Abstract
Human immunodeficiency virus type 1 (HIV-1) infection causes progressive depletion of CD4/HIV-receptor-positive T helper lymphocytes, ultimately leading to AIDS. The major HIV reservoir and site of T-helper cell infection in lymphoid tissues, however, has remained poorly defined. The authors used in situ hybridization in combination with immunohistologic labeling techniques to identify the phenotype of HIV-infected cells in lymph nodes from patients at different stages of HIV-infection. The number of HIV-infected macrophages, widely considered the major site of HIV replication, was extremely low. There was no evidence for HIV-infection of endothelial and interdigitating reticulum cells. However, HIV RNA was found in small but consistent proportions of CD45RO-positive T cells and in the vast majority of follicular dendritic cells (FDC) in a pattern suggestive of active infection in addition to HIV-immunocomplex trapping on cell membranes. FDC may therefore be a major HIV reservoir and since T-helper cells travel through the FDC meshwork during their migration within lymphoreticular tissues, it appears likely that HIV-replicating T cells may infect FDC, which then infect new T cells, thus causing a gradual dissemination of the virus to all FDC and thereby a steadily increasing infection of T-helper/memory cells within germinal centers. This results in CD4+ T cell depletion, and ultimately, in immunodeficiency.
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- 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]
- Baroni C. D., Pezzella F., Pezzella M., Macchi B., Vitolo D., Uccini S., Ruco L. P. Expression of HIV in lymph node cells of LAS patients. Immunohistology, in situ hybridization, and identification of target cells. Am J Pathol. 1988 Dec;133(3):498–506. [PMC free article] [PubMed] [Google Scholar]
- Berti E., Aversa G. G., Soligo D., Cattoretti G., Delia D., Aiello A., Parravicini C., Hall B. M., Caputo R. A6--a new 45RO monoclonal antibody for immunostaining of paraffin-embedded tissues. Am J Clin Pathol. 1991 Feb;95(2):188–193. doi: 10.1093/ajcp/95.2.188. [DOI] [PubMed] [Google Scholar]
- Biberfeld P., Chayt K. J., Marselle L. M., Biberfeld G., Gallo R. C., Harper M. E. HTLV-III expression in infected lymph nodes and relevance to pathogenesis of lymphadenopathy. Am J Pathol. 1986 Dec;125(3):436–442. [PMC free article] [PubMed] [Google Scholar]
- Freedman A. S., Munro J. M., Rice G. E., Bevilacqua M. P., Morimoto C., McIntyre B. W., Rhynhart K., Pober J. S., Nadler L. M. Adhesion of human B cells to germinal centers in vitro involves VLA-4 and INCAM-110. Science. 1990 Aug 31;249(4972):1030–1033. doi: 10.1126/science.1697696. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Gerdes J., Van Baarlen J., Pileri S., Schwarting R., Van Unnik J. A., Stein H. Tumor cell growth fraction in Hodgkin's disease. Am J Pathol. 1987 Sep;128(3):390–393. [PMC free article] [PubMed] [Google Scholar]
- Hahn B. H., Shaw G. M., Arya S. K., Popovic M., Gallo R. C., Wong-Staal F. Molecular cloning and characterization of the HTLV-III virus associated with AIDS. Nature. 1984 Nov 8;312(5990):166–169. doi: 10.1038/312166a0. [DOI] [PubMed] [Google Scholar]
- Harper M. E., Marselle L. M., Gallo R. C., Wong-Staal F. Detection of lymphocytes expressing human T-lymphotropic virus type III in lymph nodes and peripheral blood from infected individuals by in situ hybridization. Proc Natl Acad Sci U S A. 1986 Feb;83(3):772–776. doi: 10.1073/pnas.83.3.772. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hildreth J. E., Orentas R. J. Involvement of a leukocyte adhesion receptor (LFA-1) in HIV-induced syncytium formation. Science. 1989 Jun 2;244(4908):1075–1078. doi: 10.1126/science.2543075. [DOI] [PubMed] [Google Scholar]
- Höfler H., Pütz B., Ruhri C., Wirnsberger G., Klimpfinger M., Smolle J. Simultaneous localization of calcitonin mRNA and peptide in a medullary thyroid carcinoma. Virchows Arch B Cell Pathol Incl Mol Pathol. 1987;54(3):144–151. doi: 10.1007/BF02899206. [DOI] [PubMed] [Google Scholar]
- 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]
- Michie S. A., Rouse R. V. Study of murine T cell migration using the Thy-1 allotypic marker. Demonstration of antigen-specific homing to lymph node germinal centers. Transplantation. 1988 Jul;46(1):98–104. doi: 10.1097/00007890-198807000-00018. [DOI] [PubMed] [Google Scholar]
- Miedema F., Tersmette M., van Lier R. A. AIDS pathogenesis: a dynamic interaction between HIV and the immune system. Immunol Today. 1990 Aug;11(8):293–297. doi: 10.1016/0167-5699(90)90116-q. [DOI] [PubMed] [Google Scholar]
- Milani S., Herbst H., Schuppan D., Hahn E. G., Stein H. In situ hybridization for procollagen types I, III and IV mRNA in normal and fibrotic rat liver: evidence for predominant expression in nonparenchymal liver cells. Hepatology. 1989 Jul;10(1):84–92. doi: 10.1002/hep.1840100117. [DOI] [PubMed] [Google Scholar]
- Morrow W. J., Wharton M., Stricker R. B., Levy J. A. Circulating immune complexes in patients with acquired immune deficiency syndrome contain the AIDS-associated retrovirus. Clin Immunol Immunopathol. 1986 Sep;40(3):515–524. doi: 10.1016/0090-1229(86)90196-0. [DOI] [PubMed] [Google Scholar]
- Niedrig M., Rabanus J. P., L'Age Stehr J., Gelderblom H. R., Pauli G. Monoclonal antibodies directed against human immunodeficiency virus (HIV) gag proteins with specificity for conserved epitopes in HIV-1, HIV-2 and simian immunodeficiency virus. J Gen Virol. 1988 Aug;69(Pt 8):2109–2114. doi: 10.1099/0022-1317-69-8-2109. [DOI] [PubMed] [Google Scholar]
- Ost A., Baroni C. D., Biberfeld P., Diebold J., Moragas A., Noël H., Pallesen G., Rácz P., Schipper M., Tenner-Rácz K. Lymphadenopathy in HIV infection: histological classification and staging. APMIS Suppl. 1989;8:7–15. [PubMed] [Google Scholar]
- Parmentier H. K., van Wichen D., Sie-Go D. M., Goudsmit J., Borleffs J. C., Schuurman H. J. HIV-1 infection and virus production in follicular dendritic cells in lymph nodes. A case report, with analysis of isolated follicular dendritic cells. Am J Pathol. 1990 Aug;137(2):247–251. [PMC free article] [PubMed] [Google Scholar]
- Petrasch S., Perez-Alvarez C., Schmitz J., Kosco M., Brittinger G. Antigenic phenotyping of human follicular dendritic cells isolated from nonmalignant and malignant lymphatic tissue. Eur J Immunol. 1990 May;20(5):1013–1018. doi: 10.1002/eji.1830200510. [DOI] [PubMed] [Google Scholar]
- Rieckmann P., Poli G., Kehrl J. H., Fauci A. S. Activated B lymphocytes from human immunodeficiency virus-infected individuals induce virus expression in infected T cells and a promonocytic cell line, U1. J Exp Med. 1991 Jan 1;173(1):1–5. doi: 10.1084/jem.173.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ryffel B., Brockhaus M., Dürmüller U., Gudat F. Tumor necrosis factor receptors in lymphoid tissues and lymphomas. Source and site of action of tumor necrosis factor alpha. Am J Pathol. 1991 Jul;139(1):7–15. [PMC free article] [PubMed] [Google Scholar]
- Schnittman S. M., Lane H. C., Greenhouse J., Justement J. S., Baseler M., Fauci A. S. Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6058–6062. doi: 10.1073/pnas.87.16.6058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schriever F., Freedman A. S., Freeman G., Messner E., Lee G., Daley J., Nadler L. M. Isolated human follicular dendritic cells display a unique antigenic phenotype. J Exp Med. 1989 Jun 1;169(6):2043–2058. doi: 10.1084/jem.169.6.2043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schuurman H. J., Krone W. J., Broekhuizen R., Goudsmit J. Expression of RNA and antigens of human immunodeficiency virus type-1 (HIV-1) in lymph nodes from HIV-1 infected individuals. Am J Pathol. 1988 Dec;133(3):516–524. [PMC free article] [PubMed] [Google Scholar]
- Sellheyer K., Schwarting R., Stein H. Isolation and antigenic profile of follicular dendritic cells. Clin Exp Immunol. 1989 Dec;78(3):431–436. [PMC free article] [PubMed] [Google Scholar]
- Stahmer I., Zimmer J. P., Ernst M., Fenner T., Finnern R., Schmitz H., Flad H. D., Gerdes J. Isolation of normal human follicular dendritic cells and CD4-independent in vitro infection by human immunodeficiency virus (HIV-1). Eur J Immunol. 1991 Aug;21(8):1873–1878. doi: 10.1002/eji.1830210814. [DOI] [PubMed] [Google Scholar]
- Stein H., Gatter K., Asbahr H., Mason D. Y. Use of freeze-dried paraffin-embedded sections for immunohistologic staining with monoclonal antibodies. Lab Invest. 1985 Jun;52(6):676–683. [PubMed] [Google Scholar]
- 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]
- Tenner-Rácz K., Rácz P., Schmidt H., Dietrich M., Kern P., Louie A., Gartner S., Popovic M. Immunohistochemical, electron microscopic and in situ hybridization evidence for the involvement of lymphatics in the spread of HIV-1. AIDS. 1988 Aug;2(4):299–309. doi: 10.1097/00002030-198808000-00010. [DOI] [PubMed] [Google Scholar]
- Williamson D. J. Specificity of riboprobes for intracellular RNA in hybridization histochemistry. J Histochem Cytochem. 1988 Jul;36(7):811–813. doi: 10.1177/36.7.2454986. [DOI] [PubMed] [Google Scholar]


