Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1996 Aug;70(8):4953–4960. doi: 10.1128/jvi.70.8.4953-4960.1996

Human immunodeficiency virus type 1 gp120 induces anergy in human peripheral blood lymphocytes by inducing interleukin-10 production.

D Schols 1, E De Clercq 1
PMCID: PMC190447  PMID: 8764000

Abstract

The effects of recombinant gp120 on the proliferative responses and cytokine production by normal peripheral blood mononuclear cells (PBMC) were investigated. gp120 inhibited in a dose-dependent fashion the anti-CD3 monoclonal antibody (MAb)- and concanavalin A-induced proliferative responses. The production of interleukin-2 (IL-2) and IL-4 was diminished by gp120 in the anti-CD3- and concanavalin A-stimulated cultures. In unstimulated PBMC, gp120 induced the production of considerable amounts of IL-10, gamma interferon, and tumor necrosis factor alpha. The gp120-induced reduction in the proliferative responses of PBMC was at least partially reversed by the addition of IL-2, anti-CD28 MAb, or transfectants expressing CD80, CD86, or CD40 but not with exogenous IL-4. Also, a neutralizing anti-IL-10 MAb reversed the inhibitory effect of gp120 on the proliferative responses whereas exogenous IL-10 further enhanced this inhibitory effect. These findings indicate that IL-10 plays an important role in the inhibitory effect of gp120 on PBMC proliferation. The ratio of CD3+CD4+ to CD3+CD8+ T cells was the same in gp120-treated and untreated cell cultures. No apoptosis in these two T-cell populations was observed. However, the number of activated CD3+CD4+ T cells and CD3+CD8+ T cells, as judged by CD25, CD69, and HLA-DR expression, was consistently reduced. gp120 induced the expression of IL-10 in the monocyte/macrophage population, and therefore gp120 also reduced the proliferative responses of CD4+ T-cell-depleted PBMC. Taken together, our observations point to the importance of the cytokine pattern changes and, in particular, the role of IL-10 (produced by the monocytes) in the inhibitory effect of gp120. This mechanism of gp120-induced immunosuppression, if operative in vivo, could contribute to the depressed immune responses associated with human immunodeficiency virus infection and thus have important implications for immunotherapeutic strategies to slow down disease progression in AIDS.

Full Text

The Full Text of this article is available as a PDF (270.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ameglio F., Cordiali Fei P., Solmone M., Bonifati C., Prignano G., Giglio A., Caprilli F., Gentili G., Capobianchi M. R. Serum IL-10 levels in HIV-positive subjects: correlation with CDC stages. J Biol Regul Homeost Agents. 1994 Apr-Jun;8(2):48–52. [PubMed] [Google Scholar]
  2. Azuma M., Cayabyab M., Buck D., Phillips J. H., Lanier L. L. CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes. J Exp Med. 1992 Feb 1;175(2):353–360. doi: 10.1084/jem.175.2.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Azuma M., Ito D., Yagita H., Okumura K., Phillips J. H., Lanier L. L., Somoza C. B70 antigen is a second ligand for CTLA-4 and CD28. Nature. 1993 Nov 4;366(6450):76–79. doi: 10.1038/366076a0. [DOI] [PubMed] [Google Scholar]
  4. Banda N. K., Bernier J., Kurahara D. K., Kurrle R., Haigwood N., Sekaly R. P., Finkel T. H. Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med. 1992 Oct 1;176(4):1099–1106. doi: 10.1084/jem.176.4.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bejarano M. T., de Waal Malefyt R., Abrams J. S., Bigler M., Bacchetta R., de Vries J. E., Roncarolo M. G. Interleukin 10 inhibits allogeneic proliferative and cytotoxic T cell responses generated in primary mixed lymphocyte cultures. Int Immunol. 1992 Dec;4(12):1389–1397. doi: 10.1093/intimm/4.12.1389. [DOI] [PubMed] [Google Scholar]
  6. Borghi P., Fantuzzi L., Varano B., Gessani S., Puddu P., Conti L., Capobianchi M. R., Ameglio F., Belardelli F. Induction of interleukin-10 by human immunodeficiency virus type 1 and its gp120 protein in human monocytes/macrophages. J Virol. 1995 Feb;69(2):1284–1287. doi: 10.1128/jvi.69.2.1284-1287.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brinchmann J. E., Dobloug J. H., Heger B. H., Haaheim L. L., Sannes M., Egeland T. Expression of costimulatory molecule CD28 on T cells in human immunodeficiency virus type 1 infection: functional and clinical correlations. J Infect Dis. 1994 Apr;169(4):730–738. doi: 10.1093/infdis/169.4.730. [DOI] [PubMed] [Google Scholar]
  8. Capobianchi M. R., Ankel H., Ameglio F., Paganelli R., Pizzoli P. M., Dianzani F. Recombinant glycoprotein 120 of human immunodeficiency virus is a potent interferon inducer. AIDS Res Hum Retroviruses. 1992 May;8(5):575–579. doi: 10.1089/aid.1992.8.575. [DOI] [PubMed] [Google Scholar]
  9. Cayabyab M., Phillips J. H., Lanier L. L. CD40 preferentially costimulates activation of CD4+ T lymphocytes. J Immunol. 1994 Feb 15;152(4):1523–1531. [PubMed] [Google Scholar]
  10. Chehimi J., Starr S. E., Frank I., D'Andrea A., Ma X., MacGregor R. R., Sennelier J., Trinchieri G. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J Exp Med. 1994 Apr 1;179(4):1361–1366. doi: 10.1084/jem.179.4.1361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chirmule N., Goonewardena H., Pahwa S., Pasieka R., Kalyanaraman V. S., Pahwa S. HIV-1 envelope glycoproteins induce activation of activated protein-1 in CD4+ T cells. J Biol Chem. 1995 Aug 18;270(33):19364–19369. doi: 10.1074/jbc.270.33.19364. [DOI] [PubMed] [Google Scholar]
  12. Chirmule N., McCloskey T. W., Hu R., Kalyanaraman V. S., Pahwa S. HIV gp120 inhibits T cell activation by interfering with expression of costimulatory molecules CD40 ligand and CD80 (B71). J Immunol. 1995 Jul 15;155(2):917–924. [PubMed] [Google Scholar]
  13. Clerici M., Lucey D. R., Berzofsky J. A., Pinto L. A., Wynn T. A., Blatt S. P., Dolan M. J., Hendrix C. W., Wolf S. F., Shearer G. M. Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science. 1993 Dec 10;262(5140):1721–1724. doi: 10.1126/science.7903123. [DOI] [PubMed] [Google Scholar]
  14. Clerici M., Wynn T. A., Berzofsky J. A., Blatt S. P., Hendrix C. W., Sher A., Coffman R. L., Shearer G. M. Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J Clin Invest. 1994 Feb;93(2):768–775. doi: 10.1172/JCI117031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Clouse K. A., Cosentino L. M., Weih K. A., Pyle S. W., Robbins P. B., Hochstein H. D., Natarajan V., Farrar W. L. The HIV-1 gp120 envelope protein has the intrinsic capacity to stimulate monokine secretion. J Immunol. 1991 Nov 1;147(9):2892–2901. [PubMed] [Google Scholar]
  16. Dalgleish A. G., Beverley P. C., Clapham P. R., Crawford D. H., Greaves M. F., Weiss R. A. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984 Dec 20;312(5996):763–767. doi: 10.1038/312763a0. [DOI] [PubMed] [Google Scholar]
  17. Essery G., Feldmann M., Lamb J. R. Interleukin-2 can prevent and reverse antigen-induced unresponsiveness in cloned human T lymphocytes. Immunology. 1988 Jul;64(3):413–417. [PMC free article] [PubMed] [Google Scholar]
  18. Fan J., Bass H. Z., Fahey J. L. Elevated IFN-gamma and decreased IL-2 gene expression are associated with HIV infection. J Immunol. 1993 Nov 1;151(9):5031–5040. [PubMed] [Google Scholar]
  19. Francis M. L., Meltzer M. S. Induction of IFN-alpha by HIV-1 in monocyte-enriched PBMC requires gp120-CD4 interaction but not virus replication. J Immunol. 1993 Aug 15;151(4):2208–2216. [PubMed] [Google Scholar]
  20. Gimmi C. D., Freeman G. J., Gribben J. G., Sugita K., Freedman A. S., Morimoto C., Nadler L. M. B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6575–6579. doi: 10.1073/pnas.88.15.6575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Goldman F., Jensen W. A., Johnson G. L., Heasley L., Cambier J. C. gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation. J Immunol. 1994 Oct 1;153(7):2905–2917. [PubMed] [Google Scholar]
  22. Gruters R. A., Terpstra F. G., De Jong R., Van Noesel C. J., Van Lier R. A., Miedema F. Selective loss of T cell functions in different stages of HIV infection. Early loss of anti-CD3-induced T cell proliferation followed by decreased anti-CD3-induced cytotoxic T lymphocyte generation in AIDS-related complex and AIDS. Eur J Immunol. 1990 May;20(5):1039–1044. doi: 10.1002/eji.1830200514. [DOI] [PubMed] [Google Scholar]
  23. Gutierrez-Ramos J. C., Moreno de Alboran I., Martínez C. In vivo administration of interleukin-2 turns on anergic self-reactive T cells and leads to autoimmune disease. Eur J Immunol. 1992 Nov;22(11):2867–2872. doi: 10.1002/eji.1830221117. [DOI] [PubMed] [Google Scholar]
  24. Harding F. A., McArthur J. G., Gross J. A., Raulet D. H., Allison J. P. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992 Apr 16;356(6370):607–609. doi: 10.1038/356607a0. [DOI] [PubMed] [Google Scholar]
  25. Klatzmann D., Champagne E., Chamaret S., Gruest J., Guetard D., Hercend T., Gluckman J. C., Montagnier L. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature. 1984 Dec 20;312(5996):767–768. doi: 10.1038/312767a0. [DOI] [PubMed] [Google Scholar]
  26. Kootstra N. A., van 't Wout A., Huisman H. G., Miedema F., Schuitemaker H. Interference of interleukin-10 with human immunodeficiency virus type 1 replication in primary monocyte-derived macrophages. J Virol. 1994 Nov;68(11):6967–6975. doi: 10.1128/jvi.68.11.6967-6975.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lane P., Traunecker A., Hubele S., Inui S., Lanzavecchia A., Gray D. Activated human T cells express a ligand for the human B cell-associated antigen CD40 which participates in T cell-dependent activation of B lymphocytes. Eur J Immunol. 1992 Oct;22(10):2573–2578. doi: 10.1002/eji.1830221016. [DOI] [PubMed] [Google Scholar]
  28. Lanier L. L., O'Fallon S., Somoza C., Phillips J. H., Linsley P. S., Okumura K., Ito D., Azuma M. CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. J Immunol. 1995 Jan 1;154(1):97–105. [PubMed] [Google Scholar]
  29. Liegler T. J., Stites D. P. HIV-1 gp120 and anti-gp120 induce reversible unresponsiveness in peripheral CD4 T lymphocytes. J Acquir Immune Defic Syndr. 1994 Apr;7(4):340–348. [PubMed] [Google Scholar]
  30. Linsley P. S., Brady W., Grosmaire L., Aruffo A., Damle N. K., Ledbetter J. A. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991 Mar 1;173(3):721–730. doi: 10.1084/jem.173.3.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Macatonia S. E., Lau R., Patterson S., Pinching A. J., Knight S. C. Dendritic cell infection, depletion and dysfunction in HIV-infected individuals. Immunology. 1990 Sep;71(1):38–45. [PMC free article] [PubMed] [Google Scholar]
  32. Merrill J. E., Koyanagi Y., Chen I. S. Interleukin-1 and tumor necrosis factor alpha can be induced from mononuclear phagocytes by human immunodeficiency virus type 1 binding to the CD4 receptor. J Virol. 1989 Oct;63(10):4404–4408. doi: 10.1128/jvi.63.10.4404-4408.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Meyaard L., Kuiper H., Otto S. A., Wolthers K. C., van Lier R. A., Miedema F. Evidence for intact costimulation via CD28 and CD27 molecules in hyporesponsive T cells from human immunodeficiency virus-infected individuals. Eur J Immunol. 1995 Jan;25(1):232–237. doi: 10.1002/eji.1830250138. [DOI] [PubMed] [Google Scholar]
  34. Meyaard L., Otto S. A., Hooibrink B., Miedema F. Quantitative analysis of CD4+ T cell function in the course of human immunodeficiency virus infection. Gradual decline of both naive and memory alloreactive T cells. J Clin Invest. 1994 Nov;94(5):1947–1952. doi: 10.1172/JCI117545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Meyaard L., Otto S. A., Jonker R. R., Mijnster M. J., Keet R. P., Miedema F. Programmed death of T cells in HIV-1 infection. Science. 1992 Jul 10;257(5067):217–219. doi: 10.1126/science.1352911. [DOI] [PubMed] [Google Scholar]
  36. Miedema F., Meyaard L., Koot M., Klein M. R., Roos M. T., Groenink M., Fouchier R. A., Van't Wout A. B., Tersmette M., Schellekens P. T. Changing virus-host interactions in the course of HIV-1 infection. Immunol Rev. 1994 Aug;140:35–72. doi: 10.1111/j.1600-065x.1994.tb00864.x. [DOI] [PubMed] [Google Scholar]
  37. Miedema F., Petit A. J., Terpstra F. G., Schattenkerk J. K., de Wolf F., Al B. J., Roos M., Lange J. M., Danner S. A., Goudsmit J. Immunological abnormalities in human immunodeficiency virus (HIV)-infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs. J Clin Invest. 1988 Dec;82(6):1908–1914. doi: 10.1172/JCI113809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Molina J. M., Scadden D. T., Amirault C., Woon A., Vannier E., Dinarello C. A., Groopman J. E. Human immunodeficiency virus does not induce interleukin-1, interleukin-6, or tumor necrosis factor in mononuclear cells. J Virol. 1990 Jun;64(6):2901–2906. doi: 10.1128/jvi.64.6.2901-2906.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nakajima K., Martínez-Maza O., Hirano T., Breen E. C., Nishanian P. G., Salazar-Gonzalez J. F., Fahey J. L., Kishimoto T. Induction of IL-6 (B cell stimulatory factor-2/IFN-beta 2) production by HIV. J Immunol. 1989 Jan 15;142(2):531–536. [PubMed] [Google Scholar]
  40. Oh S. K., Cruikshank W. W., Raina J., Blanchard G. C., Adler W. H., Walker J., Kornfeld H. Identification of HIV-1 envelope glycoprotein in the serum of AIDS and ARC patients. J Acquir Immune Defic Syndr. 1992;5(3):251–256. [PubMed] [Google Scholar]
  41. Oyaizu N., Chirmule N., Kalyanaraman V. S., Hall W. W., Pahwa R., Shuster M., Pahwa S. Human immunodeficiency virus type 1 envelope glycoprotein gp120 produces immune defects in CD4+ T lymphocytes by inhibiting interleukin 2 mRNA. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2379–2383. doi: 10.1073/pnas.87.6.2379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Saville M. W., Taga K., Foli A., Broder S., Tosato G., Yarchoan R. Interleukin-10 suppresses human immunodeficiency virus-1 replication in vitro in cells of the monocyte/macrophage lineage. Blood. 1994 Jun 15;83(12):3591–3599. [PubMed] [Google Scholar]
  43. Schmid I., Uittenbogaart C. H., Keld B., Giorgi J. V. A rapid method for measuring apoptosis and dual-color immunofluorescence by single laser flow cytometry. J Immunol Methods. 1994 Apr 15;170(2):145–157. doi: 10.1016/0022-1759(94)90390-5. [DOI] [PubMed] [Google Scholar]
  44. Schols D., Jones D., Roncarolo M. G. Unique cytokine production profile of anergic human T cells in SCID-hu mice after staphylococcal enterotoxin B administration. J Immunol. 1995 Apr 1;154(7):3204–3212. [PubMed] [Google Scholar]
  45. Shearer G. M., Bernstein D. C., Tung K. S., Via C. S., Redfield R., Salahuddin S. Z., Gallo R. C. A model for the selective loss of major histocompatibility complex self-restricted T cell immune responses during the development of acquired immune deficiency syndrome (AIDS). J Immunol. 1986 Oct 15;137(8):2514–2521. [PubMed] [Google Scholar]
  46. Shearer G. M., Salahuddin S. Z., Markham P. D., Joseph L. J., Payne S. M., Kriebel P., Bernstein D. C., Biddison W. E., Sarngadharan M. G., Gallo R. C. Prospective study of cytotoxic T lymphocyte responses to influenza and antibodies to human T lymphotropic virus-III in homosexual men. Selective loss of an influenza-specific, human leukocyte antigen-restricted cytotoxic T lymphocyte response in human T lymphotropic virus-III positive individuals with symptoms of acquired immunodeficiency syndrome and in a patient with acquired immunodeficiency syndrome. J Clin Invest. 1985 Oct;76(4):1699–1704. doi: 10.1172/JCI112158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Thompson C. B., Lindsten T., Ledbetter J. A., Kunkel S. L., Young H. A., Emerson S. G., Leiden J. M., June C. H. CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1333–1337. doi: 10.1073/pnas.86.4.1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Vieira P., de Waal-Malefyt R., Dang M. N., Johnson K. E., Kastelein R., Fiorentino D. F., deVries J. E., Roncarolo M. G., Mosmann T. R., Moore K. W. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1172–1176. doi: 10.1073/pnas.88.4.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Wahl L. M., Corcoran M. L., Pyle S. W., Arthur L. O., Harel-Bellan A., Farrar W. L. Human immunodeficiency virus glycoprotein (gp120) induction of monocyte arachidonic acid metabolites and interleukin 1. Proc Natl Acad Sci U S A. 1989 Jan;86(2):621–625. doi: 10.1073/pnas.86.2.621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. de Waal Malefyt R., Haanen J., Spits H., Roncarolo M. G., te Velde A., Figdor C., Johnson K., Kastelein R., Yssel H., de Vries J. E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991 Oct 1;174(4):915–924. doi: 10.1084/jem.174.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. de Waal Malefyt R., Yssel H., Roncarolo M. G., Spits H., de Vries J. E. Interleukin-10. Curr Opin Immunol. 1992 Jun;4(3):314–320. doi: 10.1016/0952-7915(92)90082-p. [DOI] [PubMed] [Google Scholar]
  52. de Waal Malefyt R., Yssel H., de Vries J. E. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol. 1993 Jun 1;150(11):4754–4765. [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES