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. 1997 Feb;150(2):533–542.

HIV is trapped and masked in the cytoplasm of lymph node follicular dendritic cells.

C Tacchetti 1, A Favre 1, L Moresco 1, P Meszaros 1, P Luzzi 1, M Truini 1, F Rizzo 1, C E Grossi 1, E Ciccone 1
PMCID: PMC1858269  PMID: 9033269

Abstract

To gain further insight into the pathogenesis of human immunodeficiency virus (HIV) infection, lymph nodes from seven asymptomatic HIV+ subjects were analyzed during the latent phase of disease. Both ultrastructural and immunohistochemical analyses revealed that, in all of the cases, plasma cells producing IgM/gamma were present in germinal centers. Secreted immunoglobulins formed extracellular deposits mimicking the follicular dendritic cell network. Immunoglobulin produced by germinal center plasma cells are specific for HIV because they bind the HIV env protein gp 120. Plasma cells producing antibodies with the same specificity were also abundant in the extrafollicular regions of lymph nodes. During the latent phase of infection, the virus largely accumulates within the germinal centers. Therefore, extracellular immunoglobulin may form immune complexes, as shown by the presence of HIV-specific antibodies, HIV particles, and complement components C3c, C3d, and C1q in the interdendritic spaces. When the ultrastructural localization of HIV in germinal centers was analyzed, abundant virus particles were found in the interdendritic spaces. In addition to this extracellular localization of HIV, receptor-mediated endocytosis of viral particles by follicular dendritic cells was observed. Complete HIV particles were found within the endosomal compartment of the follicular dendritic cells and, as complete viral particles, free in the cytoplasm, indicating that the virus may escape from the endocytic compartment. As the virus is abundant in the cytoplasm, this event leads to formation of a hidden reservoir within follicular dendritic cells. In this location, HIV escapes recognition by cytotoxic T lymphocytes. In contrast, virus budding indicating a productive infection of follicular dendritic cells that would render them susceptible to T-cell-mediated lysis has been seldom observed.

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Selected References

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

  1. Albini A., Fontanini G., Masiello L., Tacchetti C., Bigini D., Luzzi P., Noonan D. M., Stetler-Stevenson W. G. Angiogenic potential in vivo by Kaposi's sarcoma cell-free supernatants and HIV-1 tat product: inhibition of KS-like lesions by tissue inhibitor of metalloproteinase-2. AIDS. 1994 Sep;8(9):1237–1244. doi: 10.1097/00002030-199409000-00004. [DOI] [PubMed] [Google Scholar]
  2. Baier M., Werner A., Bannert N., Metzner K., Kurth R. HIV suppression by interleukin-16. Nature. 1995 Dec 7;378(6557):563–563. doi: 10.1038/378563a0. [DOI] [PubMed] [Google Scholar]
  3. Briault S., Courtois-Capella M., Duarte F., Aucouturier P., Preud'Homme J. L. Isotypy of serum monoclonal immunoglobulins in human immunodeficiency virus-infected adults. Clin Exp Immunol. 1988 Nov;74(2):182–184. [PMC free article] [PubMed] [Google Scholar]
  4. Cordell J. L., Falini B., Erber W. N., Ghosh A. K., Abdulaziz Z., MacDonald S., Pulford K. A., Stein H., Mason D. Y. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem. 1984 Feb;32(2):219–229. doi: 10.1177/32.2.6198355. [DOI] [PubMed] [Google Scholar]
  5. Embretson J., Zupancic M., Ribas J. L., Burke A., Racz P., Tenner-Racz K., Haase A. T. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993 Mar 25;362(6418):359–362. doi: 10.1038/362359a0. [DOI] [PubMed] [Google Scholar]
  6. Fauci A. S. HIV. An elusive soluble suppressor. Nature. 1995 Dec 7;378(6557):561–561. doi: 10.1038/378561a0. [DOI] [PubMed] [Google Scholar]
  7. Gelderblom H. R. Assembly and morphology of HIV: potential effect of structure on viral function. AIDS. 1991 Jun;5(6):617–637. [PubMed] [Google Scholar]
  8. Grewe C., Beck A., Gelderblom H. R. HIV: early virus-cell interactions. J Acquir Immune Defic Syndr. 1990;3(10):965–974. [PubMed] [Google Scholar]
  9. Holder M. J., Abbot S. D., Milner A. E., Gregory C. D., Casamayor M., Johnson G. D., MacLennan I. C., Gordon J. IL-2 expands and maintains IgM plasmablasts from a CD5+ subset contained within the germinal centre cell-enriched (surface IgD-/CD39- buoyant) fraction of human tonsil. Int Immunol. 1993 Sep;5(9):1059–1066. doi: 10.1093/intimm/5.9.1059. [DOI] [PubMed] [Google Scholar]
  10. Joling P., Bakker L. J., Van Strijp J. A., Meerloo T., de Graaf L., Dekker M. E., Goudsmit J., Verhoef J., Schuurman H. J. Binding of human immunodeficiency virus type-1 to follicular dendritic cells in vitro is complement dependent. J Immunol. 1993 Feb 1;150(3):1065–1073. [PubMed] [Google Scholar]
  11. Koopman G., Pals S. T. Cellular interactions in the germinal center: role of adhesion receptors and significance for the pathogenesis of AIDS and malignant lymphoma. Immunol Rev. 1992 Apr;126:21–45. doi: 10.1111/j.1600-065x.1992.tb00629.x. [DOI] [PubMed] [Google Scholar]
  12. MacLennan I. C. Germinal centers. Annu Rev Immunol. 1994;12:117–139. doi: 10.1146/annurev.iy.12.040194.001001. [DOI] [PubMed] [Google Scholar]
  13. MacLennan I. C., Liu Y. J., Johnson G. D. Maturation and dispersal of B-cell clones during T cell-dependent antibody responses. Immunol Rev. 1992 Apr;126:143–161. doi: 10.1111/j.1600-065x.1992.tb00635.x. [DOI] [PubMed] [Google Scholar]
  14. Moore J. P., Koup R. A. Chemoattractants attract HIV researchers. J Exp Med. 1996 Aug 1;184(2):311–313. doi: 10.1084/jem.184.2.311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Müller S., Wang H., Silverman G. J., Bramlet G., Haigwood N., Köhler H. B-cell abnormalities in AIDS: stable and clonally-restricted antibody response in HIV-1 infection. Scand J Immunol. 1993 Oct;38(4):327–334. doi: 10.1111/j.1365-3083.1993.tb01734.x. [DOI] [PubMed] [Google Scholar]
  16. Pantaleo G., Fauci A. S. New concepts in the immunopathogenesis of HIV infection. Annu Rev Immunol. 1995;13:487–512. doi: 10.1146/annurev.iy.13.040195.002415. [DOI] [PubMed] [Google Scholar]
  17. Pantaleo G., Graziosi C., Demarest J. F., Butini L., Montroni M., Fox C. H., Orenstein J. M., Kotler D. P., Fauci A. S. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. doi: 10.1038/362355a0. [DOI] [PubMed] [Google Scholar]
  18. Pantaleo G., Graziosi C., Demarest J. F., Cohen O. J., Vaccarezza M., Gantt K., Muro-Cacho C., Fauci A. S. Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol Rev. 1994 Aug;140:105–130. doi: 10.1111/j.1600-065x.1994.tb00867.x. [DOI] [PubMed] [Google Scholar]
  19. Phillips D. M., Tan X. HIV-1 infection of the trophoblast cell line BeWo: a study of virus uptake. AIDS Res Hum Retroviruses. 1992 Sep;8(9):1683–1691. doi: 10.1089/aid.1992.8.1683. [DOI] [PubMed] [Google Scholar]
  20. Schmitz J., van Lunzen J., Tenner-Racz K., Grossschupff G., Racz P., Schmitz H., Dietrich M., Hufert F. T. Follicular dendritic cells retain HIV-1 particles on their plasma membrane, but are not productively infected in asymptomatic patients with follicular hyperplasia. J Immunol. 1994 Aug 1;153(3):1352–1359. [PubMed] [Google Scholar]
  21. Tenner-Racz K., Racz P., Bofill M., Schulz-Meyer A., Dietrich M., Kern P., Weber J., Pinching A. J., Veronese-Dimarzo F., Popovic M. HTLV-III/LAV viral antigens in lymph nodes of homosexual men with persistent generalized lymphadenopathy and AIDS. Am J Pathol. 1986 Apr;123(1):9–15. [PMC free article] [PubMed] [Google Scholar]
  22. Tenner-Racz K., Racz P., Thomé C., Meyer C. G., Anderson P. J., Schlossman S. F., Letvin N. L. Cytotoxic effector cell granules recognized by the monoclonal antibody TIA-1 are present in CD8+ lymphocytes in lymph nodes of human immunodeficiency virus-1-infected patients. Am J Pathol. 1993 Jun;142(6):1750–1758. [PMC free article] [PubMed] [Google Scholar]
  23. Tenner-Racz K., von Stemm A. M., Gühlk B., Schmitz J., Racz P. Are follicular dendritic cells, macrophages and interdigitating cells of the lymphoid tissue productively infected by HIV? Res Virol. 1994 May-Aug;145(3-4):177–182. doi: 10.1016/s0923-2516(07)80020-3. [DOI] [PubMed] [Google Scholar]
  24. Velardi A., Mingari M. C., Moretta L., Grossi C. E. Functional analysis of cloned germinal center CD4+ cells with natural killer cell-related features. Divergence from typical T helper cells. J Immunol. 1986 Nov 1;137(9):2808–2813. [PubMed] [Google Scholar]
  25. Velardi A., Tilden A. B., Millo R., Grossi C. E. Isolation and characterization of Leu 7+ germinal-center cells with the T helper-cell phenotype and granular lymphocyte morphology. J Clin Immunol. 1986 May;6(3):205–215. doi: 10.1007/BF00918700. [DOI] [PubMed] [Google Scholar]

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