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. 1991 Oct;139(4):877–887.

Cytokine influence on simian immunodeficiency virus replication within primary macrophages. TNF-alpha, but not GMCSF, enhances viral replication on a per-cell basis.

D G Walsh 1, C J Horvath 1, A Hansen-Moosa 1, J J MacKey 1, P K Sehgal 1, M D Daniel 1, R C Desrosiers 1, D J Ringler 1
PMCID: PMC1886312  PMID: 1928304

Abstract

The control of HIV-1 or SIV replication within macrophages is probably influenced by a variety of viral and cellular factors. Of the cellular factors, the authors have studied cytokine influence on SIV replication in vitro utilizing simian alveolar macrophages and uncloned SIVmacMTV, a macrophage-tropic variant. The approach allowed quantification of viral replication on a per-cell basis. As reported for HIV-1 replication in macrophages, TNF-alpha significantly increased SIV production in these macrophage cultures. GMCSF also resulted in marked increases in SIV gag protein in culture supernatants. However, after correcting for differences in total cell numbers and numbers of gag-containing cells in the treated and untreated cultures, GMCSF did not upregulate SIV production on a per-cell basis. IL-6 increased SIV replication little if at all but induced significantly greater cytopathic changes in the treated cultures compared with infected, untreated cultures. In contrast, IFN-gamma greatly decreased replication. Our results for GMCSF, IFN-gamma, and IL-6 are in contrast to previously published reports of cytokine control of HIV-1 growth in target cells, and they stress the importance of cell number analyses and the use of primary cultures in the study of lentiviral replication kinetics in macrophages.

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Selected References

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

  1. Aboulafia D., Miles S. A., Saks S. R., Mitsuyasu R. T. Intravenous recombinant tumor necrosis factor in the treatment of AIDS-related Kaposi's sarcoma. J Acquir Immune Defic Syndr. 1989;2(1):54–58. [PubMed] [Google Scholar]
  2. Armstrong J. A., Horne R. Follicular dendritic cells and virus-like particles in AIDS-related lymphadenopathy. Lancet. 1984 Aug 18;2(8399):370–372. doi: 10.1016/s0140-6736(84)90540-3. [DOI] [PubMed] [Google Scholar]
  3. Autran B., Mayaud C. M., Raphael M., Plata F., Denis M., Bourguin A., Guillon J. M., Debre P., Akoun G. Evidence for a cytotoxic T-lymphocyte alveolitis in human immunodeficiency virus-infected patients. AIDS. 1988 Jun;2(3):179–183. [PubMed] [Google Scholar]
  4. Breen E. C., Rezai A. R., Nakajima K., Beall G. N., Mitsuyasu R. T., Hirano T., Kishimoto T., Martinez-Maza O. Infection with HIV is associated with elevated IL-6 levels and production. J Immunol. 1990 Jan 15;144(2):480–484. [PubMed] [Google Scholar]
  5. Crespi M. The effect of interferon on cells persistently infected with HIV. AIDS. 1989 Jan;3(1):33–36. [PubMed] [Google Scholar]
  6. Desrosiers R. C., Ringler D. J. Use of simian immunodeficiency viruses for AIDS research. Intervirology. 1989;30(6):301–312. doi: 10.1159/000150108. [DOI] [PubMed] [Google Scholar]
  7. Dewhurst S., Embretson J. E., Anderson D. C., Mullins J. I., Fultz P. N. Sequence analysis and acute pathogenicity of molecularly cloned SIVSMM-PBj14. Nature. 1990 Jun 14;345(6276):636–640. doi: 10.1038/345636a0. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. 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]
  10. Folks T. M., Clouse K. A., Justement J., Rabson A., Duh E., Kehrl J. H., Fauci A. S. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2365–2368. doi: 10.1073/pnas.86.7.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Folks T. M., Justement J., Kinter A., Dinarello C. A., Fauci A. S. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science. 1987 Nov 6;238(4828):800–802. doi: 10.1126/science.3313729. [DOI] [PubMed] [Google Scholar]
  12. Fultz P. N., McClure H. M., Anderson D. C., Switzer W. M. Identification and biologic characterization of an acutely lethal variant of simian immunodeficiency virus from sooty mangabeys (SIV/SMM). AIDS Res Hum Retroviruses. 1989 Aug;5(4):397–409. doi: 10.1089/aid.1989.5.397. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. 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]
  16. Hammer S. M., Gillis J. M., Pinkston P., Rose R. M. Effect of zidovudine and granulocyte-macrophage colony-stimulating factor on human immunodeficiency virus replication in alveolar macrophages. Blood. 1990 Mar 15;75(6):1215–1219. [PubMed] [Google Scholar]
  17. 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]
  18. Heagy W., Groopman J., Schindler J., Finberg R. Use of IFN-gamma in patients with AIDS. J Acquir Immune Defic Syndr. 1990;3(6):584–590. [PubMed] [Google Scholar]
  19. Ho D. D., Rota T. R., Hirsch M. S. Infection of monocyte/macrophages by human T lymphotropic virus type III. J Clin Invest. 1986 May;77(5):1712–1715. doi: 10.1172/JCI112491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. Lähdevirta J., Maury C. P., Teppo A. M., Repo H. Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med. 1988 Sep;85(3):289–291. doi: 10.1016/0002-9343(88)90576-1. [DOI] [PubMed] [Google Scholar]
  23. Minassian A. A., Kalyanaraman V. S., Gallo R. C., Popovic M. Monoclonal antibodies against human immunodeficiency virus (HIV) type 2 core proteins: cross-reactivity with HIV type 1 and simian immunodeficiency virus. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6939–6943. doi: 10.1073/pnas.85.18.6939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Osborn L., Kunkel S., Nabel G. J. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2336–2340. doi: 10.1073/pnas.86.7.2336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Perno C. F., Yarchoan R., Cooney D. A., Hartman N. R., Webb D. S., Hao Z., Mitsuya H., Johns D. G., Broder S. Replication of human immunodeficiency virus in monocytes. Granulocyte/macrophage colony-stimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3'-azido-2'3'-dideoxythymidine (AZT) and other dideoxynucleoside congeners of thymidine. J Exp Med. 1989 Mar 1;169(3):933–951. doi: 10.1084/jem.169.3.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Plata F., Autran B., Martins L. P., Wain-Hobson S., Raphaël M., Mayaud C., Denis M., Guillon J. M., Debré P. AIDS virus-specific cytotoxic T lymphocytes in lung disorders. Nature. 1987 Jul 23;328(6128):348–351. doi: 10.1038/328348a0. [DOI] [PubMed] [Google Scholar]
  28. Plata F., Garcia-Pons F., Ryter A., Lebargy F., Goodenow M. M., Dat M. H., Autran B., Mayaud C. HIV-1 infection of lung alveolar fibroblasts and macrophages in humans. AIDS Res Hum Retroviruses. 1990 Aug;6(8):979–986. doi: 10.1089/aid.1990.6.979. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. Pomerantz R. J., Feinberg M. B., Trono D., Baltimore D. Lipopolysaccharide is a potent monocyte/macrophage-specific stimulator of human immunodeficiency virus type 1 expression. J Exp Med. 1990 Jul 1;172(1):253–261. doi: 10.1084/jem.172.1.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Rappersberger K., Gartner S., Schenk P., Stingl G., Groh V., Tschachler E., Mann D. L., Wolff K., Konrad K., Popovic M. Langerhans' cells are an actual site of HIV-1 replication. Intervirology. 1988;29(4):185–194. doi: 10.1159/000150045. [DOI] [PubMed] [Google Scholar]
  33. Regier D. A., Desrosiers R. C. The complete nucleotide sequence of a pathogenic molecular clone of simian immunodeficiency virus. AIDS Res Hum Retroviruses. 1990 Nov;6(11):1221–1231. doi: 10.1089/aid.1990.6.1221. [DOI] [PubMed] [Google Scholar]
  34. Remick D. G., Strieter R. M., Eskandari M. K., Nguyen D. T., Genord M. A., Raiford C. L., Kunkel S. L. Role of tumor necrosis factor-alpha in lipopolysaccharide-induced pathologic alterations. Am J Pathol. 1990 Jan;136(1):49–60. [PMC free article] [PubMed] [Google Scholar]
  35. Ringler D. J., Hancock W. W., King N. W., Letvin N. L., Daniel M. D., Desrosiers R. C., Murphy G. F. Immunophenotypic characterization of the cutaneous exanthem of SIV-infected rhesus monkeys. Apposition of degenerative Langerhans cells and cytotoxic lymphocytes during the development of acquired immunodeficiency syndrome. Am J Pathol. 1987 Feb;126(2):199–207. [PMC free article] [PubMed] [Google Scholar]
  36. Ringler D. J., Hancock W. W., King N. W., Murphy G. F. Characterization of nonhuman primate epidermal and dermal dendritic cells with monoclonal antibodies. A study of Langerhans cells and indeterminate cells in the rhesus monkey. Lab Invest. 1987 Mar;56(3):313–320. [PubMed] [Google Scholar]
  37. Ringler D. J., Hunt R. D., Desrosiers R. C., Daniel M. D., Chalifoux L. V., King N. W. Simian immunodeficiency virus-induced meningoencephalitis: natural history and retrospective study. Ann Neurol. 1988;23 (Suppl):S101–S107. doi: 10.1002/ana.410230726. [DOI] [PubMed] [Google Scholar]
  38. Ringler D. J., Walsh D. G., Chalifoux L. V., MacKey J. J., Daniel M. D., Desrosiers R. C., King N. W., Hancock W. W. Soluble and membrane-associated interleukin 2 receptor-alpha expression in rhesus monkeys infected with simian immunodeficiency virus. Lab Invest. 1990 Apr;62(4):435–443. [PubMed] [Google Scholar]
  39. Ringler D. J., Walsh D. G., MacKey J. J., Hunt R. D., King N. W. Immunophenotypic characterization of mononuclear phagocytes and dendritic cells in lymphoid organs of the rhesus monkey. Clin Immunol Immunopathol. 1988 Dec;49(3):349–364. doi: 10.1016/0090-1229(88)90125-0. [DOI] [PubMed] [Google Scholar]
  40. Ringler D. J., Wyand M. S., Walsh D. G., MacKey J. J., Chalifoux L. V., Popovic M., Minassian A. A., Sehgal P. K., Daniel M. D., Desrosiers R. C. Cellular localization of simian immunodeficiency virus in lymphoid tissues. I. Immunohistochemistry and electron microscopy. Am J Pathol. 1989 Feb;134(2):373–383. [PMC free article] [PubMed] [Google Scholar]
  41. Ringler D. J., Wyand M. S., Walsh D. G., MacKey J. J., Sehgal P. K., Daniel M. D., Desrosiers R. C., King N. W. The productive infection of alveolar macrophages by simian immunodeficiency virus. J Med Primatol. 1989;18(3-4):217–226. [PubMed] [Google Scholar]
  42. 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]
  43. Shaw G. M., Harper M. E., Hahn B. H., Epstein L. G., Gajdusek D. C., Price R. W., Navia B. A., Petito C. K., O'Hara C. J., Groopman J. E. HTLV-III infection in brains of children and adults with AIDS encephalopathy. Science. 1985 Jan 11;227(4683):177–182. doi: 10.1126/science.2981429. [DOI] [PubMed] [Google Scholar]
  44. Tenner-Rácz K., Rácz P., Dietrich M., Kern P. Altered follicular dendritic cells and virus-like particles in AIDS and AIDS-related lymphadenopathy. Lancet. 1985 Jan 12;1(8420):105–106. doi: 10.1016/s0140-6736(85)91994-4. [DOI] [PubMed] [Google Scholar]
  45. Tsunetsugu-Yokota Y., Honda M. Effect of cytokines on HIV release and IL-2 receptor alpha expression in monocytic cell lines. J Acquir Immune Defic Syndr. 1990;3(5):511–516. [PubMed] [Google Scholar]
  46. Wiley C. A., Schrier R. D., Nelson J. A., Lampert P. W., Oldstone M. B. Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7089–7093. doi: 10.1073/pnas.83.18.7089. [DOI] [PMC free article] [PubMed] [Google Scholar]

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