title: The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration.
abstract: Indinavir (IDV) is a protease inhibitor that successfully suppresses HIV-1 replication as part of anti-retroviral therapy. There is evidence to suggest that IDV may also act non-specifically upon host proteases. In this study we investigated whether IDV could modulate protease-dependent molecules involved in dendritic cell (DC) migration - a pivotal process in immunoregulation. Human monocyte-derived DC were exposed to IDV (IDV-DC) and transendothelial migration (TEM) to inflammatory chemokines was determined. TEM of IDV-DC was significantly impaired compared to non-treated DC (p<0.01). Phenotypic analysis revealed that IDV-DC had reduced DC-SIGN expression, correlating with reduced adhesion to immobilized ICAM-2. Nevertheless, the reduction in migration following exposure to IDV could not be fully attributable to DC-SIGN interactions alone. Investigation of IDV-DC interactions with the underlying matrix protein, fibronectin, demonstrated that IDV significantly impaired DC binding to immobilized fibronectin (p<0.01). IDV appeared to act upon VLA-4 and VLA-5 since addition of antagonist monoclonal antibodies (mAb) similarly reduced adhesion of non-treated DC to fibronectin. Combined blockade of DC using anti-VLA-4, VLA-5 and anti-DC-SIGN mAb inhibited TEM to a similar extent as IDV. Our results strongly suggest that IDV inhibits host proteases necessary for DC migration and may, therefore, affect DC immunoregulation in HIV-1-infected patients.
authors.affiliation: Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, GB.
authors.forename: Kathryn T
authors.initials: KT
authors.lastname: Whelan
authors.forename: Chen-Lung
authors.initials: CL
authors.lastname: Lin
authors.forename: Marina
authors.initials: M
authors.lastname: Cella
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Austyn
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Rowland-Jones
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects; D015658:HIV Infections / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis / Q000235:genetics; D019469:Indinavir / Q000494:pharmacology*; D039041:Integrin alpha4beta1 / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D000097802:CD83 Antigen; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D017320:HIV Protease Inhibitors; D007136:Immunoglobulins; D019469:Indinavir; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D000097802:CD83 Antigen; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C065289:ICAM2 protein, human