title: Impairment of CCR6+ and CXCR3+ Th Cell Migration in HIV-1 Infection Is Rescued by Modulating Actin Polymerization.
abstract: CD4+T cell repopulation of the gut is rarely achieved in HIV-1-infected individuals who are receiving clinically effective antiretroviral therapy. Alterations in the integrity of the mucosal barrier have been indicated as a cause for chronic immune activation and disease progression. In this study, we present evidence that persistent immune activation causes impairment of lymphocytes to respond to chemotactic stimuli, thus preventing their trafficking from the blood stream to peripheral organs. CCR6+and CXCR3+Th cells accumulate in the blood of aviremic HIV-1-infected patients on long-term antiretroviral therapy, and their frequency in the circulation positively correlates to levels of soluble CD14 in plasma, a marker of chronic immune activation. Th cells show an impaired response to chemotactic stimuli both in humans and in the pathogenic model of SIV infection, and this defect is due to hyperactivation of cofilin and inefficient actin polymerization. Taking advantage of a murine model of chronic immune activation, we demonstrate that cytoskeleton remodeling, induced by okadaic acid, restores lymphocyte migration in response to chemokines, both in vitro and in vivo. This study calls for novel pharmacological approaches in those pathological conditions characterized by persistent immune activation and loss of trafficking of T cell subsets to niches that sustain their maturation and activities.
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, 6500 Bellinzona, Switzerland; mariagrazia.uguccioni@irb.usi.ch valentina.cecchinato@irb.usi.ch.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cecchinato
authors.affiliation: Division of Infectious Diseases, Regional Hospital, 6903 Lugano, Switzerland.
authors.forename: Enos
authors.initials: E
authors.lastname: Bernasconi
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Speck
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, 6500 Bellinzona, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Proietti
authors.affiliation: Unit of Infection Models, German Primate Center, 37077 Göttingen, Germany.
authors.forename: Ulrike
authors.identifier: 0000-0001-6229-046X
authors.initials: U
authors.lastname: Sauermann
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, 6500 Bellinzona, Switzerland.
authors.forename: Gianluca
authors.initials: G
authors.lastname: D'Agostino
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, 6500 Bellinzona, Switzerland.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Danelon
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, 6500 Bellinzona, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Rezzonico Jost
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, 6500 Bellinzona, Switzerland.|Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grassi
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, 6500 Bellinzona, Switzerland.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Raeli
authors.affiliation: Swiss HIV Cohort Study Data Center, University Hospital, 1011 Lausanne, Switzerland; and.
authors.forename: Franziska
authors.initials: F
authors.lastname: Schöni-Affolter
authors.affiliation: Unit of Infection Models, German Primate Center, 37077 Göttingen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Stahl-Hennig
authors.affiliation: Institute for Research in Biomedicine, University of Italian Switzerland, 6500 Bellinzona, Switzerland; mariagrazia.uguccioni@irb.usi.ch valentina.cecchinato@irb.usi.ch.|Department of Biomedical Sciences, Humanitas University, 20089 Milan, Italy.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Uguccioni
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003599:Cytoskeleton / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D007150:Immunohistochemistry; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D058105:Polymerization; D060888:Real-Time Polymerase Chain Reaction; D054399:Receptors, CCR6 / Q000276:immunology; D054367:Receptors, CXCR3 / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D000199:Actins; C106311:CCR6 protein, human; C515187:CXCR3 protein, human; D054399:Receptors, CCR6; D054367:Receptors, CXCR3