Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1992 Sep 1;176(3):739–750. doi: 10.1084/jem.176.3.739

Interferon gamma induces the expression of human immunodeficiency virus in persistently infected promonocytic cells (U1) and redirects the production of virions to intracytoplasmic vacuoles in phorbol myristate acetate-differentiated U1 cells

PMCID: PMC2119360  PMID: 1512539

Abstract

Interferon gamma (IFN-gamma), a lymphokine that exerts multiple immunoregulatory effects, has been found to be elevated in the plasma, cerebrospinal fluid, and lymph nodes of human immunodeficiency virus (HIV)-infected individuals and has shown variable effects on HIV replication in acutely infected cells. In the present study, we have demonstrated that IFN-gamma is a potent modulator of HIV expression in persistently infected U1 promonocytic cells in which virus production is characterized by a constitutive state of relative latency. Direct stimulation of U1 cells with IFN-gamma (10-1,000 U/ml) activated HIV expression, as measured by reverse transcriptase (RT) activity in the culture supernatant and increased levels of cell-associated viral protein and mRNAs. These effects on virus expression were not accounted for by the induction of endogenous TNF-alpha secretion, as previously described in U1 cells stimulated with phorbol myristate acetate (PMA). At the ultrastructural level, the stimulatory activity of IFN-gamma was correlated with HIV particle production in intracytoplasmic vacuoles along with the differentiation of U1 into macrophage-like cells. Furthermore, costimulation of U1 cells with IFN-gamma and PMA significantly increased the accumulation of vacuole-associated HIV concomitant with decreasing membrane-associated particles and RT activity production, as compared with cells stimulated with PMA alone. No evidence of spontaneous secretion of intracellular vacuole- associated virus was obtained by kinetic analysis of the RT activity released in the supernatants throughout the culture period unless cells were deliberately disrupted. These findings suggest that vacuole- associated virions likely represent a relatively stable intracellular reservoir of HIV, as previously described in primary macrophages infected in vitro or in infected macrophages in the brains of patients with acquired immune deficiency syndrome. The reduced levels of RT activity observed in the culture supernatants of U1 cells stimulated with PMA in the presence of IFN-gamma were not indicative of a suppressive effect of IFN-gamma on PMA-induced expression of HIV proteins and mRNAs, either directly or mediated by the release of IFN- alpha/beta. This study suggests that IFN-gamma may play an important role as an inducer of HIV expression in infected mononuclear phagocytes.

Full Text

The Full Text of this article is available as a PDF (3.7 MB).

Selected References

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

  1. Billiau A., Dijkmans R. Interferon-gamma: mechanism of action and therapeutic potential. Biochem Pharmacol. 1990 Oct 1;40(7):1433–1439. doi: 10.1016/0006-2952(90)90437-p. [DOI] [PubMed] [Google Scholar]
  2. Cavender D. E., Edelbaum D., Welkovich L. Effects of inflammatory cytokines and phorbol esters on the adhesion of U937 cells, a human monocyte-like cell line, to endothelial cell monolayers and extracellular matrix proteins. J Leukoc Biol. 1991 Jun;49(6):566–578. doi: 10.1002/jlb.49.6.566. [DOI] [PubMed] [Google Scholar]
  3. Danis V. A., Franic G. M., Rathjen D. A., Brooks P. M. Effects of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-2, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and IL-6 on the production of immunoreactive IL-1 and TNF-alpha by human monocytes. Clin Exp Immunol. 1991 Jul;85(1):143–150. doi: 10.1111/j.1365-2249.1991.tb05695.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Duh E. J., Maury W. J., Folks T. M., Fauci A. S., Rabson A. B. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5974–5978. doi: 10.1073/pnas.86.15.5974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Emilie D., Peuchmaur M., Maillot M. C., Crevon M. C., Brousse N., Delfraissy J. F., Dormont J., Galanaud P. Production of interleukins in human immunodeficiency virus-1-replicating lymph nodes. J Clin Invest. 1990 Jul;86(1):148–159. doi: 10.1172/JCI114678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fernie B. F., Poli G., Fauci A. S. Alpha interferon suppresses virion but not soluble human immunodeficiency virus antigen production in chronically infected T-lymphocytic cells. J Virol. 1991 Jul;65(7):3968–3971. doi: 10.1128/jvi.65.7.3968-3971.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ferreira O. C., Jr, Valinsky J. E., Sheridan K., Wayner E. A., Bianco C., Garcia-Pardo A. Phorbol ester-induced differentiation of U937 cells enhances attachment to fibronectin and distinctly modulates the alpha 5 beta 1 and alpha 4 beta 1 fibronectin receptors. Exp Cell Res. 1991 Mar;193(1):20–26. doi: 10.1016/0014-4827(91)90533-z. [DOI] [PubMed] [Google Scholar]
  8. Folks T. M., Justement J., Kinter A., Schnittman S., Orenstein J., Poli G., Fauci A. S. Characterization of a promonocyte clone chronically infected with HIV and inducible by 13-phorbol-12-myristate acetate. J Immunol. 1988 Feb 15;140(4):1117–1122. [PubMed] [Google Scholar]
  9. Folks T. M., Kessler S. W., Orenstein J. M., Justement J. S., Jaffe E. S., Fauci A. S. Infection and replication of HIV-1 in purified progenitor cells of normal human bone marrow. Science. 1988 Nov 11;242(4880):919–922. doi: 10.1126/science.2460922. [DOI] [PubMed] [Google Scholar]
  10. Fox C. H., Tenner-Rácz K., Rácz P., Firpo A., Pizzo P. A., Fauci A. S. Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis. 1991 Dec;164(6):1051–1057. doi: 10.1093/infdis/164.6.1051. [DOI] [PubMed] [Google Scholar]
  11. Francis M. L., Meltzer M. S., Gendelman H. E. Interferons in the persistence, pathogenesis, and treatment of HIV infection. AIDS Res Hum Retroviruses. 1992 Feb;8(2):199–207. doi: 10.1089/aid.1992.8.199. [DOI] [PubMed] [Google Scholar]
  12. Fuchs D., Forsman A., Hagberg L., Larsson M., Norkrans G., Reibnegger G., Werner E. R., Wachter H. Immune activation and decreased tryptophan in patients with HIV-1 infection. J Interferon Res. 1990 Dec;10(6):599–603. doi: 10.1089/jir.1990.10.599. [DOI] [PubMed] [Google Scholar]
  13. Ganser A., Brücher W., Brodt H. R., Busch W., Brandhorst I., Helm E. B., Hoelzer D. Treatment of AIDS-related Kaposi's sarcoma with recombinant gamma-interferon. Onkologie. 1986 Jun;9(3):163–166. doi: 10.1159/000215998. [DOI] [PubMed] [Google Scholar]
  14. Garotta G., Thelen M., Delia D., Kamber M., Baggiolini M. GM-1, a clone of the monoblastic phagocyte U937 that expresses a large respiratory burst capacity upon activation with interferon-gamma. J Leukoc Biol. 1991 Mar;49(3):294–301. doi: 10.1002/jlb.49.3.294. [DOI] [PubMed] [Google Scholar]
  15. Gartner S., Markovits P., Markovitz D. M., Kaplan M. H., Gallo R. C., Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986 Jul 11;233(4760):215–219. doi: 10.1126/science.3014648. [DOI] [PubMed] [Google Scholar]
  16. Gendelman H. E., Orenstein J. M., Martin M. A., Ferrua C., Mitra R., Phipps T., Wahl L. A., Lane H. C., Fauci A. S., Burke D. S. Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes. J Exp Med. 1988 Apr 1;167(4):1428–1441. doi: 10.1084/jem.167.4.1428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Griffin D. E., McArthur J. C., Cornblath D. R. Neopterin and interferon-gamma in serum and cerebrospinal fluid of patients with HIV-associated neurologic disease. Neurology. 1991 Jan;41(1):69–74. doi: 10.1212/wnl.41.1.69. [DOI] [PubMed] [Google Scholar]
  18. Hammer S. M., Gillis J. M., Groopman J. E., Rose R. M. In vitro modification of human immunodeficiency virus infection by granulocyte-macrophage colony-stimulating factor and gamma interferon. Proc Natl Acad Sci U S A. 1986 Nov;83(22):8734–8738. doi: 10.1073/pnas.83.22.8734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hartshorn K. L., Neumeyer D., Vogt M. W., Schooley R. T., Hirsch M. S. Activity of interferons alpha, beta, and gamma against human immunodeficiency virus replication in vitro. AIDS Res Hum Retroviruses. 1987 Summer;3(2):125–133. doi: 10.1089/aid.1987.3.125. [DOI] [PubMed] [Google Scholar]
  20. Hass R., Lonnemann G., Männel D., Topley N., Hartmann A., Köhler L., Resch K., Goppelt-Strübe M. Regulation of TNF-alpha, IL-1 and IL-6 synthesis in differentiating human monoblastoid leukemic U937 cells. Leuk Res. 1991;15(5):327–339. doi: 10.1016/0145-2126(91)90008-h. [DOI] [PubMed] [Google Scholar]
  21. Kelsey S. M., Makin H. L., Macey M. G., Newland A. C. Gamma interferon augments functional and phenotypic characteristics of vitamin D3-induced monocytoid differentiation in the U937 human leukaemic cell line. Leuk Res. 1990;14(11-12):1027–1033. doi: 10.1016/0145-2126(90)90116-q. [DOI] [PubMed] [Google Scholar]
  22. Koenig S., Gendelman H. E., Orenstein J. M., Dal Canto M. C., Pezeshkpour G. H., Yungbluth M., Janotta F., Aksamit A., Martin M. A., Fauci A. S. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science. 1986 Sep 5;233(4768):1089–1093. doi: 10.1126/science.3016903. [DOI] [PubMed] [Google Scholar]
  23. Kornbluth R. S., Oh P. S., Munis J. R., Cleveland P. H., Richman D. D. Interferons and bacterial lipopolysaccharide protect macrophages from productive infection by human immunodeficiency virus in vitro. J Exp Med. 1989 Mar 1;169(3):1137–1151. doi: 10.1084/jem.169.3.1137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Koyanagi Y., O'Brien W. A., Zhao J. Q., Golde D. W., Gasson J. C., Chen I. S. Cytokines alter production of HIV-1 from primary mononuclear phagocytes. Science. 1988 Sep 23;241(4873):1673–1675. doi: 10.1126/science.241.4873.1673. [DOI] [PubMed] [Google Scholar]
  25. Lane H. C., Depper J. M., Greene W. C., Whalen G., Waldmann T. A., Fauci A. S. Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. Evidence for a selective defect in soluble antigen recognition. N Engl J Med. 1985 Jul 11;313(2):79–84. doi: 10.1056/NEJM198507113130204. [DOI] [PubMed] [Google Scholar]
  26. Massari F. E., Poli G., Schnittman S. M., Psallidopoulos M. C., Davey V., Fauci A. S. In vivo T lymphocyte origin of macrophage-tropic strains of HIV. Role of monocytes during in vitro isolation and in vivo infection. J Immunol. 1990 Jun 15;144(12):4628–4632. [PubMed] [Google Scholar]
  27. McElrath M. J., Pruett J. E., Cohn Z. A. Mononuclear phagocytes of blood and bone marrow: comparative roles as viral reservoirs in human immunodeficiency virus type 1 infections. Proc Natl Acad Sci U S A. 1989 Jan;86(2):675–679. doi: 10.1073/pnas.86.2.675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Meltzer M. S., Skillman D. R., Hoover D. L., Hanson B. D., Turpin J. A., Kalter D. C., Gendelman H. E. Macrophages and the human immunodeficiency virus. Immunol Today. 1990 Jun;11(6):217–223. doi: 10.1016/0167-5699(90)90086-o. [DOI] [PubMed] [Google Scholar]
  29. Merrill J. E., Chen I. S. HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease. FASEB J. 1991 Jul;5(10):2391–2397. doi: 10.1096/fasebj.5.10.2065887. [DOI] [PubMed] [Google Scholar]
  30. Murray H. W., Hillman J. K., Rubin B. Y., Kelly C. D., Jacobs J. L., Tyler L. W., Donelly D. M., Carriero S. M., Godbold J. H., Roberts R. B. Patients at risk for AIDS-related opportunistic infections. Clinical manifestations and impaired gamma interferon production. N Engl J Med. 1985 Dec 12;313(24):1504–1510. doi: 10.1056/NEJM198512123132403. [DOI] [PubMed] [Google Scholar]
  31. Murray H. W., Rubin B. Y., Masur H., Roberts R. B. Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. N Engl J Med. 1984 Apr 5;310(14):883–889. doi: 10.1056/NEJM198404053101404. [DOI] [PubMed] [Google Scholar]
  32. Orenstein J. M., Jannotta F. Human immunodeficiency virus and papovavirus infections in acquired immunodeficiency syndrome: an ultrastructural study of three cases. Hum Pathol. 1988 Mar;19(3):350–361. doi: 10.1016/s0046-8177(88)80531-8. [DOI] [PubMed] [Google Scholar]
  33. Orenstein J. M., Meltzer M. S., Phipps T., Gendelman H. E. Cytoplasmic assembly and accumulation of human immunodeficiency virus types 1 and 2 in recombinant human colony-stimulating factor-1-treated human monocytes: an ultrastructural study. J Virol. 1988 Aug;62(8):2578–2586. doi: 10.1128/jvi.62.8.2578-2586.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pantaleo G., Graziosi C., Butini L., Pizzo P. A., Schnittman S. M., Kotler D. P., Fauci A. S. Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9838–9842. doi: 10.1073/pnas.88.21.9838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pestka S., Langer J. A., Zoon K. C., Samuel C. E. Interferons and their actions. Annu Rev Biochem. 1987;56:727–777. doi: 10.1146/annurev.bi.56.070187.003455. [DOI] [PubMed] [Google Scholar]
  36. Poli G., Bressler P., Kinter A., Duh E., Timmer W. C., Rabson A., Justement J. S., Stanley S., Fauci A. S. Interleukin 6 induces human immunodeficiency virus expression in infected monocytic cells alone and in synergy with tumor necrosis factor alpha by transcriptional and post-transcriptional mechanisms. J Exp Med. 1990 Jul 1;172(1):151–158. doi: 10.1084/jem.172.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Poli G., Introna M., Zanaboni F., Peri G., Carbonari M., Aiuti F., Lazzarin A., Moroni M., Mantovani A. Natural killer cells in intravenous drug abusers with lymphadenopathy syndrome. Clin Exp Immunol. 1985 Oct;62(1):128–135. [PMC free article] [PubMed] [Google Scholar]
  38. Poli G., Kinter A., Justement J. S., Kehrl J. H., Bressler P., Stanley S., Fauci A. S. Tumor necrosis factor alpha functions in an autocrine manner in the induction of human immunodeficiency virus expression. Proc Natl Acad Sci U S A. 1990 Jan;87(2):782–785. doi: 10.1073/pnas.87.2.782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Poli G., Orenstein J. M., Kinter A., Folks T. M., Fauci A. S. Interferon-alpha but not AZT suppresses HIV expression in chronically infected cell lines. Science. 1989 May 5;244(4904):575–577. doi: 10.1126/science.2470148. [DOI] [PubMed] [Google Scholar]
  40. Pomerantz R. J., Trono D., Feinberg M. B., Baltimore D. Cells nonproductively infected with HIV-1 exhibit an aberrant pattern of viral RNA expression: a molecular model for latency. Cell. 1990 Jun 29;61(7):1271–1276. doi: 10.1016/0092-8674(90)90691-7. [DOI] [PubMed] [Google Scholar]
  41. Rieckmann P., Poli G., Fox C. H., Kehrl J. H., Fauci A. S. Recombinant gp120 specifically enhances tumor necrosis factor-alpha production and Ig secretion in B lymphocytes from HIV-infected individuals but not from seronegative donors. J Immunol. 1991 Nov 1;147(9):2922–2927. [PubMed] [Google Scholar]
  42. Rinaldo C. R., Jr, Armstrong J. A., Kingsley L. A., Zhou S., Ho M. Relation of alpha and gamma interferon levels to development of AIDS in homosexual men. J Exp Pathol. 1990;5(3):127–132. [PubMed] [Google Scholar]
  43. Rook A. H., Hooks J. J., Quinnan G. V., Lane H. C., Manischewitz J. F., Macher A. M., Masur H., Fauci A. S., Djeu J. Y. Interleukin 2 enhances the natural killer cell activity of acquired immunodeficiency syndrome patients through a gamma-interferon-independent mechanism. J Immunol. 1985 Mar;134(3):1503–1507. [PubMed] [Google Scholar]
  44. Rosenberg Z. F., Fauci A. S. Immunopathogenesis of HIV infection. FASEB J. 1991 Jul;5(10):2382–2390. doi: 10.1096/fasebj.5.10.1676689. [DOI] [PubMed] [Google Scholar]
  45. Salahuddin S. Z., Rose R. M., Groopman J. E., Markham P. D., Gallo R. C. Human T lymphotropic virus type III infection of human alveolar macrophages. Blood. 1986 Jul;68(1):281–284. [PubMed] [Google Scholar]
  46. Schacter L. P., Rozencweig M., Canetta R., Kelley S., Nicaise C., Smaldone L. Overview of hormonal therapy in advanced breast cancer. Semin Oncol. 1990 Dec;17(6 Suppl 9):38–46. [PubMed] [Google Scholar]
  47. Schnittman S. M., Psallidopoulos M. C., Lane H. C., Thompson L., Baseler M., Massari F., Fox C. H., Salzman N. P., Fauci A. S. The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science. 1989 Jul 21;245(4915):305–308. doi: 10.1126/science.2665081. [DOI] [PubMed] [Google Scholar]
  48. Wong G. H., Krowka J. F., Stites D. P., Goeddel D. V. In vitro anti-human immunodeficiency virus activities of tumor necrosis factor-alpha and interferon-gamma. J Immunol. 1988 Jan 1;140(1):120–124. [PubMed] [Google Scholar]
  49. Yamada O., Hattori N., Kurimura T., Kita M., Kishida T. Inhibition of growth of HIV by human natural interferon in vitro. AIDS Res Hum Retroviruses. 1988 Aug;4(4):287–294. doi: 10.1089/aid.1988.4.287. [DOI] [PubMed] [Google Scholar]
  50. Yamamoto J. K., Barré-Sinoussi F., Bolton V., Pedersen N. C., Gardner M. B. Human alpha- and beta-interferon but not gamma- suppress the in vitro replication of LAV, HTLV-III, and ARV-2. J Interferon Res. 1986 Apr;6(2):143–152. doi: 10.1089/jir.1986.6.143. [DOI] [PubMed] [Google Scholar]
  51. Young H. A., Hardy K. J. Interferon-gamma: producer cells, activation stimuli, and molecular genetic regulation. Pharmacol Ther. 1990;45(1):137–151. doi: 10.1016/0163-7258(90)90012-q. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES