Skip to main content

Advertisement

SpringerLink
Log in

Immunomodulatory Approaches to the Therapy of AIDS

  • Review Article
  • Immunological Basis of Disease
  • Published:
Clinical Immunotherapeutics Aims and scope Submit manuscript

Summary

Immune-based therapies are being explored on the presumption that host response to HIV is central to the pathogenesis and progression of HIV infection. Specific immune responses in most individuals serve to limit the acute stage of infection and induce a more chronic form of viral infection. Thus, immune response to HIV appears to be critical to virus control. On the other hand, HIV infection induces widespread activation of immune cells, which in turn contributes to further HIV production. Also, immune dysfunction contributes to the development of a number of clinical disorders of AIDS, including opportunistic infections, wasting syndrome, AIDS dementia complex, Kaposi’s sarcoma and lymphoproliferative disorders.

Immune-based therapies in AIDS are directed at answering 2 major questions. Can specific HIV immunity be manipulated to better contain and reduce established HIV infection, and how can the pathogenic processes induced by HIV infection be reversed so as to maintain or restore normal function and health? The interventions explored thus far have been directed towards enhancement of specific immune mechanisms early in infection, restoration of defective functions and reduction of excessive activation secondary to cytokine derangement in HIV infection. Effective therapies developed to date include interferon-α for Kaposi’s sarcoma and intermittent interleukin-2 (5-day courses every 8 weeks) to increase CD4+ counts. With greater understanding of the immunopathogenesis of HIV infection, better focused and potentially more effective therapies can be expected.

Immune-based therapies are created from an understanding of the immunopathogenesis of HIV infection. As knowledge of pathogenesis increases, more effective means of controlling HIV replication and immune damage are developed. Immune therapies are also designed to maintain normal host immune functions and thus reduce the likelihood of opportunistic diseases. However, the immunopathogenic mechanisms underlying HIV infection and AIDS are complex and involve multifaceted interactions of the virus with the immune system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fauci AS. Multifactorial nature of human immunodeficiency virus disease: implication for therapy. Science 1993; 262: 1011–8

    Article  PubMed  CAS  Google Scholar 

  2. Plata F, Dadaglio G, Chenciner N, et al. Cytotoxic T lymphocytes in HIV-induced disease: implications for therapy and vaccination. Immunodefic Rev 1989; 1: 227–46

    PubMed  CAS  Google Scholar 

  3. Fahey JL, Prince H, Weaver MM, et al. Quantitative changes in Th and Ts lymphocyte subsets that distinguish AIDS syndrome from other immune subset disorders. Am J Med 1984; 76: 95–100

    Article  PubMed  CAS  Google Scholar 

  4. Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995; 373: 117–22

    Article  PubMed  CAS  Google Scholar 

  5. Ho D, Neuman AU, Perelson AS et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995; 373: 123–6

    Article  PubMed  CAS  Google Scholar 

  6. Hofmann B, Lindhardt BO, Gerstoft J, et al. The lymphocyte transformation response to pokeweed mitogen is a highly predictive parameter for the development of AIDS. BMJ 1987; 295: 293–6

    Article  PubMed  CAS  Google Scholar 

  7. Fahey JL, Taylor JMG, Detels R, et al. The prognostic value of cellular and serologic markers in infection with HIV-1. N Engl J Med 1990; 322: 166–72

    Article  PubMed  CAS  Google Scholar 

  8. Moss AR, Bacchetti P, Osmond D, et al. Seropositivity for HIV and the development of AIDS or AIDS related conditions. BMJ 1988; 296: 745–50

    Article  PubMed  CAS  Google Scholar 

  9. Giorgi JV, Liu Z, Hultin L, et al. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4 T cell levels. J Acq Immune Defic Syndr 1993; 6: 904–12

    CAS  Google Scholar 

  10. Fan J, Bass HZ, Fahey JL. Elevated IFNγ and decreased IL-2 gene expression are associated with HIV infection. J Immunol 1993; 151: 5031–40

    PubMed  CAS  Google Scholar 

  11. Breen EC, Rezai AR, Nakajima K, et al. Infection with HIV is associated with elevated IL-6 levels and production. J Immunol 1990; 144: 480–6

    PubMed  CAS  Google Scholar 

  12. Romagnani S. Human Th1 and Th2 subsets: doubt no more. Immunol Today 1991; 11: 256–9

    Article  Google Scholar 

  13. Clerici M, Shearer GM. The T helper cell shift in AIDS: significance for pharmacotherapy. Clin Immunother 1995; 3(2): 95–101

    Article  Google Scholar 

  14. Folks TM, Clouse KA, Justement J, et al. Tumor necrosis factor-α induces expression of HIV in chronically infected T cell clone. Proc Natl Acad Sci USA 1989; 86: 2365–8

    Article  PubMed  CAS  Google Scholar 

  15. Miles SA, Martinez-Maza O, Rezai A, et al. Oncostatin M as a potent mitogen for AIDS Kaposi’s sarcoma cells. Science 1992; 255: 1432–4

    Article  PubMed  CAS  Google Scholar 

  16. Staal FJ, Ela SW, Roederer M, et al. Glutathione deficiency and human immunodeficiency virus infection. Lancet 1992; 339(8798): 909–12

    Article  PubMed  CAS  Google Scholar 

  17. Hofmann B, Nishanian P, Nguyen T, et al. Restoration of T cell function in HIV infection by reduction of intracellular cAMP levels with adenosine analogues. AIDS 1993; 7: 659–64

    Article  PubMed  CAS  Google Scholar 

  18. Amiesen JC, Capron A. Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. Immunol Today 1991; 12: 102–4

    Article  Google Scholar 

  19. Clerici M, Stocks NI, Zajoc RA, et al. Detection of three distinct patterns of T helper dysfunction in asymptomatic HIV seropositive patients. J Clin Invest 1989; 84: 1892–9

    Article  PubMed  CAS  Google Scholar 

  20. Huber C, Batchelor JR, Fuchs D, et al. Immune response-associated production of neopterin. J Exp Med 1984; 160: 310–6

    Article  PubMed  CAS  Google Scholar 

  21. Hofmann B, Bass H, Nishanian P, et al. Different lymphoid cell populations produce varied levels of neopterin, beta-2 micro-globulin and sIL-2R when stimulated by IL-2, IFN-γ and TNF-α. Clin Exp Immunol 1992; 88: 548–54

    Article  PubMed  CAS  Google Scholar 

  22. Hofmann B, Nishanian P, Fahey JL, et al. Serum increases and lymphoid cell surface losses of IL-2 receptor CD25 in HIV infection: distinctive parameters of HIV-induced change. Clin Immunol Immunopathol 1991; 61: 212–24

    Article  PubMed  CAS  Google Scholar 

  23. Bass HZ, Nishanian P, Hardy WD, et al. Immune change in HIV infection: significant correlations and differences in serum markers and lymphoid phenotypic antigens. Clin Immunol Immunopathol 1992; 64: 63–70

    Article  PubMed  CAS  Google Scholar 

  24. Kohlberg J, Shen LP, Urdea M, et al. Quantitation of cellular mRNA for TNFα, IL-6, IL-2 and IFNγ in HIV positive patients using bDNA assays. Proceedings of the First International Symposium on HIV and Cytokines; 1995 Mar 15–17; Rheims. In press

  25. Nishanian P, Huskins KR, Stehn S, et al. A simple method for improved assay demonstrate that HIV p24 antigen is present as immune complexes in most sera from HIV-infected individuals. J Infect Dis 1990; 162: 21–8

    Article  PubMed  CAS  Google Scholar 

  26. Miles SA, Balden E, Magpanty L, et al. Rapid serologic testing with immune-complex-dissociated HIV p24 antigen for early detection of HIV infection in neonates. N Engl J Med 1993; 328: 297–302

    Article  PubMed  CAS  Google Scholar 

  27. Coombs RW, Collier AC, Allain JP, et al. Plasma viremia in human immunodeficiency virus infection. N Engl J Med 1989; 321: 1626–31

    Article  PubMed  CAS  Google Scholar 

  28. Hammer S, Crumpacker C, D’Aquila R, et al. Use of virologic assays for detection of human immunodeficiency virus in clinical trials: recommendations of the AIDS clinical trials group virology committee. J Clin Microbiol 1994; 31: 2557–64

    Google Scholar 

  29. Urdea MS, Wilber JL, Yeghiazarian T, et al. Direct and quantitative detection of HIV-1 RNA in human plasma with a branched DNA signal amplification assay. AIDS 1993; 7Suppl. 2: S11–4

    Article  PubMed  CAS  Google Scholar 

  30. Hsiang JL, Myers LE, Hollinger BY, et al. Multicenter evaluation of quantification methods for plasma human immunodeficiency virus type 1 RNA. J Infect Dis 1994; 170: 553–62

    Article  Google Scholar 

  31. Mohri H, Singh MK, Ching WTW, et al. Quantitation of zidovudine-resistant human immunodeficiency virus type 1 in the blood of treated and untreated patients. Proc Natl Acad Sci USA 1993; 90: 25–9

    Article  PubMed  CAS  Google Scholar 

  32. Sheppard HW, Ascher MS, McRae B, et al. The initial immune response to HIV and immune system activation determine the outcome of HIV disease. J AIDS 1991; 4: 704–12

    CAS  Google Scholar 

  33. Wrin T, Crawford L, Sawyer L, et al. Neutralizing antibody responses to autologous and heterologous isolates of human immunodeficiency virus. J AIDS 1994; 7: 211–9

    CAS  Google Scholar 

  34. Krown SE. Interferon and other biologic agents for the treatment of Kaposi’s sarcoma. Hematol Oncol Clin North Am 1991; 5: 311–22

    PubMed  CAS  Google Scholar 

  35. Fahey JL, Taylor JMG, Detels R. A better index of HIV disease than just CD4 T cell levels [abstract]. Program and abstracts: IXth International Conference on AIDS; 1993 Jun 6–11; Berlin, abstr. no. WS-B02-5

  36. Jacobson JM, Colman N, Ostorw NA. Passive immunotherapy in the treatment of advanced human immunodeficiency virus infection. J Infect Dis 1993; 168: 298–305

    Article  PubMed  CAS  Google Scholar 

  37. Stiehm ER, Mofenson L, Zolla-Pasner S, et al. Summary of the workshop on passive immunotherapy in the prevention and treatment of HIV infection. Clin Immunol Immunopathol 1995; 75(1): 1–10

    Article  Google Scholar 

  38. Hinkula J, Bratt G, Gilljam G, et al. Immunological and virological interactions in patients receiving passive immunotherapy with HIV-1 neutralizing monoclonal antibodies. J Acq Immune Defic Syndr 1994; 7: 940–51

    CAS  Google Scholar 

  39. Walker CM, Moody DJ, Stites DP, et al. CD8 lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 1986; 234: 1563–5

    Article  PubMed  CAS  Google Scholar 

  40. Ho M, Armstrong J, McMahon D, et al. A phase I study of adoptive transfer of autologous CD8+ T lymphocytes in patients with acquired immunodeficiency syndrome (AIDS)-related complex or AIDS. Blood 1993; 81: 2093–101

    PubMed  CAS  Google Scholar 

  41. Lane HC, Zunich KM, Wilson W, et al. Syngeneic bone marrow transplantation and adoptive transfer of peripheral blood lymphocytes combined with zidovudine in human immunodeficiency virus (HIV) infection. Ann Intern Med 1990; 113: 512–9

    PubMed  CAS  Google Scholar 

  42. 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: 1677–84

    Article  PubMed  CAS  Google Scholar 

  43. Turner JL, Trauger RJ, Daigle AE, et al. HIV-1 immunogen induction of HIV-1 specific delayed-type hypersensitivity. AIDS 1994; 8: 1429–35

    Article  PubMed  CAS  Google Scholar 

  44. Lane HC, Siegel JP, Rook AH, et al. Use of interleukin-2 in patients with acquired immunodeficiency syndrome. J Biol Response Mod 1984; 3: 512–6

    PubMed  CAS  Google Scholar 

  45. Teppler H, Kaplan G, Smith K, et al. Efficacy of low doses of the polyethylene glycol derivative of interleukin-2 in modulating the immune response of patients with human immunodeficiency virus type 1 infection. J Infect Dis 1993; 167: 291–8

    Article  PubMed  CAS  Google Scholar 

  46. Kovacs JA, Baseler M, Dewar RJ, et al. Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. N Engl J Med 1995; 332: 567–75

    Article  PubMed  CAS  Google Scholar 

  47. Clerici M, Lucey DR, Berzofsky JA, et al. Interleukin-12: important cytokine in HIV-1 immunopathogenesis. Science 1993; 262: 1721–4

    Article  PubMed  CAS  Google Scholar 

  48. Giri JG, Andeson DM, Kumaki S, et al. IL-15, a novel T cell growth factor that shares activities and receptor components with IL-2. J Leukoc Biol 1995; 57: 763–6

    PubMed  CAS  Google Scholar 

  49. Lane HC, Davey Jr RT, Sherwin SA, et al. A phase I trial of recombinant human interferon-y in patients with Kaposi’s sarcoma and the acquired immunodeficiency syndrome (AIDS). J Clin Immunol 1989; 9: 351–61

    Article  PubMed  CAS  Google Scholar 

  50. Romagnani S, del Prete G, Manetti R, et al. Role of TH1/TH2 cytokines in HIV infection. Immunol Rev 1994; 140: 73–92

    Article  PubMed  CAS  Google Scholar 

  51. Dezube BJ, Pardee AB, Chapman B, et al. Pentoxifylline decreases tumor necrosis factor expression and serum triglycerides in people with AIDS. J Acq Immune Defic Syndr 1993; 6: 787–94

    CAS  Google Scholar 

  52. Paterson DL, Georghiou PR, Allworth AM, et al. Thalidomide as treatment of refractory aphthous ulceration related to human immunodeficiency virus infection. Clin Infect Dis 1995; 20: 250–4

    Article  PubMed  CAS  Google Scholar 

  53. Lederman M, Georges D, Borum P, et al. L-2-Oxothiazolidinecarboxylate (procysteine) inhibits HIV-1 expression but not interleukin-2 secretion [abstract]. Program and abstracts: IXth International Conference on AIDS; 1993 Jun 6–11; Berlin, abstr. no. PO-A28-0681

  54. de Quay B, Malinverni R, Lauterburg B. Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine. AIDS 1992; 6(8): 815–9

    Article  PubMed  Google Scholar 

  55. Nguyen BY, Clerici M, Yarchoan R, et al. Immunologic effects of human insulin-like growth factor and recombinant human growth hormone in HIV-infected patients. AIDS Res Hum Retrovir 1995; 11Suppl. 1: S164

    Google Scholar 

  56. Schambelan M, LaMarca A, Mulligan K, et al. Growth hormone therapy for AIDS wasting [abstract]. Proceedings of the 10th International Conference on AIDS; 1994 Aug 7–12; Yokohama, 2: 35

  57. Rohrbaugh ML, McGowan JJ. Gene transfer for therapy and prophylaxis of HIV-1 infection. Ann NY Acad Sci 1993 Jun 23; 685: 697–712

    Article  PubMed  CAS  Google Scholar 

  58. 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: 749–71

    Article  PubMed  CAS  Google Scholar 

  59. Fahey JL, Schooley R. Status of immune-based therapies in HIV infection and AIDS. Clin Exp Immunol 1992; 88: 1–5

    Article  PubMed  CAS  Google Scholar 

  60. Lederman MM. Host-directed and immune-based therapies for human immunodeficiency virus infection. Ann Intern Med 1995; 122: 218–22

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Microbiology and Immunology and of Medicine, Center for Interdisciplinary Research in Immunology and Disease (CIRID), Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, USA

    John L. Fahey

  2. Department of Medicine, AIDS Clinical Research Center, UCLA School of Medicine, Los Angeles, USA

    Ronald Mitsuyasu

Authors
  1. John L. Fahey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronald Mitsuyasu
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fahey, J.L., Mitsuyasu, R. Immunomodulatory Approaches to the Therapy of AIDS. Clin. Immunother. 6, 39–53 (1996). https://doi.org/10.1007/BF03259351

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03259351

Keywords

Search

Navigation