title: Varicella-Zoster Virus Downregulates Programmed Death Ligand 1 and Major Histocompatibility Complex Class I in Human Brain Vascular Adventitial Fibroblasts, Perineurial Cells, and Lung Fibroblasts.
abstract: Varicella-zoster virus (VZV) vasculopathy produces stroke, giant cell arteritis, and granulomatous aortitis, and it develops after virus reactivates from ganglia and spreads transaxonally to arterial adventitia, resulting in persistent inflammation and pathological vascular remodeling. The mechanism(s) by which inflammatory cells persist in VZV-infected arteries is unknown; however, virus-induced dysregulation of programmed death ligand 1 (PD-L1) may play a role. Specifically, PD-L1 can be expressed on virtually all nucleated cells and suppresses the immune system by interacting with the programmed cell death protein receptor 1, found exclusively on immune cells; thus, downregulation of PD-L1 may promote inflammation, as seen in some autoimmune diseases. Both flow cytometry and immunofluorescence analyses to test whether VZV infection of adventitial cells downregulates PD-L1 showed decreased PD-L1 expression in VZV-infected compared to mock-infected human brain vascular adventitial fibroblasts (HBVAFs), perineural cells (HPNCs), and fetal lung fibroblasts (HFLs) at 72 h postinfection. Quantitative RT-PCR analyses showed no change in PD-L1 transcript levels between mock- and VZV-infected cells, indicating a posttranscriptional mechanism for VZV-mediated downregulation of PD-L1. Flow cytometry analyses showed decreased major histocompatibility complex class I (MHC-I) expression in VZV-infected cells and adjacent uninfected cells compared to mock-infected cells. These data suggest that reduced PD-L1 expression in VZV-infected adventitial cells contribute to persistent vascular inflammation observed in virus-infected arteries from patients with VZV vasculopathy, while downregulation of MHC-I prevents viral clearance.
  
  
  OBJECTIVE
  Here, we provide the first demonstration that VZV downregulates PD-L1 expression in infected HBVAFs, HPNCs, and HFLs, which, together with the noted VZV-mediated downregulation of MHC-I, might foster persistent inflammation in vessels, leading to pathological vascular remodeling during VZV vasculopathy and persistent inflammation in infected lungs to promote subsequent infection of T cells and hematogenous virus spread. Identification of a potential mechanism by which persistent inflammation in the absence of effective viral clearance occurs in VZV vasculopathy and VZV infection of the lung is a step toward targeted therapy of VZV-induced disease.
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Dallas
authors.initials: D
authors.lastname: Jones
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Blackmon
authors.affiliation: Department of Medicine, Division of Allergy and Clinical Immunology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: C Preston
authors.initials: CP
authors.lastname: Neff
authors.affiliation: Department of Medicine, Division of Allergy and Clinical Immunology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Brent E
authors.initials: BE
authors.lastname: Palmer
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.|Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Don
authors.initials: D
authors.lastname: Gilden
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Hussain
authors.initials: H
authors.lastname: Badani
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA maria.nagel@ucdenver.edu.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Nagel
mesh_terms: D063194:Adventitia / Q000098:blood supply / Q000276:immunology / Q000821:virology; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D015536:Down-Regulation; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D006566:Herpesviridae Infections / Q000209:etiology / Q000276:immunology; D014645:Herpesvirus 3, Human / Q000472:pathogenicity*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D008168:Lung / Q000276:immunology / Q000821:virology; D009457:Neuroglia / Q000276:immunology / Q000821:virology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D015395:Histocompatibility Antigens Class I