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Mol Med. 1996 January; 2(1): 38–49.
PMCID: PMC2230037

Role of IgE immune complexes in the regulation of HIV-1 replication and increased cell death of infected U1 monocytes: involvement of CD23/Fc epsilon RII-mediated nitric oxide and cyclic AMP pathways.


BACKGROUND: IgE/anti-IgE immune complexes (IgE-IC) induce the release of multiple mediators from monocytes/macrophages and the monocytic cell line U937 following the ligation of the low-affinity Fc epsilon receptors (Fc epsilon RII/CD23). These effects are mediated through an accumulation of cAMP and the generation of L-arginine-dependent nitric oxide (NO). Since high IgE levels predict more rapid progression to acquired immunodeficiency syndrome, we attempted to define the effects of IgE-IC on human immunodeficiency virus (HIV) production in monocytes. MATERIALS AND METHODS: Two variants of HIV-1 chronically infected monocytic U1 cells were stimulated with IgE-IC and virus replication was quantified. NO and cAMP involvement was tested through the use of agonistic and antagonistic chemicals of these two pathways. RESULTS: IgE-IC induced p24 production by U1 cells with low-level constitutive expression of HIV-1 mRNAs and extracellular HIV capsid protein p24 levels (U1low), upon their pretreatment with interleukin 4 (IL-4) or IL-13. This effect was due to the crosslinking of CD23, as it was reversed by blocking the IgE binding site on CD23. The IgE-IC effect could also be mimicked by crosslinking of CD23 by a specific monoclonal antibody. p24 induction by IgE-IC was then shown to be due to CD23-mediated stimulation of cAMP, NO, and tumor necrosis factor alpha (TNF alpha) generation. In another variant of U1 cells with > 1 log higher constitutive production of p24 levels (U1high), IgE-IC addition dramatically decreased all cell functions tested and accelerated cell death. This phenomenon was reversed by blocking the nitric oxide generation. CONCLUSIONS: These data point out a regulatory role of IgE-IC on HIV-1 production in monocytic cells, through CD23-mediated stimulation of cAMP and NO pathways. IgE-IC can also stimulate increased cell death in high HIV producing cells through the NO pathway.

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  • 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]
  • Schuitemaker H, Kootstra NA, de Goede RE, de Wolf F, Miedema F, Tersmette M. Monocytotropic human immunodeficiency virus type 1 (HIV-1) variants detectable in all stages of HIV-1 infection lack T-cell line tropism and syncytium-inducing ability in primary T-cell culture. J Virol. 1991 Jan;65(1):356–363. [PMC free article] [PubMed]
  • Stevenson M, Stanwick TL, Dempsey MP, Lamonica CA. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 1990 May;9(5):1551–1560. [PubMed]
  • Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen IS. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990 Apr 20;61(2):213–222. [PubMed]
  • Mikovits JA, Lohrey NC, Schulof R, Courtless J, Ruscetti FW. Activation of infectious virus from latent human immunodeficiency virus infection of monocytes in vivo. J Clin Invest. 1992 Oct;90(4):1486–1491. [PMC free article] [PubMed]
  • Embretson J, Zupancic M, Ribas JL, Burke A, Racz P, Tenner-Racz K, Haase AT. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993 Mar 25;362(6418):359–362. [PubMed]
  • Mikovits JA, Raziuddin, Gonda M, Ruta M, Lohrey NC, Kung HF, Ruscetti FW. Negative regulation of human immune deficiency virus replication in monocytes. Distinctions between restricted and latent expression in THP-1 cells. J Exp Med. 1990 May 1;171(5):1705–1720. [PMC free article] [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]
  • Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, Orenstein JM, Kotler DP, Fauci AS. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. [PubMed]
  • Ishizaka K. Basic mechanisms of IgE-mediated hypersensitivity. Curr Opin Immunol. 1989 Apr;1(4):625–629. [PubMed]
  • Stevens RL, Austen KF. Recent advances in the cellular and molecular biology of mast cells. Immunol Today. 1989 Nov;10(11):381–386. [PubMed]
  • Galli SJ. New concepts about the mast cell. N Engl J Med. 1993 Jan 28;328(4):257–265. [PubMed]
  • Borish L, Mascali JJ, Rosenwasser LJ. IgE-dependent cytokine production by human peripheral blood mononuclear phagocytes. J Immunol. 1991 Jan 1;146(1):63–67. [PubMed]
  • Capron M, Jouault T, Prin L, Joseph M, Ameisen JC, Butterworth AE, Papin JP, Kusnierz JP, Capron A. Functional study of a monoclonal antibody to IgE Fc receptor (Fc epsilon R2) of eosinophils, platelets, and macrophages. J Exp Med. 1986 Jul 1;164(1):72–89. [PMC free article] [PubMed]
  • Mossalayi MD, Paul-Eugène N, Ouaaz F, Arock M, Kolb JP, Kilchherr E, Debré P, Dugas B. Involvement of Fc epsilon RII/CD23 and L-arginine-dependent pathway in IgE-mediated stimulation of human monocyte functions. Int Immunol. 1994 Jul;6(7):931–934. [PubMed]
  • Israël-Biet D, Labrousse F, Tourani JM, Sors H, Andrieu JM, Even P. Elevation of IgE in HIV-infected subjects: a marker of poor prognosis. J Allergy Clin Immunol. 1992 Jan;89(1 Pt 1):68–75. [PubMed]
  • Sample S, Chernoff DN, Lenahan GA, Serwonska MH, Rangi S, Sherman JW, Sooy CD, Hollander H, Goetzl EJ. Elevated serum concentrations of IgE antibodies to environmental antigens in HIV-seropositive male homosexuals. J Allergy Clin Immunol. 1990 Dec;86(6 Pt 1):876–880. [PubMed]
  • Paganelli R, Scala E, Ansotegui IJ, Ausiello CM, Halapi E, Fanales-Belasio E, D'Offizi G, Mezzaroma I, Pandolfi F, Fiorilli M, et al. CD8+ T lymphocytes provide helper activity for IgE synthesis in human immunodeficiency virus-infected patients with hyper-IgE. J Exp Med. 1995 Jan 1;181(1):423–428. [PMC free article] [PubMed]
  • Maurer D, Fiebiger E, Reininger B, Wolff-Winiski B, Jouvin MH, Kilgus O, Kinet JP, Stingl G. Expression of functional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals. J Exp Med. 1994 Feb 1;179(2):745–750. [PMC free article] [PubMed]
  • Delespesse G, Suter U, Mossalayi D, Bettler B, Sarfati M, Hofstetter H, Kilcherr E, Debre P, Dalloul A. Expression, structure, and function of the CD23 antigen. Adv Immunol. 1991;49:149–191. [PubMed]
  • Conrad DH. Fc epsilon RII/CD23: the low affinity receptor for IgE. Annu Rev Immunol. 1990;8:623–645. [PubMed]
  • Ouaaz F, Sola B, Issaly F, Kolb JP, Davi F, Mentz F, Arock M, Paul-Eugène N, Körner M, Dugas B, et al. Growth arrest and terminal differentiation of leukemic myelomonocytic cells induced through ligation of surface CD23 antigen. Blood. 1994 Nov 1;84(9):3095–3104. [PubMed]
  • Paul-Eugène N, Kolb JP, Sarfati M, Arock M, Ouaaz F, Debré P, Mossalayi DM, Dugas B. Ligation of CD23 activates soluble guanylate cyclase in human monocytes via an L-arginine-dependent mechanism. J Leukoc Biol. 1995 Jan;57(1):160–167. [PubMed]
  • Mossalayi MD, Arock M, Delespesse G, Hofstetter H, Bettler B, Dalloul AH, Kilchherr E, Quaaz F, Debré P, Sarfati M. Cytokine effects of CD23 are mediated by an epitope distinct from the IgE binding site. EMBO J. 1992 Dec;11(12):4323–4328. [PubMed]
  • Bécherel PA, Mossalayi MD, Ouaaz F, Le Goff L, Dugas B, Paul-Eugène N, Frances C, Chosidow O, Kilchherr E, Guillosson JJ, et al. Involvement of cyclic AMP and nitric oxide in immunoglobulin E-dependent activation of Fc epsilon RII/CD23+ normal human keratinocytes. J Clin Invest. 1994 May;93(5):2275–2279. [PMC free article] [PubMed]
  • Wang B, Rieger A, Kilgus O, Ochiai K, Maurer D, Födinger D, Kinet JP, Stingl G. Epidermal Langerhans cells from normal human skin bind monomeric IgE via Fc epsilon RI. J Exp Med. 1992 May 1;175(5):1353–1365. [PMC free article] [PubMed]
  • Montaner LJ, Gordon S. TH2 downregulation of macrophage HIV-1 replication. Science. 1995 Jan 27;267(5197):538–539. [PubMed]
  • Kolb JP, Paul-Eugene N, Damais C, Yamaoka K, Drapier JC, Dugas B. Interleukin-4 stimulates cGMP production by IFN-gamma-activated human monocytes. Involvement of the nitric oxide synthase pathway. J Biol Chem. 1994 Apr 1;269(13):9811–9816. [PubMed]
  • Byrne BC, Li JJ, Sninsky J, Poiesz BJ. Detection of HIV-1 RNA sequences by in vitro DNA amplification. Nucleic Acids Res. 1988 May 11;16(9):4165–4165. [PMC free article] [PubMed]
  • Kwok S, Ehrlich G, Poiesz B, Kalish R, Sninsky JJ. Enzymatic amplification of HTLV-I viral sequences from peripheral blood mononuclear cells and infected tissues. Blood. 1988 Oct;72(4):1117–1123. [PubMed]
  • Gendelman HE, Friedman RM, Joe S, Baca LM, Turpin JA, Dveksler G, Meltzer MS, Dieffenbach C. A selective defect of interferon alpha production in human immunodeficiency virus-infected monocytes. J Exp Med. 1990 Nov 1;172(5):1433–1442. [PMC free article] [PubMed]
  • Vercelli D, Jabara HH, Lee BW, Woodland N, Geha RS, Leung DY. Human recombinant interleukin 4 induces Fc epsilon R2/CD23 on normal human monocytes. J Exp Med. 1988 Apr 1;167(4):1406–1416. [PMC free article] [PubMed]
  • Takizawa F, Adamczewski M, Kinet JP. Identification of the low affinity receptor for immunoglobulin E on mouse mast cells and macrophages as Fc gamma RII and Fc gamma RIII. J Exp Med. 1992 Aug 1;176(2):469–475. [PMC free article] [PubMed]
  • Paul-Eugene N, Kolb JP, Abadie A, Gordon J, Delespesse G, Sarfati M, Mencia-Huerta JM, Braquet P, Dugas B. Ligation of CD23 triggers cAMP generation and release of inflammatory mediators in human monocytes. J Immunol. 1992 Nov 1;149(9):3066–3071. [PubMed]
  • Zurawski G, de Vries JE. Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today. 1994 Jan;15(1):19–26. [PubMed]
  • Nussler AK, Billiar TR. Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol. 1993 Aug;54(2):171–178. [PubMed]
  • Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993 Dec 30;329(27):2002–2012. [PubMed]
  • Stuehr DJ, Griffith OW. Mammalian nitric oxide synthases. Adv Enzymol Relat Areas Mol Biol. 1992;65:287–346. [PubMed]
  • Mossalayi MD, Arock M, Bertho JM, Blanc C, Dalloul AH, Hofstetter H, Sarfati M, Delespesse G, Debré P. Proliferation of early human myeloid precursors induced by interleukin-1 and recombinant soluble CD23. Blood. 1990 May 15;75(10):1924–1927. [PubMed]
  • Aubry JP, Pochon S, Graber P, Jansen KU, Bonnefoy JY. CD21 is a ligand for CD23 and regulates IgE production. Nature. 1992 Aug 6;358(6386):505–507. [PubMed]
  • Arock M, Le Goff L, Bécherel PA, Dugas B, Debré P, Mossalayi MD. Involvement of Fc epsilon RII/CD23 and L-arginine dependent pathway in IgE-mediated activation of human eosinophils. Biochem Biophys Res Commun. 1994 Aug 30;203(1):265–271. [PubMed]
  • De Maria R, Cifone MG, Trotta R, Rippo MR, Festuccia C, Santoni A, Testi R. Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors. J Exp Med. 1994 Nov 1;180(5):1999–2004. [PMC free article] [PubMed]
  • Cifone MG, Festuccia C, Cironi L, Cavallo G, Chessa MA, Pensa V, Tubaro E, Santoni A. Induction of the nitric oxide-synthesizing pathway in fresh and interleukin 2-cultured rat natural killer cells. Cell Immunol. 1994 Aug;157(1):181–194. [PubMed]
  • Chowdhury MI, Koyanagi Y, Horiuchi S, Hazeki O, Ui M, Kitano K, Golde DW, Takada K, Yamamoto N. cAMP stimulates human immunodeficiency virus (HIV-1) from latently infected cells of monocyte-macrophage lineage: synergism with TNF-alpha. Virology. 1993 May;194(1):345–349. [PubMed]
  • Hassan MI, Nokta MA, Pollard RB. Involvement of cAMP and protein kinase C in cytomegalovirus enhancement of human immunodeficiency virus replication. Proc Soc Exp Biol Med. 1993 Nov;204(2):216–223. [PubMed]
  • Hofmann B, Nishanian P, Nguyen T, Liu M, Fahey JL. Restoration of T-cell function in HIV infection by reduction of intracellular cAMP levels with adenosine analogues. AIDS. 1993 May;7(5):659–664. [PubMed]
  • Karupiah G, Xie QW, Buller RM, Nathan C, Duarte C, MacMicking JD. Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science. 1993 Sep 10;261(5127):1445–1448. [PubMed]
  • Croen KD. Evidence for antiviral effect of nitric oxide. Inhibition of herpes simplex virus type 1 replication. J Clin Invest. 1993 Jun;91(6):2446–2452. [PMC free article] [PubMed]
  • Mannick JB, Asano K, Izumi K, Kieff E, Stamler JS. Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation. Cell. 1994 Dec 30;79(7):1137–1146. [PubMed]
  • Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 1991 Aug;10(8):2247–2258. [PubMed]
  • Chartrain NA, Geller DA, Koty PP, Sitrin NF, Nussler AK, Hoffman EP, Billiar TR, Hutchinson NI, Mudgett JS. Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J Biol Chem. 1994 Mar 4;269(9):6765–6772. [PubMed]
  • Xie QW, Whisnant R, Nathan C. Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J Exp Med. 1993 Jun 1;177(6):1779–1784. [PMC free article] [PubMed]
  • Hamid Q, Springall DR, Riveros-Moreno V, Chanez P, Howarth P, Redington A, Bousquet J, Godard P, Holgate S, Polak JM. Induction of nitric oxide synthase in asthma. Lancet. 1993 Dec 18;342(8886-8887):1510–1513. [PubMed]
  • Pietraforte D, Tritarelli E, Testa U, Minetti M. gp120 HIV envelope glycoprotein increases the production of nitric oxide in human monocyte-derived macrophages. J Leukoc Biol. 1994 Feb;55(2):175–182. [PubMed]
  • Bukrinsky MI, Nottet HS, Schmidtmayerova H, Dubrovsky L, Flanagan CR, Mullins ME, Lipton SA, Gendelman HE. Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)-infected monocytes: implications for HIV-associated neurological disease. J Exp Med. 1995 Feb 1;181(2):735–745. [PMC free article] [PubMed]

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