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. 1997 Mar;71(3):2114–2119. doi: 10.1128/jvi.71.3.2114-2119.1997

Constitutive expression of p50 homodimer in freshly isolated human monocytes decreases with in vitro and in vivo differentiation: a possible mechanism influencing human immunodeficiency virus replication in monocytes and mature macrophages.

S R Lewin 1, P Lambert 1, N J Deacon 1, J Mills 1, S M Crowe 1
PMCID: PMC191307  PMID: 9032344

Abstract

Human immunodeficiency virus type 1 (HIV-1) replicates more efficiently in vitro in differentiated macrophages than in freshly isolated monocytes. We investigated whether this may be partly explained by changes in expression of NF-kappaB with monocyte differentiation. We demonstrated that constitutive expression of NF-kappaB in primary human monocytes changed significantly with differentiation in vitro to monocyte-derived macrophages (MDMs) and differentiation in vivo to alveolar macrophages (AMs). Freshly isolated monocytes constitutively expressed high levels of transcriptionally inactive p50 homodimer which decreased with time in culture in favor of the transcriptionally active p50/p65 and p50/RelB heterodimers. As in MDMs, AMs constitutively expressed p50/p65 and p50/RelB although at lower levels. HIV infection of fresh monocytes failed to induce p50/p65 as seen in MDMs. The replacement of p50 homodimers with transcriptionally active heterodimers following time in culture may partially explain the progressive increase in susceptibility of monocytes to HIV infection during in vitro culture. The change in NF-kappaB components with monocyte differentiation in vivo may also explain the different transcriptional activities of these cell populations in HIV-infected individuals.

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Selected References

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  1. Bachelerie F., Alcami J., Arenzana-Seisdedos F., Virelizier J. L. HIV enhancer activity perpetuated by NF-kappa B induction on infection of monocytes. Nature. 1991 Apr 25;350(6320):709–712. doi: 10.1038/350709a0. [DOI] [PubMed] [Google Scholar]
  2. Baeuerle P. A., Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. doi: 10.1146/annurev.iy.12.040194.001041. [DOI] [PubMed] [Google Scholar]
  3. Ballard D. W., Dixon E. P., Peffer N. J., Bogerd H., Doerre S., Stein B., Greene W. C. The 65-kDa subunit of human NF-kappa B functions as a potent transcriptional activator and a target for v-Rel-mediated repression. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1875–1879. doi: 10.1073/pnas.89.5.1875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bellas R. E., Hopkins N., Li Y. The NF-kappa B binding site is necessary for efficient replication of simian immunodeficiency virus of macaques in primary macrophages but not in T cells in vitro. J Virol. 1993 May;67(5):2908–2913. doi: 10.1128/jvi.67.5.2908-2913.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Crowe S., Mills J., McGrath M. S. Quantitative immunocytofluorographic analysis of CD4 surface antigen expression and HIV infection of human peripheral blood monocyte/macrophages. AIDS Res Hum Retroviruses. 1987 Summer;3(2):135–145. doi: 10.1089/aid.1987.3.135. [DOI] [PubMed] [Google Scholar]
  6. Franzoso G., Biswas P., Poli G., Carlson L. M., Brown K. D., Tomita-Yamaguchi M., Fauci A. S., Siebenlist U. K. A family of serine proteases expressed exclusively in myelo-monocytic cells specifically processes the nuclear factor-kappa B subunit p65 in vitro and may impair human immunodeficiency virus replication in these cells. J Exp Med. 1994 Oct 1;180(4):1445–1456. doi: 10.1084/jem.180.4.1445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Franzoso G., Bours V., Azarenko V., Park S., Tomita-Yamaguchi M., Kanno T., Brown K., Siebenlist U. The oncoprotein Bcl-3 can facilitate NF-kappa B-mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites. EMBO J. 1993 Oct;12(10):3893–3901. doi: 10.1002/j.1460-2075.1993.tb06067.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Franzoso G., Bours V., Park S., Tomita-Yamaguchi M., Kelly K., Siebenlist U. The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-kappa B-mediated inhibition. Nature. 1992 Sep 24;359(6393):339–342. doi: 10.1038/359339a0. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Griffin G. E., Leung K., Folks T. M., Kunkel S., Nabel G. J. Activation of HIV gene expression during monocyte differentiation by induction of NF-kappa B. Nature. 1989 May 4;339(6219):70–73. doi: 10.1038/339070a0. [DOI] [PubMed] [Google Scholar]
  11. Haskill S., Beg A. A., Tompkins S. M., Morris J. S., Yurochko A. D., Sampson-Johannes A., Mondal K., Ralph P., Baldwin A. S., Jr Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity. Cell. 1991 Jun 28;65(7):1281–1289. doi: 10.1016/0092-8674(91)90022-q. [DOI] [PubMed] [Google Scholar]
  12. Hazan U., Thomas D., Alcami J., Bachelerie F., Israel N., Yssel H., Virelizier J. L., Arenzana-Seisdedos F. Stimulation of a human T-cell clone with anti-CD3 or tumor necrosis factor induces NF-kappa B translocation but not human immunodeficiency virus 1 enhancer-dependent transcription. Proc Natl Acad Sci U S A. 1990 Oct;87(20):7861–7865. doi: 10.1073/pnas.87.20.7861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jabado N., Le Deist F., Fisher A., Hivroz C. Interaction of HIV gp120 and anti-CD4 antibodies with the CD4 molecule on human CD4+ T cells inhibits the binding activity of NF-AT, NF-kappa B and AP-1, three nuclear factors regulating interleukin-2 gene enhancer activity. Eur J Immunol. 1994 Nov;24(11):2646–2652. doi: 10.1002/eji.1830241112. [DOI] [PubMed] [Google Scholar]
  14. Kalter D. C., Nakamura M., Turpin J. A., Baca L. M., Hoover D. L., Dieffenbach C., Ralph P., Gendelman H. E., Meltzer M. S. Enhanced HIV replication in macrophage colony-stimulating factor-treated monocytes. J Immunol. 1991 Jan 1;146(1):298–306. [PubMed] [Google Scholar]
  15. Kazazi F., Mathijs J. M., Foley P., Cunningham A. L. Variations in CD4 expression by human monocytes and macrophages and their relationships to infection with the human immunodeficiency virus. J Gen Virol. 1989 Oct;70(Pt 10):2661–2672. doi: 10.1099/0022-1317-70-10-2661. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. 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]
  18. Lee T. H., Sunzeri F. J., Tobler L. H., Williams B. G., Busch M. P. Quantitative assessment of HIV-1 DNA load by coamplification of HIV-1 gag and HLA-DQ-alpha genes. AIDS. 1991 Jun;5(6):683–691. doi: 10.1097/00002030-199106000-00007. [DOI] [PubMed] [Google Scholar]
  19. Lewin S. R., Sonza S., Irving L. B., McDonald C. F., Mills J., Crowe S. M. Surface CD4 is critical to in vitro HIV infection of human alveolar macrophages. AIDS Res Hum Retroviruses. 1996 Jul 1;12(10):877–883. doi: 10.1089/aid.1996.12.877. [DOI] [PubMed] [Google Scholar]
  20. McElhinny J. A., MacMorran W. S., Bren G. D., Ten R. M., Israel A., Paya C. V. Regulation of I kappa B alpha and p105 in monocytes and macrophages persistently infected with human immunodeficiency virus. J Virol. 1995 Mar;69(3):1500–1509. doi: 10.1128/jvi.69.3.1500-1509.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Moses A. V., Ibanez C., Gaynor R., Ghazal P., Nelson J. A. Differential role of long terminal repeat control elements for the regulation of basal and Tat-mediated transcription of the human immunodeficiency virus in stimulated and unstimulated primary human macrophages. J Virol. 1994 Jan;68(1):298–307. doi: 10.1128/jvi.68.1.298-307.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nabel G., Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. doi: 10.1038/326711a0. [DOI] [PubMed] [Google Scholar]
  23. Oakes J. W., Bagasra O., Duan L., Pomerantz R. J. Association of alterations in NF-kappa B moieties with HIV type 1 proviral latency in certain monocytic cells. AIDS Res Hum Retroviruses. 1994 Oct;10(10):1213–1219. doi: 10.1089/aid.1994.10.1213. [DOI] [PubMed] [Google Scholar]
  24. Olafsson K., Smith M. S., Marshburn P., Carter S. G., Haskill S. Variation of HIV infectibility of macrophages as a function of donor, stage of differentiation, and site of origin. J Acquir Immune Defic Syndr. 1991;4(2):154–164. [PubMed] [Google Scholar]
  25. Paya C. V., Ten R. M., Bessia C., Alcami J., Hay R. T., Virelizier J. L. NF-kappa B-dependent induction of the NF-kappa B p50 subunit gene promoter underlies self-perpetuation of human immunodeficiency virus transcription in monocytic cells. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7826–7830. doi: 10.1073/pnas.89.16.7826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Perkins N. D., Schmid R. M., Duckett C. S., Leung K., Rice N. R., Nabel G. J. Distinct combinations of NF-kappa B subunits determine the specificity of transcriptional activation. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1529–1533. doi: 10.1073/pnas.89.5.1529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Poli G., Kinter A. L., Fauci A. S. Interleukin 1 induces expression of the human immunodeficiency virus alone and in synergy with interleukin 6 in chronically infected U1 cells: inhibition of inductive effects by the interleukin 1 receptor antagonist. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):108–112. doi: 10.1073/pnas.91.1.108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Raziuddin, Mikovits J. A., Calvert I., Ghosh S., Kung H. F., Ruscetti F. W. Negative regulation of human immunodeficiency virus type 1 expression in monocytes: role of the 65-kDa plus 50-kDa NF-kappa B dimer. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9426–9430. doi: 10.1073/pnas.88.21.9426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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]
  31. Roulston A., Beauparlant P., Rice N., Hiscott J. Chronic human immunodeficiency virus type 1 infection stimulates distinct NF-kappa B/rel DNA binding activities in myelomonoblastic cells. J Virol. 1993 Sep;67(9):5235–5246. doi: 10.1128/jvi.67.9.5235-5246.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Roulston A., D'Addario M., Boulerice F., Caplan S., Wainberg M. A., Hiscott J. Induction of monocytic differentiation and NF-kappa B-like activities by human immunodeficiency virus 1 infection of myelomonoblastic cells. J Exp Med. 1992 Mar 1;175(3):751–763. doi: 10.1084/jem.175.3.751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Roulston A., Lin R., Beauparlant P., Wainberg M. A., Hiscott J. Regulation of human immunodeficiency virus type 1 and cytokine gene expression in myeloid cells by NF-kappa B/Rel transcription factors. Microbiol Rev. 1995 Sep;59(3):481–505. doi: 10.1128/mr.59.3.481-505.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schmitz M. L., Baeuerle P. A. The p65 subunit is responsible for the strong transcription activating potential of NF-kappa B. EMBO J. 1991 Dec;10(12):3805–3817. doi: 10.1002/j.1460-2075.1991.tb04950.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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]
  36. Schuitemaker H., Kootstra N. A., Koppelman M. H., Bruisten S. M., Huisman H. G., Tersmette M., Miedema F. Proliferation-dependent HIV-1 infection of monocytes occurs during differentiation into macrophages. J Clin Invest. 1992 Apr;89(4):1154–1160. doi: 10.1172/JCI115697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sierra-Madero J. G., Toossi Z., Hom D. L., Finegan C. K., Hoenig E., Rich E. A. 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 Jan;169(1):18–27. doi: 10.1093/infdis/169.1.18. [DOI] [PubMed] [Google Scholar]
  38. Sonza S., Maerz A., Deacon N., Meanger J., Mills J., Crowe S. Human immunodeficiency virus type 1 replication is blocked prior to reverse transcription and integration in freshly isolated peripheral blood monocytes. J Virol. 1996 Jun;70(6):3863–3869. doi: 10.1128/jvi.70.6.3863-3869.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sonza S., Maerz A., Uren S., Violo A., Hunter S., Boyle W., Crowe S. Susceptibility of human monocytes to HIV type 1 infection in vitro is not dependent on their level of CD4 expression. AIDS Res Hum Retroviruses. 1995 Jul;11(7):769–776. doi: 10.1089/aid.1995.11.769. [DOI] [PubMed] [Google Scholar]
  40. Suzan M., Salaun D., Neuveut C., Spire B., Hirsch I., Le Bouteiller P., Querat G., Sire J. Induction of NF-KB during monocyte differentiation by HIV type 1 infection. J Immunol. 1991 Jan 1;146(1):377–383. [PubMed] [Google Scholar]
  41. Valentin A., Von Gegerfelt A., Matsuda S., Nilsson K., Asjö B. In vitro maturation of mononuclear phagocytes and susceptibility to HIV-1 infection. J Acquir Immune Defic Syndr. 1991;4(8):751–759. [PubMed] [Google Scholar]

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