Status and Current Prospects for the Immunotherapy of Human Immunodeficiency Virus (HIV) Infection

  • John W. Hadden
Conference paper

Abstract

Infection with the HIV virus and its sequelae have received considerable attention in the last decade. Acquired Immune Deficiency Disease (AIDS) has come to dwarf cancer, not in magnitude of research and treatment, but certainly in the intensity of effort and volume of new findings concerning its pathogenesis and management. The very rapid development of the understanding of this disease now allows us to focus more clearly on the major issues involved. In magnitude, the problem is considerable with an estimated 1 to 1.5 million Americans infected and a world wide total of 6–8 million infected. With close to 200,000 AIDS cases in the United States, there are estimated over 600,000 cases worldwide. By current calculations, all are expected to die of the disease. Two important features mollify these expectations. First, the growth of the disease is slowing as a result of progressive saturation of high risk groups and the reduced frequency of spread through the use of “safe sex”. The degree of spill over into the remainder of the population is relatively small. The largest open door yet to be closed remains indiscriminate heterosexual contact, particularly in the presence of concomitant venereal disease. While little can be done to prevent the spread amongst the illiterate, uninformed, or unwilling, the progress of prevention among the cooperative is encouraging. Second, the latency period of the virus in those who reduce their exposure to other immunosuppressive influences (e.g., co-passenger viruses like CMV, EBV, herpes viruses, hepatitis viruses, etc., and recreational drugs, intrarectal sperm, poor nutrition, etc.) can now exceed 10 years. Thus, a longer, healthier life can be envisioned for those who will cooperate with a healthy regimen.

Keywords

Toxicity Adenoma Sarcoma Interferon Candida 

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References

  1. Abrams D, Grieco M, Gottlieb M, Speer M (eds) (1989) AIDS/HIV Experimental Treatment, AMFAR Directory Vol 3; No. 1Google Scholar
  2. Abrams D, Wong R, Grieco M, Goosby E, Gorter R, Gordon M, Guralnik M, Kaneko Y (1990) Results of a Phase I/II placebo-controlled dose finding pilot study of lentinan in patients with HIV infection. Sum Inf Dis AIDS Meeting, San Francisco (in press)Google Scholar
  3. Ada G (1989) Prospects for a vaccine against HIV. Nature 339:331–332PubMedCrossRefGoogle Scholar
  4. Audibert F, Jolivet-Reynaud C, Jolivet M, Lise D (1989) Modulation of the immunogenic characters of the protective epitopes in synthetic vaccines. In: Hadden JW, Spreafico F, Yamamura Y, Austen KF, Dukor P, Masek K (eds) Advances in Immunopharmacology 4. Pergamon Press, New York, p 133Google Scholar
  5. Barcellini W, Meroni PL, Frasca D, Sguotti C, Borghi MO, Uberti-Foppa C, Buzzetti P, Lazzarin A, Doria G, Moroni M, Zanussi C (1987) Effect of subcutaneous thymopentin treatment in drug addicts with persistant generalized lymphadenopathy. Clin Exp Immunol 67:537–543PubMedGoogle Scholar
  6. Bekesi JG, Tsang PH, Wallace JI, Roboz JP (1987) Immunorestorative properties of isoprinosine in the treatment of patients at high risk of developing ARC or AIDS. J Clin Lab Immunol 24:155–161PubMedGoogle Scholar
  7. Bolognesi DP (1989) Progress in vaccines against AIDS. Science 246:1233–1234PubMedCrossRefGoogle Scholar
  8. Brook MG, Gor D, Forster S, Harris JRW, Jeffries DJ, Thomas HC (1989) Anti-HIV effects of alpha interferon. Lancet 1(8628):42PubMedCrossRefGoogle Scholar
  9. Carey JT, Lederman MM, Tossii Z, Edmonds K, Hodder S, Calabrese LH, Proffitt MR, Johnson CE, Ellner JJ (1987) Augmentation of skin test reactivity and lymphocyte blastogenesis in patients with AIDS treated transfer factor. JAMA 257:651–655PubMedCrossRefGoogle Scholar
  10. Carter WA, Brodsky I, Pellegrino MG, Henriques HF, Parenti DM, Schulof RS, Robinson WE, Volsky DJ, Paxton H, Kariko K, Suhadchik RJ, Strayer DR, Levin M, Einck L, Simon GL, Scheib RG, Montefiori DC, Mitchell WM, Paul D, Meyer III WA, Reichenback N, Gillespie DH (1987) Clinical, immunological and virological effects of ampligen, a mismatched double-stranded RNA in patients with AIDS or AIDS-related complex. Lancet 6:1286–1292CrossRefGoogle Scholar
  11. Conant MA, Goldstein G, Hirsch RL, Meyerson LA, Kremer AB (1990) The effect of thymopentin treatment on progression of disease and surragate markers in HIV infected patients without AIDS. J Cell Biochem Suppl 14D:148 UCLA Symposia on Molecular and Cell Biology, San Fransisco AIDS Meeting Abstract #L411Google Scholar
  12. Coombs RW, Collier AC, Allain JP, Nilora B, Leuther M, Gjerset GF, Corey L (1989) Plasma viremia in human immunodeficiency virus infection. N Eng J Med 321:1626–1631CrossRefGoogle Scholar
  13. Danner SA, Schuurman HJ, Lange JMA, Gmelig-Meyling FHJ, Schellekens PThA, Huber J, Kater L (1986) Implantation of cultured thymic fragments in patients with acquired immunodeficiency syndrome. Arch Int Med 146:1133–1136CrossRefGoogle Scholar
  14. Dardenne M, Savino W, Gagnerault MC, Itoh T, Bach JF (1989) Neuroendocrine control of thymic hormonal production. I Prolactin stimulates in vivo and in vitro the production of thymulin by human and murine thymic epithelial cells. Endocrinology 125:3–12PubMedCrossRefGoogle Scholar
  15. Davey V, Johnson RP, Lane HC (submitted 1989) A placebo-controlled trial of interferon alpha-2b in asymptomatic HIV infection. V Int Conf AIDS, MontrealGoogle Scholar
  16. deClercq E (1990) Targets and strategies for the antiviral chemotherapy of AIDS. Trends in Pharmacol 11:198–205CrossRefGoogle Scholar
  17. Denning SM, Kurtzberg J, Le PT, Tuck DT, Singer KH, Haynes BF (1988) Human thymic epithelial cells directly induce activation of autologous immature thymocytes. Proc Natl Aca Sci 85:3125–3129CrossRefGoogle Scholar
  18. DeSimone C, Albertini F, Almaviva M, Angarano G, Chioda F, Costigliola P, Delia S, Ferlini A, Gritti F, Mazzarello G, Milazzo F, Montioni M, Marciso P, Pastore G, Raise E, Santini G, Sorice F, Terragna A, Visco G, Vullo V (1988) Clinical and immunological assessment in HIV+ subjects receiving inosine-pranobex: A randomized, multicentric study. Med Onc Tum Pharmacother 10:299–303Google Scholar
  19. DeSimone C, Albertini F, Almaviva M, Angarano G, Chioda F, Costigliola P, Delia S, Ferlini A, Gritti F, Pauluzzi S, Raise E, Santini G, Sorice F, Terragna A, Visco G, Vullo V (1989) The place of methisoprinol (inosine pranobex, isoprinosine) for the therapy of HIV-infected subjects. EOS J Immunol Immunopharmacol 9:184–185Google Scholar
  20. DeSimone C, Antonaci S, Chirigos S, Delia S, DiFabio S, Good RA, Hadden JW, Jirillo E, Lockey R, Milazzo F, Scalise G, Tinelli M (1990) Report of the symposium of the use of intravenous gammaglobulin (IVIG) in adults infected with HIV. Clin Exp Immunol (in press)Google Scholar
  21. Galy AHM, Dinarello CA, Kupper S, Kameda A, Hadden JW (1990) Effects of cytokines on human epithelial cells in culture. Cellular Immunology (in press)Google Scholar
  22. Girard M (1990) Prospects for an AIDS vaccine. Cancer Det Prev 14:411413Google Scholar
  23. Glasky AJ, Gordon J (1986) Inosiplex treatment of acquired immunodeficiencies: A clinical model for effective immunomodulation. Meth and Find Exp Clin Pharm 8(1):35–40Google Scholar
  24. Goldstein G, Audhya TK (1985) Thymopoietin to thymopentin: Experimental studies. Sury Immunol Res 4(Suppl 1):1–10Google Scholar
  25. Gottlieb AA and Trial Investigators (1988) A phase 3 controlled trial of ImReg-1 in AIDS/ARC patients. IV Int Conf AIDS, Stockholm, SwedenGoogle Scholar
  26. Gupta S, Gottlieb MS (1986) Treatment of the acquired immune deficiency syndrome. J Clin Immunol 6:183–193PubMedCrossRefGoogle Scholar
  27. Hadden JW (1984) Perspectives of the immunotherapy of AIDS. In: Selikoff IJ, Teirstein A, Hirschman SZ (eds) Ann NY Aca Sci 437:76–87Google Scholar
  28. Hadden JW (1985) Thymomimetic drugs. In: Miescher PA, Solis L, Ghione M (eds) Immunopharmacology. Raven Press, New York, p 183Google Scholar
  29. Hadden JW (1987) Current status of the immunotherapy of AIDS and the AIDS-related complex. In: Wormser GP, Stahl RE, Bottone EJ (eds) AIDS and other manifestations of HIV infection. Noyes Publications, New Jersey, p 992Google Scholar
  30. Hadden JW (1989) Current immunotherapeutic efforts and future prospects in human HIV disease. In: Hadden JW, Spreafico F, Yamamura Y, Austen KF, Dukor P, Masek K (eds) Advances in immunopharmacology 4. Pergamon Press, New York, p 19Google Scholar
  31. Hadden JW, Caspritz G, Zheng QY, Chen H, Wolstencroft R, Hadden EM (1989) Thymosin, interleukins, isoprinosine and imuthiol do not reconstitute T cells in athymic nude mice. Int J Immunopharmacol 11:13–19PubMedCrossRefGoogle Scholar
  32. Hadden JW, Chen H, Wang Y, Galy A, Hadden EM (1989) Strategies of immune reconstitution: Effects of lymphokines on murine T cell development in vitro and in vivo. Life Sci 44:5–12CrossRefGoogle Scholar
  33. Hadden JW, Galy A, Chen H, Hadden EM (1989) A pituitary factor induces thymic epithelial cell proliferation in vitro. Brain, Behavior & Immunity 3:149–159CrossRefGoogle Scholar
  34. Hadden JW, Giner-Sorolla, A (1981) Isoprinosine and NPT 15392: Modulators of lymphocyte and macrophage development and function. In: Hersh EM, Chirigos MA, Mastrangelo MJ (eds) Progress in cancer research and therapy vol 16: Augmenting agents in cancer therapy, Raven Press, New York, p 497Google Scholar
  35. Handzel ZT, Galili-Weisstraub E, Burstein R, Berner Y, Pecht M, Netzer L, Trainin N, Barzilai N, Levin S, Bentwich Z (1984) Immune derangements in asymptomatic male homosexuals in Israel: A pre-AIDS condition? In: Selikoff IJ, Teirstein A, Hirschmann SZ (eds) Ann NY Aca Sci 437:549–553Google Scholar
  36. Hersh EM, Funk CY, Ryschon KL, Peterson EA, Mosier DE (1990a) Effective therapy of the LP-BM5 murine retrovirus induced lymphoproliferative immunodeficiency disease with dithyldithiocarbamate. AIDS Res Human Retroviruses (submitted)Google Scholar
  37. Hersh EM, Funk CY, Peterson EA, Ryschon KL, Mosier DE (1990b) Dose response and timing effects in the therapy of LP-BM5 murine retrovirus induced lymphoproliferative immunodeficiency disease with dithyldithiocarbamate. AIDS Current Science (submitted)Google Scholar
  38. Hersh EM, Abrams D, Bartlett J, Brewton G, Galpin J, Gill P, Gorter R, Gottlieb M, Jonikas JJ, Landesman S, Levine A, Marcel A, Peterson EA, Whiteside M, Zahradnik J, Negron C, Boutitie F, Caraux J, Dupuy J-M, Salmi R (1990c) A randomized, double-blind, placebo-controlled, multicenter study of sodium ditiocarb (diethyldithiocarbamate) therapy in patients with ARC and AIDS. JAMA (submitted)Google Scholar
  39. Ho DD, Moudoil T, Alam M (1989) Quantitation of human immundeficiency virus type I in the blood of infected persons. N Eng J Med 321:1621–1625CrossRefGoogle Scholar
  40. Hoehler F, Robins DS (1988) Incidence of acquired immune deficiency syndrome in patients with persistant generalized lymphadenopathy: Immunologic risk factors and effects of short-term immunotherapy with inosine pranobex. Curr Ther Res 43:688–700Google Scholar
  41. Holland HK, Saral R, Rossi JJ, Donnenberg AD, Buns WH, Beschorner WE, Farzadegan H, Jones RJ, Quinnan GV, Vogelsang GB, Vriesendorp HM, Wingard JR, Zaia JA, Santos GW (1989) Allogenic bone marrow transplantation, ziduvine and human immunodeficiency virus type I (HIV-I) infection. Ann Int Med III:973–981Google Scholar
  42. Jackson GG, Perkins JT, Rubenis M, Paul DA, Knigge M, Despotas JC, Spencer P (1988) Passive immunoneutralization of HIV P24 antigenemia in patients with advanced AIDS by infusion of human plasma. IV Int Conf AIDS 96:35–37 Lancet 17:2(8612):647–652Google Scholar
  43. Jurgensen HJ, and Scandinavian Isoprinosine Study Group (1989) Influence on development of AIDS in patients with human immunodeficiency virus (HIV) infection; efficacy and safety of isoprinosine (inosine pranobex, methisoprinol): A randomized, double blind, placebo-controlled, multicenter study in Danmark and Sweden. EOS J Immunol Immunopharmac 9:185–186 (in press New Eng J Med)Google Scholar
  44. Kahn JO, Allan JD, Hodges TL, Kaplan LD, Arni CJ, Fitch HF, Izu AE, Mordenti J, Sherwin SA, Groopman JE, Volberding PA (1990) The safety and pharmacokinetics of recombinant soluble CD4 (rCD4) in subjects with the acquired immundeficiency syndrome (AIDS) and AIDS-related complex. Ann Int Med 112:254–261PubMedGoogle Scholar
  45. Kaplan CS, Peterson EA, Yocum D, Hersh EM (1989) A randomized controlled dose response study of intravenous sodium diethyldithiocarbamate in patients with advanced human immunodeficiency virus infection. Life Sci 45:iii-ixPubMedCrossRefGoogle Scholar
  46. Karpas A, Hill F, Youle M, Cullen V, Gray J, Byron N, Hayhoe F, Tenant-Flowers M, Howard L, Gilgen D, Oates JK, Hawkins D, Gazzar JB (1988) Effects of passive immunization in patients with the acquired immunodeficiency syndrome-related complex and acquired immunodeficiency syndrome. Proc Natl Aca Sci 85:9234–9237CrossRefGoogle Scholar
  47. Kelley KW, Brief SB, Westly HJ, Novakofski J, Bechtel PJ, Simon J, Walker EB (1986) GH3 pituitary adenoma cells can reverse thymic aging in rats. Proc Natl Acad Sci 83:5663–5667PubMedCrossRefGoogle Scholar
  48. Lane HC (1989) The role of immunomodulators in the treatment of patients with AIDS. AIDS 3 Suppl(1):181s-185sCrossRefGoogle Scholar
  49. Lane HC, Masur H, Gelmann EP, Fauci AS (1985) Therapeutic approaches to patients with AIDS. Ca Res 45:4674s-4676sGoogle Scholar
  50. Lang J (1989) Long term administration of ditiocarb in HIV-seropositive subjects. V Int Conf AIDS, MontrealGoogle Scholar
  51. Lang JM, Touraine JL, Trepo C, Choutet P, Kirkstetter M, Falkenrodt A, Herviou L, Livrozet JM, Retornaz G, Touraine F, Renoux G, Renoux M, Musset M, Caraux J, and AIDS-Imuthiol French Study Group (1988) Randomized, double-blind, placebo-controlled trial of ditiocarb sodium (“Imuthiol”) in human immunodeficiency virus infection. Lancet 24(2)861–3:702–706Google Scholar
  52. Le PT, Kurstzberg J, Brandt SJ, Niedel JE, Haynes BF, Singer KH (1988) Human epithelial cells produce granulocyte and macrophage colony-stimulating factors. J of Immunol 141:1211–1217Google Scholar
  53. Le PT, Tuck DT, Dinarello CA, Haynes BF, Singer KH (1987) Human thymic epithelial cells produce interleukin 1. J of Immunol 138:2520–2526Google Scholar
  54. Luster MI, Germolec DR, White KL, Fuchs BA, Fort MM, Tomaszewski JE, Thompson M, Blair PC, McCay JA, Munsun AE, Rosenthal GJ (1989) A comparison of three nucleoside analogs with anti-retroviral activity on immune and hematopoietic functions in mice: In vitro toxicity to precursor cells and microstromal environment. Tox and App Pharmacol 101:328–339CrossRefGoogle Scholar
  55. Murphy PM, Lane HC, Gallin JI, Fauci AS (1988) Marked disparity in incidence of bacterial infections in patients with the acquired immunodeficiency syndrome receiving interleukin-2 or interferon-y. Ann Int Med 108:36–41PubMedGoogle Scholar
  56. Pahwa S, Pahwa R, Saxinger C, Gallo RC, Good RA (1985) Influence if the human T-lymphotropic virus/lymphoadenopathy-associated virus on functions of human lymphocytes: Evidence for immunosuppressive effects and polyclonal B-cell activation by banded viral preparations. Proc Natl Acad Sci 82:8198–8202PubMedCrossRefGoogle Scholar
  57. Plata F (1989) HIV-specific cytotoxic T lymphocytes. Res Immunol 140:89124CrossRefGoogle Scholar
  58. Renoux G, Renoux M (1984) Diethyldithiocarbamate (DTC): A biological augmenting agent specific for T cells. In: Fenichel RL and Chirigos MA (eds) Immune modultion agents and their mechanisms, Dekker Publications, New York, p. 7Google Scholar
  59. Reisinger EC, Kern P, Erhst M, Bock P, Flao HD, Dietrich M, German DTC Study Group (1990) Inhibition of HIV progression by dithiocarb. Lancet 335:679–682PubMedCrossRefGoogle Scholar
  60. Russell DH (1989) New aspects of prolactin and immunity: A lymphocyte-derived prolactin-like product and nuclear protein Kinase C activation. TIPS 10:40–44PubMedGoogle Scholar
  61. Sandstrom E (1989) Antiviral therapy in human immunodeficiency virus infection. Drugs 38(3):417–450PubMedCrossRefGoogle Scholar
  62. Savino W, Bartoccioni E, Homo-Delarche F, Gagnerault MC, Itoh T, Dardenne M (1988) Thymic hormone containing cells. IX Steroids in vitro modulate thymulin secretion by human and murine thymic epithelial cells. J Steroid Biochem 30:479–489PubMedCrossRefGoogle Scholar
  63. Savino W, Huang PC, Corrigan A, Berrih S, Dardenne M (1984) Thymic hormone-containing cells. V Immunohistological detection of metallothionein within the cells bearing thymulin (a zinc containing hormone) in human and mouse thymuses. J Histiochem & Cytochem 32:942–946CrossRefGoogle Scholar
  64. Schwartz DH, Skowron G, Merigan TC (1990) Safety and effects of Interleukin-2 plus Zidovudine in asymptomatic individuals infected with human immunodeficiency virus. Sum Inf Dis AIDS Meeting, San Francisco (in press)Google Scholar
  65. Schooley RT, Merigan TC, Gaut P, Hisch MS, Holodniy M, Flynn T, Liu S, Byington RE, Henochowicz S, Gubish E, Spriggs D, Kufe D, Schindler J, Dawson A, Thomas D, Hanson DG, Letwin B, Liu T, Gulinello J, Kennedy S, Fisher R, Ho, DD (1990) Recombinant soluble CD4 therapy in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Ann Int Med 112:247–253PubMedGoogle Scholar
  66. Serate MB, Sztein SA (1989) Characterization of the immunoregulatory properties of thymosin alpha 1 on interleukin-2 production and interleukin-2 receptor expression in normal human lymphocytes. Int J Immunopharm 11:789–800CrossRefGoogle Scholar
  67. Silvestris F, Gernone A, Frassanito M, Dammacco F (1989) Immunologic effects of long-term thymopentin treatment in patients with HIV-induced lymphadenopathy syndrome. J Lab Clin Med 113:139–144PubMedGoogle Scholar
  68. Siegal JP, Djeu JY, Stocks NI, Masur H, Gelmann EP, Quinnan Jr. GV (1985) Sera from patients with the acquired immunodeficiency syndrome inhibit production of interleukin-2 by normal lymphocytes. J Clin Invest 75:1957–1964CrossRefGoogle Scholar
  69. Sinha SK, Sizemore RC, Gottlieb AA (1988) Immunomodulatory components present in imreg-1, an experimental immunosupportive biologic. Bio/technology 6:810–815CrossRefGoogle Scholar
  70. Strayer DR (1988) Ampligen therapy in ARC/pre-ARC: Immune/virological effects and clinical improvement. Abstracts, IV Int Conf AIDS, Stockholm, SwedenGoogle Scholar
  71. Volberding PA, Lagakos SW, Koch MA, Pettinelli C, Myers MW, Booth DK, Balfour HH, Reichman RC, Bartlett JA, Hirsch MS, Murphy RL, Hardy WD, Soeiro R, Fischl MA, Bartlett JG, Merigan TC, Hyslop NE, Richman DD, Valentin FT, Corey L and the AIDS Clinical Trials Group of the Nat’l Inst of All and Inf Dis (1990) Zidovudine in asymptomatic human immunodeficiency virus infection. New Eng J Med 322:941–949PubMedCrossRefGoogle Scholar
  72. Wiranowska M, Kaido T, Caspritz G, Cook J, Hadden JW (1987) Interleukin2 and coculture with thymic epithelial cells synergistically induce prothymocyte differentiation and proliferation. Thymus 10:231–235PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • John W. Hadden
    • 1
  1. 1.Immunopharmacology DivisionUniversity of South Florida Medical CollegeTampaUSA

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