Virus Genes

, Volume 28, Issue 1, pp 5–18 | Cite as

The Changes in the T helper 1 (Th1) and T helper 2 (Th2) Cytokine Balance During HIV-1 Infection are Indicative of an Allergic Response to Viral Proteins that may be Reversed by Th2 Cytokine Inhibitors and Immune Response Modifiers – a Review and Hypothesis

  • Yechiel Becker

Abstract

The HIV-1 infection in humans induces an early cellular immune response to react to the viral proteins with a cytotoxic T cell (CTL) response that fails to inhibit virus replication and the spread of the virus. It became evident that the progression of the disease causes chronic changes to the immune system of which a gradual increase in IgE antibodies is one of its features. When the HIV-1 epidemic began, the relation between the gradual increase in IgE content and AIDS was not understood, but later it became a marker for disease prognosis. The advances in the knowledge on T helper 1 (Th1) and T helper 2 (Th2) cells revealed that Th1 cells produce cytokines that stimulate the proliferation of CTLs. Th2 cells produce cytokines that are responsible for the activation of the humoral immune response in healthy people. Studies on both Th1 and Th2 cytokine synthesis revealed an aberration in HIV-1 infected people. Clerici and Shearer presented a hypothesis (1993) whereby Th1 cell activity declines and Th2 activity increases (the Th1 → Th2 switch hypothesis) in HIV-1 infected people. In fact, experiments concerning this hypothesis ultimately supported the premise that the switch involves a critical change in the cytokine balance, which leads to the contraction of AIDS. However, the research community must still discern why such a Th1 → Th2 switch takes place in infected people and how it can be reversed. The present review points to the fact that a similar Th1 → Th2 switch constitutes the response of allergic people to environmental allergens. HIV-1 patients and allergic people that are exposed to allergens respond with an increased synthesis of Th2 cytokines and IgE, together with a decrease in Th1 cytokines. The studies on allergen-induced Th2 cells revealed that the Th2 cytokine IL-4 induces B cells to synthesize IgE, and cytokine IL-5 is the inducer of eosinophilia, just as in HIV-1 infection. The difference between the HIV-1 infection and allergies is the ability of IL-4 to induce the synthesis in T cells of the HIV-1 coreceptor CXCR4 that selects from the replicating virus a syncytium-inducing (SI) virus, a variant virus that replicates rapidly. The present hypothesis implicates the viral proteins in the induction of Th2 cytokine synthesis. This suggests that in viral proteins, allergen-like domains may be responsible for the activation of Th2 cytokine synthesis. Based on the analogy of the responses of humans to allergens and HIV-1, the following hypotheses is suggested: (a) Removal of allergen-like domains from viral genes by genetic engineering may provide viral proteins for vaccine development. (b) Attempts to treat allergic patients with IL-4 receptor inhibitors suggests that the “Th2 → Th1 Reversion” constitutes a possible approach to inhibiting the Th2 cytokines and inducing a revival of the anti-viral Th1 response.

HIV-1 infection allergic response to HIV-1 Th1 to Th2 switch Th2 to Th1 reversion Inhibition of JL-4 immune response modifiers Modifications in gp120 implications for vaccines 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Klausner R.D., Fauci A.S., Corey L., Nabel G.J., Gale H., Berkley S., et al, Science 300, 2036–2039, 2003.Google Scholar
  2. 2.
    Becker Y., Virus Genes 27,3, 269–282, 2003.Google Scholar
  3. 3.
    Wright D.N., Nelson R.P., Ledford D.K., Fernandez-Caldas E., Trudeau W.L., and Lockey R.F., J Allergy Clin Immunol 85, 445–452, 1990.Google Scholar
  4. 4.
    Murray H.W., Rubin B.Y., Masur H., and Roberts R.B., New Engl J Med 313, 1504–1510, 1985.Google Scholar
  5. 5.
    Israël-Biet D., Labrousse F., Tourani J.-M., Sors H., Andrieu J.-M., and Even P., J Allergy Clin Immunol 89, 68–75, 1992.Google Scholar
  6. 6.
    Ammann A.J., Abrams D., Conant M., Chudwin D., Cowan M., Volberding P., Lewis B., and Casavant C., Clin Immunol Immunopathol 27, 315–325, 1983.Google Scholar
  7. 7.
    Romagnani S., Del Prete G., Maggi E., Parronchi P., Tiri A., Macchia D., Giudizi M.G., Almerigogna F., and Ricci M., Clin Immunol Immunpathol 50, S13–S23, 1989.Google Scholar
  8. 8.
    Miguez-Burbano M.J., Shor-Posner G., Fletcher M.A., Lu Y., Moreno J.N., Carcamo C., Page B., Quesada J., Sauberlich H., and Baum M.K., Allergy 50, 157–161, 1995.Google Scholar
  9. 9.
    Shor-Posner G., Miguez-Burbano J.M., Lu Y., Feaster D., Fletcher M.A., Sauberlich H., and Baum M.K., J Allergy Clin Immunol 95, 886–892, 1995.Google Scholar
  10. 10.
    Mazza D.S., Grieco M.H., Reddy M.M., and Meriney D., Annals of Allergy, Asthma Immunol 74, 411–414, 1995.Google Scholar
  11. 11.
    Koutsonikolis A., Nelson R.P., Fernandez-Caldas E., Brigino E.N., Seleznick M., Good R.A., and Lockey R.F., J Allergy Clin Immunol 97, 692–697, 1996.Google Scholar
  12. 12.
    Vigano A., Principi N., Crupi L., Ornorato J., Vincenzo Z.G., and Salvaggio A., J Allergy Clin Immunol 95, 627–634, 1995.Google Scholar
  13. 13.
    Secord E.A., Kleiner G.I., Auci D.L., Smith-Norowitz T., Chice S., Finkilstein A., Nowakowski M., Fikrig S., and Durkin H.G., J Allergy Clin Immunol 98, 979–984, 1996.Google Scholar
  14. 14.
    Khalife J., Guy B., Capron M., Kieny M.P., Ameisen J.C., Montagnier L., Lecocq J.P., and Capron A., AIDS Res Hum Retroviruses 4, 3–9, 1988.Google Scholar
  15. 15.
    Duglas N., Dereuddre-Bosquet N., Goujard C., Dormont D., Tardieu M., and Delfraissy J.-F., AIDS Res Hum Retroviruses 16, 251–258, 2000.Google Scholar
  16. 16.
    Clerici M., Hakim F.T., Venzon D. J., Blatt S., Hendrix C.W., Wynn T.A., and Shearer G.M., J Clin Invest 91, 759–765, 1993.Google Scholar
  17. 17.
    Clerici M. and Shearer G.M., Immunol Today 14, 107–111, 1993.Google Scholar
  18. 18.
    Romagnani S., Del Prete G., Manetti R., Ravina A., Annunziato F., De Carli M., Mazzetti M., Piccinni M.-P., D'Elios M.M., Parronchi P., Sampognaro S., and Maggi E., Immunol Rev 140, 73–92, 1994.Google Scholar
  19. 19.
    Maggi E., Mazzetti M., Ravina A., Annunziato F., De Carli M., Piccinni P., Manetti R., Carbonari M., Pesce A.M., Del Prete G., and Romagnani S., Science 265, 244–248, 1994.Google Scholar
  20. 20.
    Graziosi C., Pantaleo G., Gantt K.R., Fortin J.-P., Demarest J.F., Cohen O.J., Sékaly R.P., and Fauci A.S., Science 265, 248–252, 1994.Google Scholar
  21. 21.
    Graziosi C., Gantt K.R., Vaccarezza M., Demarest J.F., Daucher MB., Saag M.S., Shaw G.M., Quinn T.C., Cohen O.J., Welbon C.C., Pantaleo G., and Fauci A.S., Proc Natl Acad Sci USA 93, 4386–4391, 1996.Google Scholar
  22. 22.
    Tanaka M., Hirabayashi Y., Gatanaga H., Aizawa S., Hachiya A., Takahashi Y., Tashiro E., Kohsaka T., Oyamada M., Ida S., and Oka S., Scand J Immunol 50, 550–554, 1999.Google Scholar
  23. 23.
    Maggi E., Grazia Giudizi M., Biagiotti R., Annunziato F., Manetti R., Piccinni M.-P., Parronchi P., Sampognaro S., Giannarini L., Zuccati G., and Romagnani S., J Exp Med 180, 489–495, 1994.Google Scholar
  24. 24.
    Autran B. Legac E., Blanc C., and Debré P., J Immunol 154, 1408–1417, 1995.Google Scholar
  25. 25.
    Meroni L., Trabattoni D., Balotta C., Riva C., Gori A., Moroni M., Luisa Villa M., Clerici M., and Galli M., AIDS 10, 23–30, 1996.Google Scholar
  26. 26.
    Klein S.A., Dobmeyer J.M., Dobmeyer T.S., Pape M., Ottmann O.G., Helm E.B., Hoelzer D., and Rossol R., AIDS 11, 1111–1118, 1997.Google Scholar
  27. 27.
    Wasik T.J., Jagodzinski P.P., Hyjek E.M., Wustner J., Trinchieri G., Lischner H.W., and Kozbor D., J Immunol 158, 6029–6036, 1997.Google Scholar
  28. 28.
    Mirza O., Henriksen A., Ipsen H., Larsen J.N., Wissenbach M., Sprangfort M.D., and Gajhede M., J Immunol 165, 331–338, 2000.Google Scholar
  29. 29.
    Ichikawa S., Hatanaka H., Yuciki T., Iwamoto N., Kojima S., Nishiyama C., Ogura K., Okumura Y., and Inagaki F., J Biol Chem 273, 356–360, 1998.Google Scholar
  30. 30.
    Aalberse R.C., J Allergy Clin Immunol 106, 228–238, 2000.Google Scholar
  31. 31.
    Trumpfheller C., Tenner-Racz K., Racz P., Fleishcer B., and Frosch S., Clin Exp Immunol 112, 92–99, 1998.Google Scholar
  32. 32.
    Torres Y., Medrano F.J., Rey C., Calderón E.J., Sánchez-Quijano A., Lissen E., and Leal M., Eur J Clin Invest 28, 930–936, 1998.Google Scholar
  33. 33.
    Valentin A., Lu W., Rosati M., Schneider R., Albert J., Karlsson A., and Pavlakis G.N., Proc Natl Acad Sci 95, 8866–8891, 1998.Google Scholar
  34. 34.
    Wang J., Harada A., Matsushita S., Matsumi S., Zhang Y., Shioda T., Nagai Y., and Matsushima K., J Leukoc Biol 64, 642–649, 1998.Google Scholar
  35. 35.
    Biasin M., Boasso A., Piacentini L., Trabattoni D., Magri G., Deshmuks R., Deshpande A., and Clerici M., AIDS 17, 1563–1565, 2003.Google Scholar
  36. 36.
    Kwa D., van Rij R.P., Boeser-Nunnink B., Vingerhoed J., and Schuitemaker H., AIDS 17, 981–985, 2003.Google Scholar
  37. 37.
    Nakayama E.E., Meyer L., Iwamoto A., Persoz A., Nagai Y., Rouzioux C., Delfraissy J.-F., Debre P., McIlroy D., Theodorou I., Shioda T., and The SEROCO Study Group, J Infect Dis 185, 1183–1186, 2002.Google Scholar
  38. 38.
    Mackewicz C.E., Ortega H., and Levy J.A., Cell Immunol 153, 329–343, 1994.Google Scholar
  39. 39.
    Levy J.A., Mackewicz C.E., and Barker E., Immunol Today 17, 217–224, 1996.Google Scholar
  40. 40.
    Zhang L., Yu W., He T., Yu J., Caffrey R.E., Dalmasso E.A., Fu S., Pham T., Mei J., Jo J.J., Zhang W., Lopez P., and Ho D.D., Science 298, 995–1000, 2002.Google Scholar
  41. 41.
    Ong P.Y., Takaaki O., Brandt C., Strickland I., Boguniewicz M., Ganz T., Gallo R.L., and Leung D.Y.M., N Engl J Med 347, 1151–1160, 2002.Google Scholar
  42. 42.
    Herrick C.A., MacLeod, Glusac E., Tigelaar R.E., and Bottomly K., J Clin Invest 105, 765–775, 2000.Google Scholar
  43. 43.
    Kelly-Welch A.E., Hanson E.M., Boothby M.R., and Keegan A.D., Science 300, 1527–1528, 2003.Google Scholar
  44. 44.
    Imani F., Proud D., and Griffin D.E., J Immunol 162, 1597–1602, 1999.Google Scholar
  45. 45.
    Mueller T.D., Zhang J.-L., Sebald W., and Duschel A., Biochimica et Biophysics Acta 1592, 237–250, 2002.Google Scholar
  46. 46.
    Stolzenberger S., Haake M., and Duschl A., Eur J Biochem 268, 4809–4814, 2001.Google Scholar
  47. 47.
    Cornelis S., Fache I., Vand der Heyden J., Guisez Y., Tavernier J., Devos R., Fiers W., and Plaetinck G., Eur J Immunol 25, 1857–1864, 1995.Google Scholar
  48. 48.
    Chen J.X., Watanabe S., Muto A., Miyajima A., Yokota T., and Arai K.-I., J Allergy Clin Immunol 94, 605–611,1994.Google Scholar
  49. 49.
    Ingley E., Cutler R.L., Fung M.-C., Sanderson C.J., and Young I.G., Eur J Biochem 196, 623–629, 1991.Google Scholar
  50. 50.
    Van der Weshuizen F.H., Pretorius P.J., and de Wet W.J., Biochem Biophysical Res Communications 227, 576–580, 1996.Google Scholar
  51. 51.
    Kozyrev I.L., Miura T., Haga T., Kuwata T., and Hayami M., Arch Virol 146, 1051–1062, 2001.Google Scholar
  52. 52.
    Kozyrev I.L., Miura T., Takemura T., Kuwata T., Ui M., Ibuki K., Iida T., and Hayami M., J Gen Virol 83, 1183–1188, 2002.Google Scholar
  53. 53.
    Tiffany H.L., Alkhatib G., Combadiere C., Berger E.A., and Murphy P.M., J Immunol 160, 1385–1392, 1998.Google Scholar
  54. 54.
    Heijink I.H., Kauffman H.F., Postma D.S., de Monchy J.G.R., and Vellenga E., Eur J Immunol 33, 2206–2215, 2003.Google Scholar
  55. 55.
    So E.-Y., Kim S.-H., Park H.-H., Cho B.-S., and Lee C.-E., FEBS Lett 518, 53–59, 2002.Google Scholar
  56. 56.
    Beutner K.R., Spruance S.L., Hougham A.J., Fox T.L., Owens M.L., and Douglas J.M., J Am Acad Dermatol 38, 230–239, 1998.Google Scholar
  57. 57.
    Wagner T.L., Horton V.L., Carlson G.L., Myhre P.E., Gibson S.J., Imbertson L.M., and Tomai M.A., Cytokine 9, 837–845, 1997.Google Scholar
  58. 58.
    Stanely M.A., Clin Exper Dermatol 27, 571–577, 2002.Google Scholar
  59. 59.
    Wagner T.L., Ahonen C.L., Couture A.M., Gibson S.J., Miller R.L., Smith R.M., Reiter M.J., Vasilakos J.P., and Tomai M.A., Cellular Immunol 191, 10–19, 1999.Google Scholar
  60. 60.
    Kim T.S., Kang B.Y., Cho D., and Kim S.H., Immunology 109, 407–414, 2003.Google Scholar
  61. 61.
    Editorial Nature Med 9, 803, 2003.Google Scholar
  62. 62.
    Letvin N.L., and Walker B.D., Nature Med 9 861–866, 2003.Google Scholar
  63. 63.
    Mckay P.F., Lifton M.A., Williams K.C., and Letvin N.L., J Virol 77, 4695–4702, 2003.Google Scholar
  64. 64.
    Pantaleo G., Demarest J.F., Soudeyns H., Graziosi C., Denis F., Adelsberger J.W., Borrow P., Saag M.S., Shaw G.M., Sekaly R.P., et al, Nature 370, 463–467, 1994.Google Scholar
  65. 65.
    McMichael A.J. and Hanke T., Nature Med 9 874–880, 2003.Google Scholar
  66. 66.
    Becker Y. “Modified Viral Proteins, methods for producing them and vaccines containing them”. Filed on 25 September 2003 and has since informally allocated as United States Provisional Application No. 60/505, 615 (Y. Becker, applicant and inventor).Google Scholar
  67. 67.
    Sabin A.B., Natl Acad Sci USA, 89 8852–8859, 1992.Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Yechiel Becker
    • 1
  1. 1.Department of Molecular Virology, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael

Personalised recommendations