Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Dec 15;100(12):3154–3163. doi: 10.1172/JCI119871

Interferon-gamma and tumor necrosis factor-alpha specifically induce formation of cytomegalovirus-permissive monocyte-derived macrophages that are refractory to the antiviral activity of these cytokines.

C Söderberg-Nauclér 1, K N Fish 1, J A Nelson 1
PMCID: PMC508529  PMID: 9399963

Abstract

Monocytes/macrophages are key cells in the pathogenesis of human cytomegalovirus (HCMV). Although HCMV infection in monocytes is restricted to early events of gene expression, productive infection has been demonstrated in differentiated macrophages in vitro. We examined the cellular and cytokine components that are essential for HCMV replication in Concanavalin A-stimulated monocyte-derived macrophages (MDM). By negative selection, depletion of CD8+ T lymphocytes, but not CD4+ T lymphocytes, CD19+ B cells, or CD56+ NK cells, resulted in a 60-70% reduction in the number of HCMV-infected MDM, and a 4 log decrease in virus production. Neutralization of IFN-gamma and TNF-alpha, but not IL-1, IL-2, or TGF-beta, decreased production of virus by 4 logs and 2 logs, respectively. Subsequently, addition of recombinant IFN-gamma or TNF-alpha to purified monocyte cultures was sufficient to produce HCMV-permissive MDM. While IFN-gamma and TNF-alpha possess antiviral properties, addition of these cytokines to permissive MDM cultures did not affect production of HCMV. Thus, rather than inhibiting replication of HCMV, IFN-gamma and TNF-alpha specifically induce differentiation of monocytes into HCMV-permissive MDM, which are resistant to the antiviral effects of these cytokines.

Full Text

The Full Text of this article is available as a PDF (689.1 KB).

Selected References

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

  1. Abe E., Ishimi Y., Jin C. H., Hong M. H., Sato T., Suda T. Granulocyte-macrophage colony-stimulating factor is a major macrophage fusion factor present in conditioned medium of concanavalin A-stimulated spleen cell cultures. J Immunol. 1991 Sep 15;147(6):1810–1815. [PubMed] [Google Scholar]
  2. Adams D. O. The granulomatous inflammatory response. A review. Am J Pathol. 1976 Jul;84(1):164–192. [PMC free article] [PubMed] [Google Scholar]
  3. Biswas P., Poli G., Kinter A. L., Justement J. S., Stanley S. K., Maury W. J., Bressler P., Orenstein J. M., Fauci A. S. 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. J Exp Med. 1992 Sep 1;176(3):739–750. doi: 10.1084/jem.176.3.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boros D. L. Granulomatous inflammations. Prog Allergy. 1978;24:183–267. doi: 10.1159/000401230. [DOI] [PubMed] [Google Scholar]
  5. Britt W. J., Vugler L. G. Oligomerization of the human cytomegalovirus major envelope glycoprotein complex gB (gp55-116). J Virol. 1992 Nov;66(11):6747–6754. doi: 10.1128/jvi.66.11.6747-6754.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chou S. W. Acquisition of donor strains of cytomegalovirus by renal-transplant recipients. N Engl J Med. 1986 May 29;314(22):1418–1423. doi: 10.1056/NEJM198605293142205. [DOI] [PubMed] [Google Scholar]
  7. Chou S. W. Cytomegalovirus infection and reinfection transmitted by heart transplantation. J Infect Dis. 1987 May;155(5):1054–1056. doi: 10.1093/infdis/155.5.1054. [DOI] [PubMed] [Google Scholar]
  8. Chou S. W. Reactivation and recombination of multiple cytomegalovirus strains from individual organ donors. J Infect Dis. 1989 Jul;160(1):11–15. doi: 10.1093/infdis/160.1.11. [DOI] [PubMed] [Google Scholar]
  9. Chou S., Kim D. Y., Norman D. J. Transmission of cytomegalovirus by pretransplant leukocyte transfusions in renal transplant candidates. J Infect Dis. 1987 Mar;155(3):565–567. doi: 10.1093/infdis/155.3.565. [DOI] [PubMed] [Google Scholar]
  10. Dankner W. M., McCutchan J. A., Richman D. D., Hirata K., Spector S. A. Localization of human cytomegalovirus in peripheral blood leukocytes by in situ hybridization. J Infect Dis. 1990 Jan;161(1):31–36. doi: 10.1093/infdis/161.1.31. [DOI] [PubMed] [Google Scholar]
  11. Davignon J. L., Castanié P., Yorke J. A., Gautier N., Clément D., Davrinche C. Anti-human cytomegalovirus activity of cytokines produced by CD4+ T-cell clones specifically activated by IE1 peptides in vitro. J Virol. 1996 Apr;70(4):2162–2169. doi: 10.1128/jvi.70.4.2162-2169.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fennie E. H., Lie Y. S., Low M. A., Gribling P., Anderson K. P. Reduced mortality in murine cytomegalovirus infected mice following prophylactic murine interferon-gamma treatment. Antiviral Res. 1988 Nov;10(1-3):27–39. doi: 10.1016/0166-3542(88)90012-5. [DOI] [PubMed] [Google Scholar]
  13. Fish K. N., Stenglein S. G., Ibanez C., Nelson J. A. Cytomegalovirus persistence in macrophages and endothelial cells. Scand J Infect Dis Suppl. 1995;99:34–40. [PubMed] [Google Scholar]
  14. Gnann J. W., Jr, Ahlmén J., Svalander C., Olding L., Oldstone M. B., Nelson J. A. Inflammatory cells in transplanted kidneys are infected by human cytomegalovirus. Am J Pathol. 1988 Aug;132(2):239–248. [PMC free article] [PubMed] [Google Scholar]
  15. Gu J. J., Harriss J. V., Ozato K., Gottlieb P. D. Induction by concanavalin A of specific mRNAs and cytolytic function in a CD8-positive T cell hybridoma. J Immunol. 1994 Nov 15;153(10):4408–4417. [PubMed] [Google Scholar]
  16. Haagmans B. L., Stals F. S., van der Meide P. H., Bruggeman C. A., Horzinek M. C., Schijns V. E. Tumor necrosis factor alpha promotes replication and pathogenicity of rat cytomegalovirus. J Virol. 1994 Apr;68(4):2297–2304. doi: 10.1128/jvi.68.4.2297-2304.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Haagmans B. L., van der Meide P. H., Stals F. S., van den Eertwegh A. J., Claassen E., Bruggeman C. A., Horzinek M. C., Schijns V. E. Suppression of rat cytomegalovirus replication by antibodies against gamma interferon. J Virol. 1994 Apr;68(4):2305–2312. doi: 10.1128/jvi.68.4.2305-2312.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Heise M. T., Virgin H. W., 4th The T-cell-independent role of gamma interferon and tumor necrosis factor alpha in macrophage activation during murine cytomegalovirus and herpes simplex virus infections. J Virol. 1995 Feb;69(2):904–909. doi: 10.1128/jvi.69.2.904-909.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Huang S., Hendriks W., Althage A., Hemmi S., Bluethmann H., Kamijo R., Vilcek J., Zinkernagel R. M., Aguet M. Immune response in mice that lack the interferon-gamma receptor. Science. 1993 Mar 19;259(5102):1742–1745. doi: 10.1126/science.8456301. [DOI] [PubMed] [Google Scholar]
  20. Ibanez C. E., Schrier R., Ghazal P., Wiley C., Nelson J. A. Human cytomegalovirus productively infects primary differentiated macrophages. J Virol. 1991 Dec;65(12):6581–6588. doi: 10.1128/jvi.65.12.6581-6588.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Klein J. R., Pasternack M. S., Bevan M. J. Activation requirements for antigen- and mitogen-induced interferon-gamma release from cytotoxic T lymphocytes. J Immunol. 1985 Apr;134(4):2456–2461. [PubMed] [Google Scholar]
  22. Klein J. R., Raulet D. H., Pasternack M. S., Bevan M. J. Cytotoxic T lymphocytes produce immune interferon in response to antigen or mitogen. J Exp Med. 1982 Apr 1;155(4):1198–1203. doi: 10.1084/jem.155.4.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kondo K., Kaneshima H., Mocarski E. S. Human cytomegalovirus latent infection of granulocyte-macrophage progenitors. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11879–11883. doi: 10.1073/pnas.91.25.11879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kondo K., Xu J., Mocarski E. S. Human cytomegalovirus latent gene expression in granulocyte-macrophage progenitors in culture and in seropositive individuals. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11137–11142. doi: 10.1073/pnas.93.20.11137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. 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]
  27. Lathey J. L., Spector S. A. Unrestricted replication of human cytomegalovirus in hydrocortisone-treated macrophages. J Virol. 1991 Nov;65(11):6371–6375. doi: 10.1128/jvi.65.11.6371-6375.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Leist T. P., Eppler M., Zinkernagel R. M. Enhanced virus replication and inhibition of lymphocytic choriomeningitis virus disease in anti-gamma interferon-treated mice. J Virol. 1989 Jun;63(6):2813–2819. doi: 10.1128/jvi.63.6.2813-2819.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Link H., Battmer K., Stumme C. Cytomegalovirus infection in leucocytes after bone marrow transplantation demonstrated by mRNA in situ hybridization. Br J Haematol. 1993 Nov;85(3):573–577. doi: 10.1111/j.1365-2141.1993.tb03350.x. [DOI] [PubMed] [Google Scholar]
  30. Lucin P., Jonjić S., Messerle M., Polić B., Hengel H., Koszinowski U. H. Late phase inhibition of murine cytomegalovirus replication by synergistic action of interferon-gamma and tumour necrosis factor. J Gen Virol. 1994 Jan;75(Pt 1):101–110. doi: 10.1099/0022-1317-75-1-101. [DOI] [PubMed] [Google Scholar]
  31. Maciejewski J. P., Bruening E. E., Donahue R. E., Sellers S. E., Carter C., Young N. S., St Jeor S. Infection of mononucleated phagocytes with human cytomegalovirus. Virology. 1993 Aug;195(2):327–336. doi: 10.1006/viro.1993.1383. [DOI] [PubMed] [Google Scholar]
  32. McInnes A., Rennick D. M. Interleukin 4 induces cultured monocytes/macrophages to form giant multinucleated cells. J Exp Med. 1988 Feb 1;167(2):598–611. doi: 10.1084/jem.167.2.598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Meyers J. D., Flournoy N., Thomas E. D. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis. 1986 Mar;153(3):478–488. doi: 10.1093/infdis/153.3.478. [DOI] [PubMed] [Google Scholar]
  34. Meylan P. R., Guatelli J. C., Munis J. R., Richman D. D., Kornbluth R. S. Mechanisms for the inhibition of HIV replication by interferons-alpha, -beta, and -gamma in primary human macrophages. Virology. 1993 Mar;193(1):138–148. doi: 10.1006/viro.1993.1110. [DOI] [PubMed] [Google Scholar]
  35. Minton E. J., Tysoe C., Sinclair J. H., Sissons J. G. Human cytomegalovirus infection of the monocyte/macrophage lineage in bone marrow. J Virol. 1994 Jun;68(6):4017–4021. doi: 10.1128/jvi.68.6.4017-4021.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pavić I., Polić B., Crnković I., Lucin P., Jonjić S., Koszinowski U. H. Participation of endogenous tumour necrosis factor alpha in host resistance to cytomegalovirus infection. J Gen Virol. 1993 Oct;74(Pt 10):2215–2223. doi: 10.1099/0022-1317-74-10-2215. [DOI] [PubMed] [Google Scholar]
  37. Peterson P. K., Gekker G., Chao C. C., Hu S. X., Edelman C., Balfour H. H., Jr, Verhoef J. Human cytomegalovirus-stimulated peripheral blood mononuclear cells induce HIV-1 replication via a tumor necrosis factor-alpha-mediated mechanism. J Clin Invest. 1992 Feb;89(2):574–580. doi: 10.1172/JCI115623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Postlethwaite A. E., Jackson B. K., Beachey E. H., Kang A. H. Formation of multinucleated giant cells from human monocyte precursors. Mediation by a soluble protein from antigen-and mitogen-stimulated lymphocytes. J Exp Med. 1982 Jan 1;155(1):168–178. doi: 10.1084/jem.155.1.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schut R. L., Gekker G., Hu S., Chao C. C., Pomeroy C., Jordan M. C., Peterson P. K. Cytomegalovirus replication in murine microglial cell cultures: suppression of permissive infection by interferon-gamma. J Infect Dis. 1994 May;169(5):1092–1096. doi: 10.1093/infdis/169.5.1092. [DOI] [PubMed] [Google Scholar]
  40. Sinclair J. H., Baillie J., Bryant L. A., Taylor-Wiedeman J. A., Sissons J. G. Repression of human cytomegalovirus major immediate early gene expression in a monocytic cell line. J Gen Virol. 1992 Feb;73(Pt 2):433–435. doi: 10.1099/0022-1317-73-2-433. [DOI] [PubMed] [Google Scholar]
  41. Sinzger C., Müntefering H., Löning T., Stöss H., Plachter B., Jahn G. Cell types infected in human cytomegalovirus placentitis identified by immunohistochemical double staining. Virchows Arch A Pathol Anat Histopathol. 1993;423(4):249–256. doi: 10.1007/BF01606887. [DOI] [PubMed] [Google Scholar]
  42. Sinzger C., Plachter B., Stenglein S., Jahn G. Immunohistochemical detection of viral antigens in smooth muscle, stromal, and epithelial cells from acute human cytomegalovirus gastritis. J Infect Dis. 1993 Jun;167(6):1427–1432. doi: 10.1093/infdis/167.6.1427. [DOI] [PubMed] [Google Scholar]
  43. Sitkovsky M. V., Pasternack M. S., Eisen H. N. Inhibition of cytotoxic T lymphocyte activity by concanavalin A. J Immunol. 1982 Oct;129(4):1372–1376. [PubMed] [Google Scholar]
  44. Sitkovsky M. V., Pasternack M. S., Lugo J. P., Klein J. R., Eisen H. N. Isolation and partial characterization of concanavalin A receptors on cloned cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1984 Mar;81(5):1519–1523. doi: 10.1073/pnas.81.5.1519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Stanton G. J., Jordan C., Hart A., Heard H., Langford M. P., Baron S. Nondetectable levels of interferon gamma is a critical host defense during the first day of herpes simplex virus infection. Microb Pathog. 1987 Sep;3(3):179–183. doi: 10.1016/0882-4010(87)90094-5. [DOI] [PubMed] [Google Scholar]
  46. Stein J., Volk H. D., Liebenthal C., Krüger D. H., Prösch S. Tumour necrosis factor alpha stimulates the activity of the human cytomegalovirus major immediate early enhancer/promoter in immature monocytic cells. J Gen Virol. 1993 Nov;74(Pt 11):2333–2338. doi: 10.1099/0022-1317-74-11-2333. [DOI] [PubMed] [Google Scholar]
  47. Stenberg R. M., Depto A. S., Fortney J., Nelson J. A. Regulated expression of early and late RNAs and proteins from the human cytomegalovirus immediate-early gene region. J Virol. 1989 Jun;63(6):2699–2708. doi: 10.1128/jvi.63.6.2699-2708.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Söderberg C., Larsson S., Bergstedt-Lindqvist S., Möller E. Definition of a subset of human peripheral blood mononuclear cells that are permissive to human cytomegalovirus infection. J Virol. 1993 Jun;67(6):3166–3175. doi: 10.1128/jvi.67.6.3166-3175.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Taylor-Wiedeman J., Sissons J. G., Borysiewicz L. K., Sinclair J. H. Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol. 1991 Sep;72(Pt 9):2059–2064. doi: 10.1099/0022-1317-72-9-2059. [DOI] [PubMed] [Google Scholar]
  50. Taylor-Wiedeman J., Sissons P., Sinclair J. Induction of endogenous human cytomegalovirus gene expression after differentiation of monocytes from healthy carriers. J Virol. 1994 Mar;68(3):1597–1604. doi: 10.1128/jvi.68.3.1597-1604.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Tegtmeier G. E. Cytomegalovirus infection as a complication of blood transfusion. Semin Liver Dis. 1986 Feb;6(1):82–95. doi: 10.1055/s-2008-1040796. [DOI] [PubMed] [Google Scholar]
  52. Weinberg J. B., Hobbs M. M., Misukonis M. A. Phenotypic characterization of gamma interferon-induced human monocyte polykaryons. Blood. 1985 Dec;66(6):1241–1246. [PubMed] [Google Scholar]
  53. Weinberg J. B., Hobbs M. M., Misukonis M. A. Recombinant human gamma-interferon induces human monocyte polykaryon formation. Proc Natl Acad Sci U S A. 1984 Jul;81(14):4554–4557. doi: 10.1073/pnas.81.14.4554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Weinshenker B. G., Wilton S., Rice G. P. Phorbol ester-induced differentiation permits productive human cytomegalovirus infection in a monocytic cell line. J Immunol. 1988 Mar 1;140(5):1625–1631. [PubMed] [Google Scholar]
  55. Wentworth B. B., French L. Plaque assay of cytomegalovirus strains of human origin. Proc Soc Exp Biol Med. 1970 Nov;135(2):253–258. doi: 10.3181/00379727-135-35031. [DOI] [PubMed] [Google Scholar]
  56. von Laer D., Serr A., Meyer-König U., Kirste G., Hufert F. T., Haller O. Human cytomegalovirus immediate early and late transcripts are expressed in all major leukocyte populations in vivo. J Infect Dis. 1995 Aug;172(2):365–370. doi: 10.1093/infdis/172.2.365. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES