1. Constitutive expression of stromal derived factor-1 by mucosal epithelia and its role in HIV transmission and propagation
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Mariagrazia Uguccioni, Bernhard Moser, X Y Li, Fernando Arenzana-Seisdedos, Christina M. Parker, Ellen C. Ebert, Jan Marsal, Ali Amara, William W. Agace, José L. Pablos, Thierry Delaunay, Arthur I. Roberts, Sylvia Thelen, Génomique, développement et pouvoir pathogène (GD2P), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), Immunologie Virale, Institut Pasteur [Paris] (IP), Robert Wood Johnson Medical School [Piscataway, NJ] (RWJMS), Hospital Universitario 12 de Octubre [Madrid], Universität Bern [Bern] (UNIBE), Institut National de la Recherche Agronomique (INRA), and This work was supported by grants from the Swedish Foundation for International Cooperation in Research and Higher Education (STINT) and the Swedish Medical Research Council (MFR 3131) to W.W.A., grants from the NIH to C.M.P. (DK52978) and to E.C.E. (DK42166), a grant from the Agence Nationale de Recherche sur le SIDA (ANRS) to A.A., grant 438+/050291 from the Swiss National Science Foundation to B.M., and grant 98/0356 from the Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo (FIS) to J.L.P. One of the authors of this paper, C.M.P., had a financial interest in Millennium Pharmaceuticals Inc.
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Receptors, CXCR4 ,Chemokine ,Stromal cell ,Receptors, CCR5 ,Chemokine receptor CCR5 ,[SDV]Life Sciences [q-bio] ,CXCR4 ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Chemokine receptor ,0302 clinical medicine ,Viral entry ,Humans ,Intestinal Mucosa ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,biology ,Agricultural and Biological Sciences(all) ,Biochemistry, Genetics and Molecular Biology(all) ,virus diseases ,HIV ,Virology ,Chemokine CXCL12 ,3. Good health ,VIROLOGIE ,CCL20 ,Immunology ,biology.protein ,General Agricultural and Biological Sciences ,Chemokines, CXC ,Ex vivo ,030215 immunology - Abstract
International audience; HIV particles that use the chemokine receptor CXCR4 as a coreceptor for entry into cells (X4-HIV) inefficiently transmit infection across mucosal surfaces [1], despite their presence in seminal fluid and mucosal secretions from infected individuals 2, 3, 4. In addition, although intestinal lymphocytes are susceptible to infection with either X4-HIV particles or particles that use the chemokine receptor CCR5 for viral entry (R5-HIV) during ex vivo culture [5], only systemic inoculation of R5-chimeric simian-HIV (S-HIV) results in a rapid loss of CD4+ intestinal lymphocytes in macaques [6]. The mechanisms underlying the inefficient capacity of X4-HIV to transmit infection across mucosal surfaces and to infect intestinal lymphocytes in vivo have remained elusive. The CCR5 ligands RANTES, MIP-1α and MIP-1β suppress infection by R5-HIV-1 particles via induction of CCR5 internalization, and individuals whose peripheral blood lymphocytes produce high levels of these chemokines are relatively resistant to infection 7, 8, 9. Here, we show that the CXCR4 ligand stromal derived factor-1 (SDF-1) is constitutively expressed by mucosal epithelial cells at sites of HIV transmission and propagation. Furthermore, CXCR4 is selectively downmodulated on intestinal lymphocytes within the setting of prominent SDF-1 expression. We postulate that mucosally derived SDF-1 continuously downmodulates CXCR4 on resident HIV target cells, thereby reducing the transmission and propagation of X4 HIV at mucosal sites. Moreover, such a mechanism could contribute to the delayed emergence of X4 isolates, which predominantly occurs during the later stages of the HIV infection.
- Published
- 2000
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