Regulation of Macrophage Activation and HIV Replication

  • Luis J. Montaner
  • Georges Herbein
  • Siamon Gordon
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 374)


In normal immune responses, macrophages play a key role in the host’s defence system combating disease, clearing foreign antigens and protecting against invading microrganisms. The ability of the macrophage (mØ) to mediate effective immune responses is associated with its capacity to respond and control its activation upon encountering the appropriate exogenous or endogenous signal. Activation is defined by the stimulus which changes or predisposes to changes in cellular activity, while activation potential is the ability to undergo activation. Since immune activation involves all aspects of immunological responses, we will differentiate between two general types of cytokine-orientated activation when discussing macrophages: pro-inflammatory and immuno-regulatory. Pro-inflammatory activation refers to the state of immunological “alarm” mediated by TNF-α, IL-1β, IL-6 and chemokines, while immuno-regulatory activation refers to responses mediated by IFNs, IL-2, IL-4, IL-10, IL-12, and IL-13. Although discussed separately, these types of activation are not mutually exclusive and seldom occur in isolation.


Human Immunodeficiency Virus Human Immunodeficiency Virus Type Alveolar Macrophage Kupffer Cell Macrophage Activation 
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  1. 1.
    Gartner S, Markovits P, Markovitz DM, et al. The role of mononuclear phagocytes in HTLV III/LAV infection. Science. 1986; 233; 215–219.PubMedCrossRefGoogle Scholar
  2. 2.
    Gendelman HE, Orenstein JM, Martin MA, et al. Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes. J. Exp. Med. 1988; 167; 1428–1441.PubMedCrossRefGoogle Scholar
  3. 3.
    Gendelman HE, Orenstein JM, Baca LM, et al. The macrophage in the persistence and pathogenesis of HIV infection. AIDS. 1989; 475–495.Google Scholar
  4. 4.
    Schuitemaker H, Kootstra NA, de Goede REY, et al. Monocytotropic human immunodeficiency virus type 1 (HIV-1) variants detectable at all stages ofHIV-1 infection lack T-cell line tropism and syncytiuminducing ability in primary T cell culture. J. Virol. 1991; 65; 356–363.PubMedGoogle Scholar
  5. 5.
    Poli G, Bressler P, Kinter A, et al. Interleukin-6 induces human immunodeficiency virus expression in infected monocytic cells alone and in synergy with tumor necrosis factor a by transcriptional and post-transcriptional mechanisms. J. Exp. Med. 1990; 172; 151–158.PubMedCrossRefGoogle Scholar
  6. 6.
    von Briessen H, von Mallinckrodt C, Esser R, et al. Effects of cytokines and lipopolysaccharides on HIV infection of human macrophages. Res. Virol. 1991; 142; 197–204.CrossRefGoogle Scholar
  7. 7.
    Koyanagi Y, O’Brien WA, Qi Zhao J, et al. Cytokines alter production of HIV-1 from primary mononuclear phagocytes. Science. 1988; 241; 1673–1675.PubMedCrossRefGoogle Scholar
  8. 8.
    Kazazi F, Mathijs JM, Chang J, et al. Recombinant interleukin 4 stimulates human immunodeficiency virus production by infected monocytes and macrophages. J. Gen. Virol. 1992; 73; 941–949.PubMedCrossRefGoogle Scholar
  9. 9.
    Montaner LJ, Griffin P, Gordon S. Interleukin-10 (IL-10) inhibits initial reverse transcription of HIV-1 and mediates a virostatic latent state in primary blood-derived human macrophages in vitro. J. Gen. Virol. 1994; In press.Google Scholar
  10. 10.
    Saville MW, Paga K, Foli A, et al. Interlukin-10 suppresses human immunodeficiency virus-1 replication in vitro in cells of the monocyte/macrophage lineage. Blood. 1994; 83; 3591–3599.PubMedGoogle Scholar
  11. 11.
    Chehimi J, Starr SE, Frank I, et al. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J. Exp. Med. 1994; 179; 1361–1366.PubMedCrossRefGoogle Scholar
  12. 12.
    Montaner LJ, Doyle AG, Collin M, et al. Interleukin 13 inhibits human immunodeficiency virus type 1 production in primary blood-derived human macrophages in vitro. J. Exp. Med. 1993; 178; 743–747.PubMedCrossRefGoogle Scholar
  13. 13.
    Kornbluth RS, Oh PS, Munis JR, et al. Interferons and bacterial liposaccharide protect macrophages from productive infection by human inununodefrciency virus in vitro. J. Exp. Med. 1989; 169; 1137–1151.PubMedCrossRefGoogle Scholar
  14. 14.
    Fauci AS. Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science. 1993; 262; 1011–1018.PubMedCrossRefGoogle Scholar
  15. 15.
    Merrill JE, Koyanagi Y, Zack J, et al. Induction of interleukin-1 and tumor necrosis factor alpha in brain cultures by human ummunodeficiency virus type 1. J. Virol. 1992; 66; 2217–2225.PubMedGoogle Scholar
  16. 16.
    Herbein G, Keshav S, Collin M, et al. HIV-1 induces tumour necrosis factor and IL-1 gene expression in primary human macrophages independent of productive infection. Clin. Exp. Immunol. 1994; 95; 442–449.PubMedCrossRefGoogle Scholar
  17. 17.
    Vyakarnam A, McKeating J, Meager A, Beverly PC. Tumour necrosis factors (alpha, beta) induced by HIV-1 in peripheral blood mononuclear cells potentiate virus replication. AIDS. 1990; 4; 21–27.PubMedCrossRefGoogle Scholar
  18. 18.
    Herbein G, Montaner LJ, Gordon S. Tumor necrosis factor displays a bifunctional action on HIV-1 replication in human primary macrophages. “MRCAIDS Workshop”. 1994; Manchester, UK; Abstr. 26.Google Scholar
  19. 19.
    Rieder P, Riethmuller G. Loss of circulating T4+ monocytes in patients infected with HTLV III. Lancet. 1986; 270.Google Scholar
  20. 20.
    Landevirta J, Maury CPJ, Teppo AM, Repo H. Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am. J. Med. 1988; 85; 289–291.CrossRefGoogle Scholar
  21. 21.
    Merrill JE, Koyanagi Y, Chen ISY. Interleukin-1 and tumor necrosis factor alpha can be induced from mononuclear phagocytes by human immunodeficiency virus type 1 to the CD4 receptor. J. Virol. 1989; 63; 4404–4408.PubMedGoogle Scholar
  22. 22.
    Gessani S, Puddu P, Varano B, et al. Induction of beta interferon by human immunodeficiency virus type 1 and its gp-120 protein in human monocytes-macrophages. Role of beta interferon in the restriction of virus replication. J. Virol. 1994; 68; 1983–1986.PubMedGoogle Scholar
  23. 23.
    Wahl SM, Allen JB, Gartner S, et al. HIV-1 and its envelope glycoprotein down-regulate chemotactic ligand receptors and chemotactic function of peripheral blood monocytes. J. Immunol. 1989; 142; 3553–3559.PubMedGoogle Scholar
  24. 24.
    Ehrenreich H, Rieckmann P, Sinowatz F, et al. Potent stimulation of monocytic endothelin-1 production by HIV-1 glycoprotein 120. J. Immunol. 1993; 150; 4601–4609.PubMedGoogle Scholar
  25. 25.
    Lathey JL, Kanangat S, Rouse BT. Differential expression of tumor necrosis factor a and interleukin 113 compared with interleukin 6 in monocytes from human immunodeficiency virus-positive individuals measured by polymerase chain reaction. AIDS. 1994; 7; 109–115.Google Scholar
  26. 26.
    Longo N, Zabay JM, Sempere JM, et al. Altered production of PGE-2, IL-113 and TNF-a by peripheral blood monocytes from HIV-positive individuals at early stages of HIV infection. AIDS. 1993; 6; 1017–1023.Google Scholar
  27. 27.
    Francis ML, Meltzer MS. Induction of IFN-a by HIV-1 in monocyte-enriched PBMC requires gp120CD4 interaction but not virus replication. J. Immunol. 1993; 151; 2208–2216.PubMedGoogle Scholar
  28. 28.
    Szebeni J, Dieffenbatch C, Wahl SM, et al. Induction of alpha interferon by HIV type 1 in human monocyte-macrophage cultures. J. Virol. 1991; 65; 6362–6364.PubMedGoogle Scholar
  29. 29.
    Denis M, Ghadirian E. Alveolar macrophages from subjects infected with HIV-1 express macrophage inflammatory protein-la: contribution to the CD8+ alveolitis. Clin. Exp. Immunol. 1994; 96; 187–192.PubMedCrossRefGoogle Scholar
  30. 30.
    Agostini C, Trentin L, Zambello R, et al. Release of granulocyte-macrophage colony-stymulating factor by alveolar macrophages in the lung of HIV-1-infected patients. J. Immunol. 1992; 149; 3379–3385.PubMedGoogle Scholar
  31. 31.
    Lau AS, Williams BRG. Interferon and tumor necrosis factor in the pathogenesis of HIV infection. J. Exp. Pathology. 1990; 5; 111–122.Google Scholar
  32. 32.
    DeStefano E, Friedman RM, Friedman-Kien AE, et al. Acid-Labile human leukocyte interferon in homosexual men with Kaposi’s sarcoma and lymphadenopathy. J. Infect. Dis. 1982; 146; 451–455.PubMedCrossRefGoogle Scholar
  33. 33.
    Lau AS, Read SE, William BRG. Down regulation of interferon alpha but not y receptor expression in vivo in the acquired immunodeficiency syndrome. J. Clin. Invest. 1988; 82; 1415–1421.PubMedCrossRefGoogle Scholar
  34. 34.
    Goodwin JS, Ceuppens J. Regulation of the immune response by prostaglandins. J. Clin. Immunol. 1983; 3; 295–315.PubMedCrossRefGoogle Scholar
  35. 35.
    Rossol S, Gianni G, Rossol-Voth R, et al. Cytokine-mediated regulation of monocyte/macrophage cytotoxicity in human immunodeficiency virus-1 infection. Med. Microbiol. Immunol. 1992; 181; 267–281.PubMedCrossRefGoogle Scholar
  36. 36.
    Trinchieri G. Interleukin-12 and its role in the generation of Thl cells. Immunol. Today. 1993; 14; 335–337.PubMedCrossRefGoogle Scholar
  37. 37.
    Brunda MJ. Interleukin-12. J. Leukoc. Biol. 1994; 55; 280–288.PubMedGoogle Scholar
  38. 38.
    Reiner NE. Altered cell signaling and mononuclear phagocyte deactivation during intracellular infection. Immunol. Today. 1994; 15; 374–381.PubMedCrossRefGoogle Scholar
  39. 39.
    Pietraforte D, Tritarelli E, Testa U, Minetti M. gp 120 HIV envelope glycoprotein increases the production of nitric oxide in human monocyte-derived macrophages. J. Leukoc. Biol. 1994; 55; 175–182.PubMedGoogle Scholar
  40. 40.
    Durrbaum-Landmann I, Kaltenhauser E, Hans-Dieter F, Ernst M. HIV-1 envelope protein gp120 affects phenotype and function of monocytes in vitro. J. Leukoc. Biol. 1994; 55; 545–551.PubMedGoogle Scholar
  41. 41.
    Shiratsuchi H, Johnson JL, Toossi Z, Ellner JJ. Modulation of the effector function of the human monocytes for Mycobacterium avium by human immunodeficiency virus-1 envelope glycoprotein gp 120. J. Clin. Invest. 1994; 93; 885–891.PubMedCrossRefGoogle Scholar
  42. 42.
    Wagner RP, Levitz SM, Tabuni A, Kornfield H. HIV-1 envelope protein (gp 120) inhibits the activity of human bronchoalveolar macrophages against Cryptococcus neoformans. Am Rev. Respir. Dis. 1992; 146; 1434–1438.PubMedGoogle Scholar
  43. 43.
    Dukes CS, Matthews TJ, Weinberg JB. Human immunodeficiency virus type 1 infection of human monocytes and macrophages does not alter their ability to generate an oxidative burst. J. Infect. Dis. 1993; 168; 459–462.PubMedCrossRefGoogle Scholar
  44. 44.
    Chen TP, Roberts RL, Wu KG, et al. Decreased superoxide anion and hydrogen peroxide production by neutrophile and monocytes in human immunodeficiency virus-infected children and adults. Pediatr. Res. 1993; 34; 544–550.PubMedCrossRefGoogle Scholar
  45. 45.
    Wehle K, Schirmer M, Dunnebacke-Hinz J, et al. Quantitative differences in phagocitosis and degradation of Pneumocystis carinii by alveolar macrophages in AIDS and non-HIV patients in vivo. Cytopathology. 1993; 4; 231–236.PubMedCrossRefGoogle Scholar
  46. 46.
    Roilides E, Holmes A, Blake C, et al. Defective antifungal activity of monocyte-derived macrophages from human immunodeficiency virus-infected children against Aspergillus fumigatus. J. Infect. Dis. 1993; 168; 1562–1565.PubMedCrossRefGoogle Scholar
  47. 47.
    Baldwin GC, Fleischmann J, Chung Y, et al. Human immunodeficiency virus causes mononuclear phagocyte dysfunction. Proc. Natl. Acad. Sci. USA. 1990; 87; 3933–3937.PubMedCrossRefGoogle Scholar
  48. 48.
    Kent SJ, Stent G, Sonza S, et al. HIV-1 infection of monocyte-derived macrophages reduces Fc and complement receptor expression. Clin. Exp. Immunol. 1994; 95; 450–454.PubMedCrossRefGoogle Scholar
  49. 49.
    Denis M. Human monocyte/macrophages: NO or no NO? J. Leukoc. Biol. 1994; 55; 682–684.PubMedGoogle Scholar
  50. 50.
    Murray JF, Mills J. Pulmonary infectious complications of human immunodeficiency virus infection. Part I and Part II. Am. Rev. Respir. Dis. 1990; 141; 1356–1372, 1582–1598.Google Scholar
  51. 51.
    Sierra-Madero JG, Toossi Z, Hom DL, et al. Relationship between load of virus in alveolar macrophages from human immunodeficiency virus type 1-infected persons, production of cytokines, and clinical status. J. Infect. Dis. 1994; 169; 18–27.PubMedCrossRefGoogle Scholar
  52. 52.
    Shall TJ, Bacon K, Toy KJ, Goeddel DV. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature. 1990; 347; 669–671.CrossRefGoogle Scholar
  53. 53.
    Taub D, Conlon K, Lloyd A, et al. Preferential migration of activated CD4+ and CD8+ cells in response to MIP-la and MP-1ß. Science. 1993; 260; 355–358.PubMedCrossRefGoogle Scholar
  54. 54.
    Matsushima K, Larsen CG, Dubois G, Oppenheim JJ. Purification and characterization of a novel chemotactic and activating factor produced by a human myelomonocytic cell line. J. Exp. Med. 1989; 169; 1485–1490.PubMedCrossRefGoogle Scholar
  55. 55.
    Hufert FT, Schmitz J, Schreiber M, et al. Human Kupffer cells infected with HIV-1 in vivo. J. Aquir. Immune Def. Syndr. 1993; 6; 772–777.Google Scholar
  56. 56.
    Schmitt MP, Gendrault JL, Schweitzer C, et al. Permissivity of primary cultures of human Kupffer cells for HIV-1. AIDS Res. Human Retroviruses. 1990; 6; 987–991.Google Scholar
  57. 57.
    Tyor WR, Glass JD, Baumrind N, et al. Cytokine expression of macrophages in HIV-1-associated vacuolar myelopathy. Neurology. 1993; 43; 1002–1009.PubMedCrossRefGoogle Scholar
  58. 58.
    Mosmann TR, Coffman RL. Thl and Th2 cells: Different patterns of lymphokine secretion lead to different functional properties. Ann. Rev. Immunol. 1989; 7; 145–173.CrossRefGoogle Scholar
  59. 59.
    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; 15; 19–26.PubMedCrossRefGoogle Scholar
  60. 60.
    Clerici M, Shearer G. A Thl-> Th2 switch is critical step in the etiology of HIV infection. Immunol. Today. 1993; 14; 107–110.PubMedCrossRefGoogle Scholar
  61. 61.
    Maggi E, Mazzetti M, Ravina A, et al. Ability of HIV to promote a Thl to Tho shift and to replicate preferentially in Th2 and Tho cells. Science. 1994; 265; 244–248.PubMedCrossRefGoogle Scholar
  62. 62.
    Graziosi C, Pantaleo G, Gantt KR, et al. Lack of Evidence for the dichotomy of Thl and Th2 predominance in HIV-infected individuals. Science. 1994; 265; 248–252.PubMedCrossRefGoogle Scholar
  63. 63.
    Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances mutine macrophage mannose receptor activity: A marker of alternative immunologic macrophage activation. J. Exp. Med. 1992; 176; 287–292.PubMedCrossRefGoogle Scholar
  64. 64.
    Doyle AG, Herbein G, Montaner LJ, et al. Interleukin-13 alters the activation state of murine macrophages in vitro: comparison with interleukin-4 and interferon-y. Eur. J. Immunol. 1994; 24; 1441–1445.PubMedCrossRefGoogle Scholar
  65. 65.
    Zack JA, Arrigo SJ, Weitsman SR, et al. HIV-1 entry into quiescent primary lymphocytes:molecular analysis reveals a labile, latent viral structure. Cell. 1990; 61; 213–222.PubMedCrossRefGoogle Scholar
  66. 66.
    Zarling JM, Ledbetter JA, Sias J, et al. HIV-infected humans, but not chimpanzees, have circulating cytotoxic T lymphocytes that lyse uninfected CD4+ cells. J. Immunol. 1990; 144; 2992–2998.PubMedGoogle Scholar
  67. 67.
    Brenner BG, Dascal A, Margolese RG, Wainberg MA. Natural killer cell function in patients with acquired immunodeficiency syndrome and related diseases. J. Leukoc. Biol. 1989; 46; 75–83.PubMedGoogle Scholar
  68. 68.
    Tanneau F, McChesney M, Lopez O, et al. Primary cytotoxicity against the envelope glycoprotein of human immunodeficiency virus-1: evidence for antibody-dependent cellular cytotoxicity in vivo. J. Infect. Dis. 1990; 162; 837–843.PubMedCrossRefGoogle Scholar
  69. 69.
    Nottet HSLM, de Graff L, de Vos NM, et al. Down-regulation of human immunodeficiency virus type 1 (HIV-1) production after stimulation of monocyte-derived macrophages infected with HIV-1. J. Infect. Dis. 1993; 167; 810–817.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Luis J. Montaner
    • 1
  • Georges Herbein
    • 2
  • Siamon Gordon
    • 1
  1. 1.Sir William Dunn School of PathologyUniversity of OxfordOxfordUK
  2. 2.Institute of Virology and INSERM U74Louis Pasteur UniversityStrasbourgFrance

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