title: Downmodulation of CCR7 by HIV-1 Vpu results in impaired migration and chemotactic signaling within CD4⁺ T cells.
abstract: The chemokine receptor CCR7 plays a crucial role in the homing of central memory and naive T cells to peripheral lymphoid organs. Here, we show that the HIV-1 accessory protein Vpu downregulates CCR7 on the surface of CD4(+) T cells. Vpu and CCR7 were found to specifically interact and colocalize within the trans-Golgi network, where CCR7 is retained. Downmodulation of CCR7 did not involve degradation or endocytosis and was strictly dependent on Vpu expression. Stimulation of HIV-1-infected primary CD4(+) T cells with the CCR7 ligand CCL19 resulted in reduced mobilization of Ca(2+), reduced phosphorylation of Erk1/2, and impaired migration toward CCL19. Specific amino acid residues within the transmembrane domain of Vpu that were previously shown to be critical for BST-2 downmodulation (A14, A18, and W22) were also necessary for CCR7 downregulation. These results suggest that BST-2 and CCR7 may be downregulated via similar mechanisms.
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Ramirez
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; School of Medicine, Università Vita-Salute San Raffaele, 20132 Milan, Italy; AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Marylinda
authors.initials: M
authors.lastname: Famiglietti
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Bharatwaj
authors.initials: B
authors.lastname: Sowrirajan
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Ana Beatriz
authors.initials: AB
authors.lastname: DePaula-Silva
authors.affiliation: Department of Core Facilities, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Rodesch
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Barker
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address: vicente.planelles@path.utah.edu.
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002465:Cell Movement / Q000276:immunology*; D054415:Chemokine CCL19 / Q000276:immunology / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D015536:Down-Regulation; D057809:HEK293 Cells; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000276:immunology*; D006801:Humans; D008024:Ligands; D054400:Receptors, CCR7 / Q000276:immunology*; D054334:Viral Regulatory and Accessory Proteins / Q000276:immunology*; D000086082:Viroporin Proteins
chemical_list: D054415:Chemokine CCL19; D054298:Human Immunodeficiency Virus Proteins; D008024:Ligands; D054400:Receptors, CCR7; D054334:Viral Regulatory and Accessory Proteins; C515460:CCL19 protein, human; C515370:CCR7 protein, human; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins