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J Exp Med. 1992 September 1; 176(3): 739–750.
PMCID: PMC2119360

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

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Pestka S, Langer JA, Zoon KC, Samuel CE. Interferons and their actions. Annu Rev Biochem. 1987;56:727–777. [PubMed]
  • Billiau A, Dijkmans R. Interferon-gamma: mechanism of action and therapeutic potential. Biochem Pharmacol. 1990 Oct 1;40(7):1433–1439. [PubMed]
  • Young HA, Hardy KJ. Interferon-gamma: producer cells, activation stimuli, and molecular genetic regulation. Pharmacol Ther. 1990;45(1):137–151. [PubMed]
  • Rinaldo CR, Jr, Armstrong JA, Kingsley LA, 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]
  • Fuchs D, Forsman A, Hagberg L, Larsson M, Norkrans G, Reibnegger G, Werner ER, Wachter H. Immune activation and decreased tryptophan in patients with HIV-1 infection. J Interferon Res. 1990 Dec;10(6):599–603. [PubMed]
  • Griffin DE, McArthur JC, Cornblath DR. Neopterin and interferon-gamma in serum and cerebrospinal fluid of patients with HIV-associated neurologic disease. Neurology. 1991 Jan;41(1):69–74. [PubMed]
  • Murray HW, Rubin BY, Masur H, Roberts RB. Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. N Engl J Med. 1984 Apr 5;310(14):883–889. [PubMed]
  • Murray HW, Hillman JK, Rubin BY, Kelly CD, Jacobs JL, Tyler LW, Donelly DM, Carriero SM, Godbold JH, Roberts RB. 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. [PubMed]
  • Rook AH, Hooks JJ, Quinnan GV, Lane HC, Manischewitz JF, Macher AM, Masur H, Fauci AS, Djeu JY. 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]
  • Lane HC, Depper JM, Greene WC, Whalen G, Waldmann TA, Fauci AS. 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. [PubMed]
  • Emilie D, Peuchmaur M, Maillot MC, Crevon MC, Brousse N, Delfraissy JF, Dormont J, Galanaud P. Production of interleukins in human immunodeficiency virus-1-replicating lymph nodes. J Clin Invest. 1990 Jul;86(1):148–159. [PMC free article] [PubMed]
  • Yamamoto JK, Barré-Sinoussi F, Bolton V, Pedersen NC, Gardner MB. 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. [PubMed]
  • Wong GH, Krowka JF, Stites DP, Goeddel DV. 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]
  • 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. [PubMed]
  • Hammer SM, Gillis JM, Groopman JE, Rose RM. 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. [PubMed]
  • Hartshorn KL, Neumeyer D, Vogt MW, Schooley RT, Hirsch MS. Activity of interferons alpha, beta, and gamma against human immunodeficiency virus replication in vitro. AIDS Res Hum Retroviruses. 1987 Summer;3(2):125–133. [PubMed]
  • Kornbluth RS, Oh PS, Munis JR, Cleveland PH, Richman DD. 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. [PMC free article] [PubMed]
  • Koyanagi Y, O'Brien WA, Zhao JQ, Golde DW, Gasson JC, Chen IS. Cytokines alter production of HIV-1 from primary mononuclear phagocytes. Science. 1988 Sep 23;241(4873):1673–1675. [PubMed]
  • Rosenberg ZF, Fauci AS. Immunopathogenesis of HIV infection. FASEB J. 1991 Jul;5(10):2382–2390. [PubMed]
  • Schnittman SM, Psallidopoulos MC, Lane HC, Thompson L, Baseler M, Massari F, Fox CH, Salzman NP, Fauci AS. 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. [PubMed]
  • McElrath MJ, Pruett JE, Cohn ZA. 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. [PubMed]
  • Massari FE, Poli G, Schnittman SM, Psallidopoulos MC, Davey V, Fauci AS. 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]
  • Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science. 1986 Sep 5;233(4768):1089–1093. [PubMed]
  • Merrill JE, Chen IS. HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease. FASEB J. 1991 Jul;5(10):2391–2397. [PubMed]
  • Salahuddin SZ, Rose RM, Groopman JE, Markham PD, Gallo RC. Human T lymphotropic virus type III infection of human alveolar macrophages. Blood. 1986 Jul;68(1):281–284. [PubMed]
  • Gartner S, Markovits P, Markovitz DM, Kaplan MH, Gallo RC, Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986 Jul 11;233(4760):215–219. [PubMed]
  • Gendelman HE, Orenstein JM, Martin MA, Ferrua C, Mitra R, Phipps T, Wahl LA, Lane HC, Fauci AS, Burke DS, et al. 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. [PMC free article] [PubMed]
  • Orenstein JM, Meltzer MS, Phipps T, Gendelman HE. 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. [PMC free article] [PubMed]
  • Orenstein JM, 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. [PubMed]
  • Meltzer MS, Skillman DR, Hoover DL, Hanson BD, Turpin JA, Kalter DC, Gendelman HE. Macrophages and the human immunodeficiency virus. Immunol Today. 1990 Jun;11(6):217–223. [PubMed]
  • Poli G, Orenstein JM, Kinter A, Folks TM, Fauci AS. Interferon-alpha but not AZT suppresses HIV expression in chronically infected cell lines. Science. 1989 May 5;244(4904):575–577. [PubMed]
  • Francis ML, Meltzer MS, Gendelman HE. Interferons in the persistence, pathogenesis, and treatment of HIV infection. AIDS Res Hum Retroviruses. 1992 Feb;8(2):199–207. [PubMed]
  • Folks TM, Justement J, Kinter A, Schnittman S, Orenstein J, Poli G, Fauci AS. 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]
  • Pomerantz RJ, Trono D, Feinberg MB, 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. [PubMed]
  • Duh EJ, Maury WJ, Folks TM, Fauci AS, Rabson AB. 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. [PubMed]
  • Poli G, Bressler P, Kinter A, Duh E, Timmer WC, Rabson A, Justement JS, Stanley S, Fauci AS. 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. [PMC free article] [PubMed]
  • Poli G, Kinter A, Justement JS, Kehrl JH, Bressler P, Stanley S, Fauci AS. 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. [PubMed]
  • Danis VA, Franic GM, Rathjen DA, Brooks PM. 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. [PubMed]
  • Kelsey SM, Makin HL, Macey MG, Newland AC. 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. [PubMed]
  • 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. [PubMed]
  • Cavender DE, 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. [PubMed]
  • Ferreira OC, Jr, Valinsky JE, Sheridan K, Wayner EA, 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. [PubMed]
  • 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. [PubMed]
  • Fernie BF, Poli G, Fauci AS. 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. [PMC free article] [PubMed]
  • Folks TM, Kessler SW, Orenstein JM, Justement JS, Jaffe ES, Fauci AS. Infection and replication of HIV-1 in purified progenitor cells of normal human bone marrow. Science. 1988 Nov 11;242(4880):919–922. [PubMed]
  • Pantaleo G, Graziosi C, Butini L, Pizzo PA, Schnittman SM, Kotler DP, Fauci AS. Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9838–9842. [PubMed]
  • Fox CH, Tenner-Rácz K, Rácz P, Firpo A, Pizzo PA, Fauci AS. Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis. 1991 Dec;164(6):1051–1057. [PubMed]
  • Rieckmann P, Poli G, Fox CH, Kehrl JH, Fauci AS. 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]
  • 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. [PubMed]
  • Schacter LP, 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]
  • Ganser A, Brücher W, Brodt HR, Busch W, Brandhorst I, Helm EB, Hoelzer D. Treatment of AIDS-related Kaposi's sarcoma with recombinant gamma-interferon. Onkologie. 1986 Jun;9(3):163–166. [PubMed]

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