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. 1995 Apr;69(4):2133–2139. doi: 10.1128/jvi.69.4.2133-2139.1995

Replication of macrophage-tropic and T-cell-tropic strains of human immunodeficiency virus type 1 is augmented by macrophage-endothelial cell contact.

P N Gilles 1, J L Lathey 1, S A Spector 1
PMCID: PMC188880  PMID: 7884860

Abstract

Macrophages perform a central role in the pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection and have been implicated as the cell type most prominent in the development of central nervous system impairment. In this study, we evaluated the effect of interaction between macrophages and endothelial cells on HIV-1 replication. Upregulation of HIV-1 replication was consistently observed in monocyte-derived macrophages (hereafter called macrophages) cocultured with either umbilical vein endothelial cells or brain microvascular endothelial cells. HIV-1 p24 antigen production of laboratory-adapted strains and patient-derived isolates was increased 2- to 1,000-fold in macrophage-endothelial cocultures, with little or no detectable replication in cultures containing endothelial cells only. The upregulation of HIV-1 in macrophage-endothelial cocultures was observed not only for viruses with the non-syncytium-inducing, macrophage-tropic phenotype but also for viruses previously characterized as syncytium inducing and T-cell tropic. In contrast, cocultures of macrophages with glioblastoma, astrocytoma, cortical neuronal, fibroblast, and placental cells failed to increase HIV-1 replication. Enhancement of HIV-1 replication in macrophage-endothelial cocultures required cell-to-cell contact; conditioned media from endothelial cells or macrophage-endothelial cocultures failed to augment HIV-1 replication in macrophages. Additionally, antibody to leukocyte function-associated antigen (LFA-1), a macrophage-endothelial cell adhesion molecule, inhibited the enhanced HIV-1 replication in macrophage-endothelial cell cocultures. Thus, these data indicate that macrophage-endothelial cell contact enhances HIV-1 replication in macrophages for both macrophage-tropic and previously characterized T-cell-tropic strains and that antibody against LFA-1 can block the necessary cell-to-cell interaction required for the observed upregulation. These findings may have important implications for understanding the ability of HIV-1 to replicate efficiently in tissue macrophages, including those in the brain and at the blood-brain barrier.

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Selected References

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  1. Andeweg A. C., Leeflang P., Osterhaus A. D., Bosch M. L. Both the V2 and V3 regions of the human immunodeficiency virus type 1 surface glycoprotein functionally interact with other envelope regions in syncytium formation. J Virol. 1993 Jun;67(6):3232–3239. doi: 10.1128/jvi.67.6.3232-3239.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barré-Sinoussi F., Chermann J. C., Rey F., Nugeyre M. T., Chamaret S., Gruest J., Dauguet C., Axler-Blin C., Vézinet-Brun F., Rouzioux C. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868–871. doi: 10.1126/science.6189183. [DOI] [PubMed] [Google Scholar]
  3. Beekhuizen H., van Furth R. Monocyte adherence to human vascular endothelium. J Leukoc Biol. 1993 Oct;54(4):363–378. [PubMed] [Google Scholar]
  4. Bozzette S. A., McCutchan J. A., Spector S. A., Wright B., Richman D. D. A cross-sectional comparison of persons with syncytium- and non-syncytium-inducing human immunodeficiency virus. J Infect Dis. 1993 Dec;168(6):1374–1379. doi: 10.1093/infdis/168.6.1374. [DOI] [PubMed] [Google Scholar]
  5. Cheng-Mayer C., Shioda T., Levy J. A. Host range, replicative, and cytopathic properties of human immunodeficiency virus type 1 are determined by very few amino acid changes in tat and gp120. J Virol. 1991 Dec;65(12):6931–6941. doi: 10.1128/jvi.65.12.6931-6941.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chesebro B., Wehrly K., Nishio J., Perryman S. Macrophage-tropic human immunodeficiency virus isolates from different patients exhibit unusual V3 envelope sequence homogeneity in comparison with T-cell-tropic isolates: definition of critical amino acids involved in cell tropism. J Virol. 1992 Nov;66(11):6547–6554. doi: 10.1128/jvi.66.11.6547-6554.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Collin M., Illei P., James W., Gordon S. Definition of the range and distribution of human immunodeficiency virus macrophage tropism using PCR-based infectivity measurements. J Gen Virol. 1994 Jul;75(Pt 7):1597–1603. doi: 10.1099/0022-1317-75-7-1597. [DOI] [PubMed] [Google Scholar]
  8. Davis L. E., Hjelle B. L., Miller V. E., Palmer D. L., Llewellyn A. L., Merlin T. L., Young S. A., Mills R. G., Wachsman W., Wiley C. A. Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Neurology. 1992 Sep;42(9):1736–1739. doi: 10.1212/wnl.42.9.1736. [DOI] [PubMed] [Google Scholar]
  9. De Jong J. J., De Ronde A., Keulen W., Tersmette M., Goudsmit J. Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype: analysis by single amino acid substitution. J Virol. 1992 Nov;66(11):6777–6780. doi: 10.1128/jvi.66.11.6777-6780.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Desrosiers R. C., Hansen-Moosa A., Mori K., Bouvier D. P., King N. W., Daniel M. D., Ringler D. J. Macrophage-tropic variants of SIV are associated with specific AIDS-related lesions but are not essential for the development of AIDS. Am J Pathol. 1991 Jul;139(1):29–35. [PMC free article] [PubMed] [Google Scholar]
  11. Epstein L. G., Gendelman H. E. Human immunodeficiency virus type 1 infection of the nervous system: pathogenetic mechanisms. Ann Neurol. 1993 May;33(5):429–436. doi: 10.1002/ana.410330502. [DOI] [PubMed] [Google Scholar]
  12. Epstein L. G., Kuiken C., Blumberg B. M., Hartman S., Sharer L. R., Clement M., Goudsmit J. HIV-1 V3 domain variation in brain and spleen of children with AIDS: tissue-specific evolution within host-determined quasispecies. Virology. 1991 Feb;180(2):583–590. doi: 10.1016/0042-6822(91)90072-j. [DOI] [PubMed] [Google Scholar]
  13. Fujita K., Silver J., Peden K. Changes in both gp120 and gp41 can account for increased growth potential and expanded host range of human immunodeficiency virus type 1. J Virol. 1992 Jul;66(7):4445–4451. doi: 10.1128/jvi.66.7.4445-4451.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Gelbard H. A., Nottet H. S., Swindells S., Jett M., Dzenko K. A., Genis P., White R., Wang L., Choi Y. B., Zhang D. Platelet-activating factor: a candidate human immunodeficiency virus type 1-induced neurotoxin. J Virol. 1994 Jul;68(7):4628–4635. doi: 10.1128/jvi.68.7.4628-4635.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gelman B. B. Diffuse microgliosis associated with cerebral atrophy in the acquired immunodeficiency syndrome. Ann Neurol. 1993 Jul;34(1):65–70. doi: 10.1002/ana.410340112. [DOI] [PubMed] [Google Scholar]
  17. Gendelman H. E., Baca L. M., Husayni H., Turpin J. A., Skillman D., Kalter D. C., Orenstein J. M., Hoover D. L., Meltzer M. S. Macrophage-HIV interaction: viral isolation and target cell tropism. AIDS. 1990 Mar;4(3):221–228. [PubMed] [Google Scholar]
  18. Gendelman H. E., Orenstein J. M., Baca L. M., Weiser B., Burger H., Kalter D. C., Meltzer M. S. The macrophage in the persistence and pathogenesis of HIV infection. AIDS. 1989 Aug;3(8):475–495. doi: 10.1097/00002030-198908000-00001. [DOI] [PubMed] [Google Scholar]
  19. Grant I., Atkinson J. H., Hesselink J. R., Kennedy C. J., Richman D. D., Spector S. A., McCutchan J. A. Evidence for early central nervous system involvement in the acquired immunodeficiency syndrome (AIDS) and other human immunodeficiency virus (HIV) infections. Studies with neuropsychologic testing and magnetic resonance imaging. Ann Intern Med. 1987 Dec;107(6):828–836. doi: 10.7326/0003-4819-107-6-828. [DOI] [PubMed] [Google Scholar]
  20. Grimaila R. J., Fuller B. A., Rennert P. D., Nelson M. B., Hammarskjöld M. L., Potts B., Murray M., Putney S. D., Gray G. Mutations in the principal neutralization determinant of human immunodeficiency virus type 1 affect syncytium formation, virus infectivity, growth kinetics, and neutralization. J Virol. 1992 Apr;66(4):1875–1883. doi: 10.1128/jvi.66.4.1875-1883.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Groenink M., Fouchier R. A., Broersen S., Baker C. H., Koot M., van't Wout A. B., Huisman H. G., Miedema F., Tersmette M., Schuitemaker H. Relation of phenotype evolution of HIV-1 to envelope V2 configuration. Science. 1993 Jun 4;260(5113):1513–1516. doi: 10.1126/science.8502996. [DOI] [PubMed] [Google Scholar]
  22. Hogg N., Bates P. A., Harvey J. Structure and function of intercellular adhesion molecule-1. Chem Immunol. 1991;50:98–115. [PubMed] [Google Scholar]
  23. Huang Z. B., Potash M. J., Simm M., Shahabuddin M., Chao W., Gendelman H. E., Eden E., Volsky D. J. Infection of macrophages with lymphotropic human immunodeficiency virus type 1 can be arrested after viral DNA synthesis. J Virol. 1993 Nov;67(11):6893–6896. doi: 10.1128/jvi.67.11.6893-6896.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Koyanagi Y., Miles S., Mitsuyasu R. T., Merrill J. E., Vinters H. V., Chen I. S. Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms. Science. 1987 May 15;236(4803):819–822. doi: 10.1126/science.3646751. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Kure K., Weidenheim K. M., Lyman W. D., Dickson D. W. Morphology and distribution of HIV-1 gp41-positive microglia in subacute AIDS encephalitis. Pattern of involvement resembling a multisystem degeneration. Acta Neuropathol. 1990;80(4):393–400. doi: 10.1007/BF00307693. [DOI] [PubMed] [Google Scholar]
  27. Kusumi K., Conway B., Cunningham S., Berson A., Evans C., Iversen A. K., Colvin D., Gallo M. V., Coutre S., Shpaer E. G. Human immunodeficiency virus type 1 envelope gene structure and diversity in vivo and after cocultivation in vitro. J Virol. 1992 Feb;66(2):875–885. doi: 10.1128/jvi.66.2.875-885.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. LaRosa G. J., Davide J. P., Weinhold K., Waterbury J. A., Profy A. T., Lewis J. A., Langlois A. J., Dreesman G. R., Boswell R. N., Shadduck P. Conserved sequence and structural elements in the HIV-1 principal neutralizing determinant. Science. 1990 Aug 24;249(4971):932–935. doi: 10.1126/science.2392685. [DOI] [PubMed] [Google Scholar]
  29. Lafon M. E., Steffan A. M., Gendrault J. L., Klein-Soyer C., Gloeckler-Tondre L., Royer C., Kirn A. Interaction of human immunodeficiency virus with human macrovascular endothelial cells in vitro. AIDS Res Hum Retroviruses. 1992 Sep;8(9):1567–1570. doi: 10.1089/aid.1992.8.1567. [DOI] [PubMed] [Google Scholar]
  30. Lathey J. L., Spector D. H., Spector S. A. Human cytomegalovirus-mediated enhancement of human immunodeficiency virus type-1 production in monocyte-derived macrophages. Virology. 1994 Feb 15;199(1):98–104. doi: 10.1006/viro.1994.1101. [DOI] [PubMed] [Google Scholar]
  31. Levy J. A. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev. 1993 Mar;57(1):183–289. doi: 10.1128/mr.57.1.183-289.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Liu Z. Q., Wood C., Levy J. A., Cheng-Mayer C. The viral envelope gene is involved in macrophage tropism of a human immunodeficiency virus type 1 strain isolated from brain tissue. J Virol. 1990 Dec;64(12):6148–6153. doi: 10.1128/jvi.64.12.6148-6153.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Masliah E., Achim C. L., Ge N., DeTeresa R., Terry R. D., Wiley C. A. Spectrum of human immunodeficiency virus-associated neocortical damage. Ann Neurol. 1992 Sep;32(3):321–329. doi: 10.1002/ana.410320304. [DOI] [PubMed] [Google Scholar]
  34. Merrill J. E., Chen I. S. HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease. FASEB J. 1991 Jul;5(10):2391–2397. doi: 10.1096/fasebj.5.10.2065887. [DOI] [PubMed] [Google Scholar]
  35. Moses A. V., Bloom F. E., Pauza C. D., Nelson J. A. Human immunodeficiency virus infection of human brain capillary endothelial cells occurs via a CD4/galactosylceramide-independent mechanism. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10474–10478. doi: 10.1073/pnas.90.22.10474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Peden K., Emerman M., Montagnier L. Changes in growth properties on passage in tissue culture of viruses derived from infectious molecular clones of HIV-1LAI, HIV-1MAL, and HIV-1ELI. Virology. 1991 Dec;185(2):661–672. doi: 10.1016/0042-6822(91)90537-l. [DOI] [PubMed] [Google Scholar]
  37. Petito C. K., Cash K. S. Blood-brain barrier abnormalities in the acquired immunodeficiency syndrome: immunohistochemical localization of serum proteins in postmortem brain. Ann Neurol. 1992 Nov;32(5):658–666. doi: 10.1002/ana.410320509. [DOI] [PubMed] [Google Scholar]
  38. Potash M. J., Zeira M., Huang Z. B., Pearce T. E., Eden E., Gendelman H. E., Volsky D. J. Virus-cell membrane fusion does not predict efficient infection of alveolar macrophages by human immunodeficiency virus type 1 (HIV-1). Virology. 1992 Jun;188(2):864–868. doi: 10.1016/0042-6822(92)90543-x. [DOI] [PubMed] [Google Scholar]
  39. Power C., Kong P. A., Crawford T. O., Wesselingh S., Glass J. D., McArthur J. C., Trapp B. D. Cerebral white matter changes in acquired immunodeficiency syndrome dementia: alterations of the blood-brain barrier. Ann Neurol. 1993 Sep;34(3):339–350. doi: 10.1002/ana.410340307. [DOI] [PubMed] [Google Scholar]
  40. Resnick L., Berger J. R., Shapshak P., Tourtellotte W. W. Early penetration of the blood-brain-barrier by HIV. Neurology. 1988 Jan;38(1):9–14. doi: 10.1212/wnl.38.1.9. [DOI] [PubMed] [Google Scholar]
  41. Rhodes R. H. Evidence of serum-protein leakage across the blood-brain barrier in the acquired immunodeficiency syndrome. J Neuropathol Exp Neurol. 1991 Mar;50(2):171–183. doi: 10.1097/00005072-199103000-00008. [DOI] [PubMed] [Google Scholar]
  42. Rich E. A., Chen I. S., Zack J. A., Leonard M. L., O'Brien W. A. Increased susceptibility of differentiated mononuclear phagocytes to productive infection with human immunodeficiency virus-1 (HIV-1). J Clin Invest. 1992 Jan;89(1):176–183. doi: 10.1172/JCI115559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schmidtmayerova H., Bolmont C., Baghdiguian S., Hirsch I., Chermann J. C. Distinctive pattern of infection and replication of HIV1 strains in blood-derived macrophages. Virology. 1992 Sep;190(1):124–133. doi: 10.1016/0042-6822(92)91198-4. [DOI] [PubMed] [Google Scholar]
  44. Schrier R. D., McCutchan J. A., Wiley C. A. Mechanisms of immune activation of human immunodeficiency virus in monocytes/macrophages. J Virol. 1993 Oct;67(10):5713–5720. doi: 10.1128/jvi.67.10.5713-5720.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Schuitemaker H., Koot M., Kootstra N. A., Dercksen M. W., de Goede R. E., van Steenwijk R. P., Lange J. M., Schattenkerk J. K., Miedema F., Tersmette M. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J Virol. 1992 Mar;66(3):1354–1360. doi: 10.1128/jvi.66.3.1354-1360.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schuitemaker H., Kootstra N. A., de Goede R. E., 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. doi: 10.1128/jvi.65.1.356-363.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sharer L. R. Pathology of HIV-1 infection of the central nervous system. A review. J Neuropathol Exp Neurol. 1992 Jan;51(1):3–11. doi: 10.1097/00005072-199201000-00002. [DOI] [PubMed] [Google Scholar]
  48. Sharma D. P., Zink M. C., Anderson M., Adams R., Clements J. E., Joag S. V., Narayan O. Derivation of neurotropic simian immunodeficiency virus from exclusively lymphocytetropic parental virus: pathogenesis of infection in macaques. J Virol. 1992 Jun;66(6):3550–3556. doi: 10.1128/jvi.66.6.3550-3556.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Shioda T., Levy J. A., Cheng-Mayer C. Small amino acid changes in the V3 hypervariable region of gp120 can affect the T-cell-line and macrophage tropism of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9434–9438. doi: 10.1073/pnas.89.20.9434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Smith T. W., DeGirolami U., Hénin D., Bolgert F., Hauw J. J. Human immunodeficiency virus (HIV) leukoencephalopathy and the microcirculation. J Neuropathol Exp Neurol. 1990 Jul;49(4):357–370. doi: 10.1097/00005072-199007000-00001. [DOI] [PubMed] [Google Scholar]
  51. Spector D. H., Wade E., Wright D. A., Koval V., Clark C., Jaquish D., Spector S. A. Human immunodeficiency virus pseudotypes with expanded cellular and species tropism. J Virol. 1990 May;64(5):2298–2308. doi: 10.1128/jvi.64.5.2298-2308.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Spencer D. C., Price R. W. Human immunodeficiency virus and the central nervous system. Annu Rev Microbiol. 1992;46:655–693. doi: 10.1146/annurev.mi.46.100192.003255. [DOI] [PubMed] [Google Scholar]
  53. Spencer L. T., Ogino M. T., Dankner W. M., Spector S. A. Clinical significance of human immunodeficiency virus type 1 phenotypes in infected children. J Infect Dis. 1994 Mar;169(3):491–495. doi: 10.1093/infdis/169.3.491. [DOI] [PubMed] [Google Scholar]
  54. Weiser B., Peress N., La Neve D., Eilbott D. J., Seidman R., Burger H. Human immunodeficiency virus type 1 expression in the central nervous system correlates directly with extent of disease. Proc Natl Acad Sci U S A. 1990 May;87(10):3997–4001. doi: 10.1073/pnas.87.10.3997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. de Jong J. J., Goudsmit J., Keulen W., Klaver B., Krone W., Tersmette M., de Ronde A. Human immunodeficiency virus type 1 clones chimeric for the envelope V3 domain differ in syncytium formation and replication capacity. J Virol. 1992 Feb;66(2):757–765. doi: 10.1128/jvi.66.2.757-765.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]

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