Tat antigen. J Virol 78:3792–3796 [CrossRef]
    [Google Scholar]
  32. Neimark J., Briand J. P. 1993; Development of a fully automated multichannel peptide synthesizer with integrated TFA cleavage capability. Pept Res 6:219–228
    [Google Scholar]
  33. Noonan D. M., Gringeri A., Meazza R. 7 other authors 2003; Identification of immunodominant epitopes in inactivated Tat-vaccinated healthy and HIV-1-infected volunteers. J Acquir Immune Defic Syndr 33:47–55 [CrossRef]
    [Google Scholar]
  34. Olszewska W., Obeid O. E., Steward M. W. 2000; Protection against measles virus-induced encephalitis by anti-mimotope antibodies: the role of antibody affinity. Virology 272:98–105 [CrossRef]
    [Google Scholar]
  35. Pauza C. D., Trivedi P., Wallace M. 7 other authors 2000; Vaccination with tat toxoid attenuates disease in simian/HIV-challenged macaques. Proc Natl Acad Sci U S A 97:3515–3519 [CrossRef]
    [Google Scholar]
  36. Re M. C., Furlini G., Vignoli M. 7 other authors 1995; Effect of antibody to HIV-1 Tat protein on viral replication in vitro and progression of HIV-1 disease in vivo . J Acquir Immune Defic Syndr Hum Retrovirol 10:408–416 [CrossRef]
    [Google Scholar]
  37. Re M. C., Vignoli M., Furlini G., Gibellini D., Colangeli V., Vitone F., La Placa M. 2001; Antibodies against full-length Tat protein and some low-molecular-weight Tat-peptides correlate with low or undetectable viral load in HIV-1 seropositive patients. J Clin Virol 21:81–89 [CrossRef]
    [Google Scholar]
  38. Reiss P., de Wolf F., Kuiken C. L., de Ronde A., Dekker J., Boucher C. A., Debouck C., Lange J. M., Goudsmit J. 1991; Contribution of antibody response to recombinant HIV-1 gene-encoded products nef, rev, tat, and protease in predicting development of AIDS in HIV-1-infected individuals. J Acquir Immune Defic Syndr 4:165–172
    [Google Scholar]
  39. Rhim H., Echetebu C. O., Herrmann C. H., Rice A. P. 1994; Wild-type and mutant HIV-1 and HIV-2 Tat proteins expressed in Escherichia coli as fusions with glutathione S -transferase. J Acquir Immune Defic Syndr 7:1116–1121
    [Google Scholar]
  40. Richardson M. W., Mirchandani J., Duong J., Grimaldo S., Kocieda V., Hendel H., Khalili K., Zagury J. F., Rappaport J. 2003; Antibodies to Tat and Vpr in the GRIV cohort: differential association with maintenance of long-term non-progression status in HIV-1 infection. Biomed Pharmacother 57:4–14 [CrossRef]
    [Google Scholar]
  41. Rodman T. C., To S. E., Hashish H., Manchester K. 1993; Epitopes for natural antibodies of human immunodeficiency virus (HIV)-negative (normal) and HIV-positive sera are coincident with two key functional sequences of HIV Tat protein. Proc Natl Acad Sci U S A 90:7719–7723 [CrossRef]
    [Google Scholar]
  42. Rodman T. C., Lutton J. D., Jiang S., Al-Kouatly H. B., Winston R. 2001; Circulating natural IgM antibodies and their corresponding human cord blood cell-derived Mabs specifically combat the Tat protein of HIV. Exp Hematol 29:1004–1009 [CrossRef]
    [Google Scholar]
  43. Rubartelli A., Poggi A., Sitia R., Zocchi M. R. 1998; HIV-I Tat: a polypeptide for all seasons. Immunol Today 19:543–545 [CrossRef]
    [Google Scholar]
  44. Secchiero P., Zella D., Capitani S., Gallo R. C., Zauli G. 1999; Extracellular HIV-1 tat protein up-regulates the expression of surface CXC-chemokine receptor 4 in resting CD4+ T cells. J Immunol 162:2427–2431
    [Google Scholar]
  45. Silvera P., Richardson M. W., Greenhouse J. 7 other authors 2002; Outcome of simian–human immunodeficiency virus strain 89.6p challenge following vaccination of rhesus macaques with human immunodeficiency virus Tat protein. J Virol 76:3800–3809 [CrossRef]
    [Google Scholar]
  46. Simonsen O., Schou C., Heron I. 1987; Modification of the ELISA for the estimation of tetanus antitoxin in human sera. J Biol Stand 15:143–157 [CrossRef]
    [Google Scholar]
  47. Steinaa L., Sorensen A. M., Nielsen J. O., Hansen J. E. 1994; Antibody to HIV-1 Tat protein inhibits the replication of virus in culture. Arch Virol 139:263–271 [CrossRef]
    [Google Scholar]
  48. Tahtinen M., Ranki A., Valle S. L., Ovod V., Krohn K. 1997; B-cell epitopes in HIV-1 Tat and Rev proteins colocalize with T-cell epitopes and with functional domains. Biomed Pharmacother 51:480–487 [CrossRef]
    [Google Scholar]
  49. Tikhonov I., Ruckwardt T. J., Hatfield G. S., Pauza C. D. 2003; Tat-neutralizing antibodies in vaccinated macaques. J Virol 77:3157–3166 [CrossRef]
    [Google Scholar]
  50. Tosi G., Meazza R., de Lerma Barbaro A. 7 other authors 2000; Highly stable oligomerization forms of HIV-1 Tat detected by monoclonal antibodies and requirement of monomeric forms for the transactivating function on the HIV-1 LTR. Eur J Immunol 30:1120–1126 [CrossRef]
    [Google Scholar]
  51. Viscidi R. P., Mayur K., Lederman H. M., Frankel A. D. 1989; Inhibition of antigen-induced lymphocyte proliferation by Tat protein from HIV-1. Science 246:1606–1608 [CrossRef]
    [Google Scholar]
  52. Westendorp M. O., Frank R., Ochsenbauer C., Stricker K., Dhein J., Walczak H., Debatin K. M., Krammer P. H. 1995; Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 375:497–500 [CrossRef]
    [Google Scholar]
  53. Zagury J. F., Sill A., Blattner W. 12 other authors 1998; Antibodies to the HIV-1 Tat protein correlated with nonprogression to AIDS: a rationale for the use of Tat toxoid as an HIV-1 vaccine. J Hum Virol 1:282–292
    [Google Scholar]
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