title: Human T-Lymphotropic Virus Type 1-Induced Overexpression of Activated Leukocyte Cell Adhesion Molecule (ALCAM) Facilitates Trafficking of Infected Lymphocytes through the Blood-Brain Barrier.
abstract: Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease develops upon infiltration of HTLV-1-infected lymphocytes into the central nervous system, mostly the thoracic spinal cord. The central nervous system is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. In this study, we investigated the role of activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, in the crossing of the BBB by HTLV-1-infected lymphocytes. We demonstrated that ALCAM is overexpressed on the surface of HTLV-1-infected lymphocytes, both in chronically infected cell lines and in primary infected CD4(+) T lymphocytes. ALCAM overexpression results from the activation of the canonical NF-κB pathway by the viral transactivator Tax. In contrast, staining of spinal cord sections of HAM/TSP patients showed that ALCAM expression is not altered on the BBB endothelium in the context of HTLV-1 infection. ALCAM blockade or downregulation of ALCAM levels significantly reduced the migration of HTLV-1-infected lymphocytes across a monolayer of human BBB endothelial cells. This study suggests a potential role for ALCAM in HAM/TSP pathogenesis.
  
  
  
  Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease is the consequence of the infiltration of HTLV-1-infected lymphocytes into the central nervous system (CNS), mostly the thoracic spinal cord. The CNS is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. The mechanism of migration of lymphocytes into the CNS is unclear. Here, we show that the viral transactivator Tax increases activated leukocyte cell adhesion molecule (ALCAM/CD166) expression. This molecule facilitates the migration of lymphocytes across the BBB endothelium. Targeting this molecule could be of interest in preventing or reducing the development of HAM/TSP.
authors.affiliation: Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 3569, Paris, France.|Cellule Pasteur, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Master Biosciences, Ecole Normale Supérieure (ENS) de Lyon, Lyon, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Curis
authors.affiliation: Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 3569, Paris, France.|Cellule Pasteur, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Percher
authors.affiliation: Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 3569, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Jeannin
authors.affiliation: Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 3569, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Montange
authors.affiliation: Equipe Oncogenèse Rétrovirale, ENS de Lyon, and Equipe labélisée Ligue Nationale Contre le Cancer, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR 5308, Lyon, France.
authors.forename: Sébastien A
authors.initials: SA
authors.lastname: Chevalier
authors.affiliation: Département de Neuropathologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France.
authors.forename: Danielle
authors.initials: D
authors.lastname: Seilhean
authors.affiliation: Departamento de Ciencias Neurológicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Luis
authors.initials: L
authors.lastname: Cartier
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.affiliation: Service de Neurologie, Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gout
authors.affiliation: Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 3569, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Gessain
authors.affiliation: Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 3569, Paris, France.|Cellule Pasteur, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Ceccaldi
authors.affiliation: Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, Paris, France pafonso@pasteur.fr.|Centre National de la Recherche Scientifique (CNRS) UMR 3569, Paris, France.
authors.forename: Philippe V
authors.initials: PV
authors.lastname: Afonso
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D001812:Blood-Brain Barrier; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000502:physiology* / Q000821:virology*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D042783:Endothelial Cells / Q000737:chemistry; D005326:Fetal Proteins / Q000378:metabolism*; D016356:Gene Products, tax / Q000378:metabolism; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D015703:Antigens, CD; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D016356:Gene Products, tax; D016328:NF-kappa B; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C514970:tax protein, Human T-lymphotrophic virus 1