Clinical Immunotherapeutics

, Volume 1, Issue 2, pp 89–94 | Cite as


Clinical Potential in the Treatment of AIDS
  • Seth H. Pincus
Leading Article


Immunotoxins directed against human immunodeficiency virus (HIV) may be of use in treating AIDS by eliminating HIV-infected cells that are actively secreting virus and serving as a nidus for the spread of the infection. These immunotoxins may be directed either toward viral structures expressed on the surface of cells or toward cell populations known to be sites of HIV replication.

The HIV envelope proteins gp120 and gp 41 are the major antigenic structures expressed on infected cells. They may be targeted with CD4 (the viral receptor) or with monoclonal antibodies. Activated lymphocytes expressing the interleukin-2 receptor are an important reservoir of HIV replication.

The efficacy of these immunotoxins has been established in vitro, and mechanisms of enhancement of immunotoxin action have been defined. A CD4-based immunotoxin has completed phase I clinical trials.


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  1. 1.
    Johnston MI, Hoth DF. Present status and future prospects for HIV therapies. Science 1993; 260: 1286–93PubMedCrossRefGoogle Scholar
  2. 2.
    Stein DS, Timpone JG, Gradon JD, et al. Immune-based therapeutics: scientific rationale and the promising approaches to the treatment of the human immunodeficiency virus-infected individual. Clin Infect Dis 1993; 17: 749–71PubMedCrossRefGoogle Scholar
  3. 3.
    Redfield RR, Birx DL, Ketter N, et al. A phase I evaluation of the safety and immunogenicity of vaccination with recombinant gp 160 in patients with early human immunodeficiency virus infection. N Engl J Med 1991; 324: 1677–84PubMedCrossRefGoogle Scholar
  4. 4.
    Jacobson JM, Colman N, Ostrow NA, et al. Passive immunotherapy in the treatment of advanced human immunodeficiency virus infection. J Infect Dis 1993; 168: 298–305PubMedCrossRefGoogle Scholar
  5. 5.
    Zolla-Pazner S, Gorny MK. Passive immunization for the prevention and treatment of HIV infection. AIDS 1992; 6: 1235–47PubMedCrossRefGoogle Scholar
  6. 6.
    Riddell SR, Gilbert MJ, Greenberg PD. CD8+ cytotoxic T cell therapy of cytomegalovirus and HIV infection. Curr Opin Immunol 1993; 5: 484–91PubMedCrossRefGoogle Scholar
  7. 7.
    Pincus SH. Immunotoxins. In Rosenberg M, et al., editors. Pharmacology of monoclonal antibodies. Berlin: Springer-Verlag, 1994. In pressGoogle Scholar
  8. 8.
    Ramakrishnan S, Fryxell D, Mohanraj D, et al. Cytotoxic conjugates containing translational inhibitory proteins. Annu Rev Pharmacol Toxicol 1992; 32: 579–621PubMedCrossRefGoogle Scholar
  9. 9.
    Pincus SH, Wehrly K, Chesebro B. Treatment of HIV tissue culture infection with monoclonal antibody-ricin A chain conjugates. J Immunol 1989; 142: 3070–5PubMedGoogle Scholar
  10. 10.
    Pincus SH, Cole RL, Hersh EM, et al. In vitro efficacy of anti-HIV immunotoxins targeted by various antibodies to the envelope protein. J Immunol 1991; 146: 4315–24PubMedGoogle Scholar
  11. 11.
    Till MA, Zolla-Pazner S, Gorny MK, et al. Human immunodeficiency virus-infected T cells and monocytes are killed by monoclonal human anti-gp41 antibodies coupled to ricin A chain. Proc Natl Acad Sci USA 1989; 86: 1987–91PubMedCrossRefGoogle Scholar
  12. 12.
    Kim Y-W, Chang TW. Potential use of immunoconjugates for AIDS therapy. AIDS Res Hum Retroviruses 1992; 8: 1033–8PubMedCrossRefGoogle Scholar
  13. 13.
    Matsushita S, Koito A, Maeda Y, et al. Selective killing of HIV-infected cells by anti-gp120 immunotoxins. AIDS Res Hum Retroviruses 1990; 6: 193–203PubMedCrossRefGoogle Scholar
  14. 14.
    Chaudhary VK, Mizukami T, Fuerst TR, et al. Selective killing of HIV-infected cells by recombinant human CD4-Pseudomonas exotoxin hybrid protein. Nature 1988; 335: 369–72PubMedCrossRefGoogle Scholar
  15. 15.
    Berger EA, Clouse KA, Chaudhary VK, et al. CD4-Pseudomonas exotoxin hybrid protein blocks the spread of human immunodeficiency virus infection in vitro and is active against cells expressing the envelope glycoproteins from diverse primate immunodeficiency retroviruses. Proc Natl Acad Sci USA 1989; 86: 9539–43PubMedCrossRefGoogle Scholar
  16. 16.
    Till MA, Ghetie V, Gregory T, et al. HIV-infected cells are killed by rCD4-ricin A chain. Science 1988; 242: 1166–8PubMedCrossRefGoogle Scholar
  17. 17.
    Tsubota H, Winkler G, Meade HM, et al. CD4-Pseudomonas exotoxin conjugates delay but do not fully inhibit human immunodeficiency virus replication in lymphocytes in vitro. J Clin Invest 1990; 86: 1684–9PubMedCrossRefGoogle Scholar
  18. 18.
    Aullo P, Alcami J, Popoff MR, et al. A recombinant diphtheria toxin related human CD4 fusion protein specifically kills HIV infected cells which express gp120 but selects fusion toxin resistant cells which carry HIV. EMBO J 1992; 11: 575–83PubMedGoogle Scholar
  19. 19.
    Finberg RW, Wahl SM, Allen JB, et al. Selective elimination of HIV-1-infected cells with an interleukin-2 receptor-specific cytotoxin. Science 1991; 252: 1703–5PubMedCrossRefGoogle Scholar
  20. 20.
    Shang F, Huang H, Revesz K, et al. Characterization of monoclonal antibodies against the human immunodeficiency virus matrix protein p17: identification of epitopes exposed at the surfaces of infected cells. J Virol 1991; 65: 4798–804PubMedGoogle Scholar
  21. 21.
    Kennedy PE, Moss B, Berger EA. Primary HIV-1 refractory to neutralization by soluble CD4 are potently inhibited by CD4-Pseudomonas exotoxin. Virology 1993; 192: 375–9PubMedCrossRefGoogle Scholar
  22. 22.
    Bell KD, Ramilo O, Vitetta ES. Combined use of an immunotoxin and cyclosporine to prevent both activated and quiescent peripheral blood T cells from producing type 1 human immunodeficiency virus. Proc Natl Acad Sci USA 1993; 90: 1411–5PubMedCrossRefGoogle Scholar
  23. 23.
    Ramilo O, Bell KD, Uhr JW, et al. Role of CD25+ and CD25−T cells in acute HIV infection in vitro. J Immunol 1993; 150: 5202–8PubMedGoogle Scholar
  24. 24.
    Zarling JM, Moran PA, Haffar O, et al. Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4+ cells by monoclonal antibodies [letter]. Nature 1990; 347: 92–5PubMedCrossRefGoogle Scholar
  25. 25.
    Olsnes S, Sandvig K, Peterson OW, et al. Immunotoxins: entry into cells and mechanisms of action. Immunol Today 1989; 10: 291–5PubMedGoogle Scholar
  26. 26.
    Ramakrishnan S, Houston LL. Inhibition of human acute lymphoblastic leukemia cells by immunotoxins: potentiation by chloroquine. Science 1984; 223: 58–61PubMedCrossRefGoogle Scholar
  27. 27.
    Pincus SH, McClure J. Soluble CD4 enhances the efficacy of immunotoxins directed against gp41 of the human immunodeficiency virus. Proc Nat Acad Sci USA 1993; 90: 332–6PubMedCrossRefGoogle Scholar
  28. 28.
    Pincus SH, Wehrly K. AZT demonstrates anti-HIV-1 activity in persistently infected cell lines: implications for combination chemotherapy and immunotherapy. J Infect Dis 1990; 162: 1233PubMedCrossRefGoogle Scholar
  29. 29.
    Ashorn P, Moss B, Weinstein JN, et al. Elimination of infectious human immunodeficiency virus from human T-cell cultures by synergistic action of CD4-Pseudomonas exotoxin and reverse transcriptase inhibitors. Proc Natl Acad Sci USA 1990; 87: 8889–93PubMedCrossRefGoogle Scholar
  30. 30.
    Olson MC, Ramakrishnan S, Anand R. Ribosomal inhibitory proteins from plants inhibit HIV-1 replication in acutely infected peripheral blood mononuclear cells. AIDS Res Hum Retroviruses 1991; 7: 1025–30PubMedCrossRefGoogle Scholar
  31. 31.
    Vitetta ES, Stone M, Amlot P, et al. Phase I immunotoxin trial in patients with B-cell lymphoma. Cancer Res 1991; 51: 4052–8PubMedGoogle Scholar
  32. 32.
    Trown PW, Reardan DT, Carroll SF, et al. Improved pharmacokinetics and tumor localization of immunotoxins constructed with the Mr 30,000 form of ricin A chain. Cancer Res 1991; 51: 4219–25PubMedGoogle Scholar
  33. 33.
    Davey Jr RT, Boenning CM, Herpin BR, et al. A phase I study of recombinant CD4-Pseudomonas exotoxin (CD4-PE40) in HIV-infected individuals. Proceedings of the VIII International Conference on AIDS; 1992 Jul 19–24; Amsterdam, 1992: Mo8Google Scholar
  34. 34.
    Batra JK, Kasturi S, Gallo MG, et al. Insertion of constant region domains of human IgG1 into CD4-PE40 increases its plasma half-life. Mol Immunol 1993; 30: 379–86PubMedCrossRefGoogle Scholar
  35. 35.
    Yokota T, Milenic DE, Whitlow M, et al. Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res 1992; 52: 3402–8PubMedGoogle Scholar
  36. 36.
    Letvin NL, Chalifoux LV, Reimann KA, et al. In vivo administration of lymphocyte-specific monoclonal antibodies in non-human primates. Delivery of ribosome-inactivating proteins to spleen and lymph node T cells. J Clin Invest 1986; 78: 666–73PubMedCrossRefGoogle Scholar
  37. 37.
    Vitetta ES, Thorpe PE, Uhr JW. Immunotoxins: magic bullets or misguided missiles? Immunol Today 1993; 14: 252–8PubMedCrossRefGoogle Scholar
  38. 38.
    Strand V, Lipsky PE, Cannon GW, et al. Effects of administration of an anti-CD5 plus immunoconjugate in rheumatoid arthritis: results of two phase two studies. Arthritis Rheum 1993; 36: 620–30PubMedCrossRefGoogle Scholar
  39. 39.
    Pincus SH, Wehrly K, Tschachler E, et al. Variants selected by treatment of human immunodeficiency virus-infected cells with an immunotoxin. J Exp Med 1990; 172: 745–57PubMedCrossRefGoogle Scholar
  40. 40.
    Davey Jr RT, Boening CM, Herpin BR, et al. A phase I multidose trial of CD4-Pseudomonas exotoxin (sCD4-PE40) in HIV-1-infected individuals [abstract]. Proceedings of the IX International Conference on AIDS; 1993 Jun 6–11; Berlin, 1993: 478Google Scholar

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Seth H. Pincus
    • 1
  1. 1.Laboratory of Microbial Structure and FunctionNIAID Rocky Mountain LaboratoriesHamiltonUSA

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