title: Kaposi sarcoma herpesvirus-encoded vFLIP and vIRF1 regulate antigen presentation in lymphatic endothelial cells.
abstract: Kaposi sarcoma-associated herpesvirus (KSHV) is etiologically linked to Kaposi sarcoma (KS), a tumor genetically akin to lymphatic endothelial cells (LECs). We obtained the immune transcriptional signature of KS and used KSHV-infected LECs (KLECs) as an in vitro model to determine the effects of KSHV on transcription and expression of genes involved in immunity. The antigen presentation, interferon (IFN) response, and cytokine transcriptomes of KLECs resemble those of KS. Transcription of genes involved in class I presentation is increased in KS and after infection of LECs, but MHC-I and ICAM-1 surface expression are down-regulated in KLECs. Inhibition of IFN induction of MHC-I transcription indicates that KSHV regulates MHC-I transcription. We show that MHC-I transcription is regulated by the KSHV-encoded viral FLICE inhibitory protein (vFLIP) and by viral IFN regulatory factor 1 (vIRF1). vFLIP up-regulates MHC-I and ICAM-1 through activation of NF-kappaB and stimulates T-cell proliferation, revealing a mechanism to prevent uncontrolled viral dissemination. In contrast, vIRF1 inhibits basal and IFN- and vFLIP-induced MHC-I transcription and surface expression through its interaction with the transcriptional coactivator p300, contributing to immune evasion. We propose that regulation of MHC-I by vFLIP and vIRF1 plays a crucial role in the host-pathogen equilibrium.
authors.affiliation: Cancer Research United Kingdom Viral Oncology Group, Wolfson Institute for Biomedical Research, University College London, UK.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Lagos
authors.forename: Matthew W B
authors.initials: MW
authors.lastname: Trotter
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Vart
authors.forename: Hsei-Wei
authors.initials: HW
authors.lastname: Wang
authors.forename: Nick C
authors.initials: NC
authors.lastname: Matthews
authors.forename: Amy
authors.initials: A
authors.lastname: Hansen
authors.forename: Ornella
authors.initials: O
authors.lastname: Flore
authors.forename: Frances
authors.initials: F
authors.lastname: Gotch
authors.forename: Chris
authors.initials: C
authors.lastname: Boshoff
mesh_terms: D017951:Antigen Presentation; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000276:immunology*; D002478:Cells, Cultured; D004729:Endothelium, Lymphatic / Q000166:cytology / Q000276:immunology / Q000821:virology*; D005786:Gene Expression Regulation / Q000276:immunology; D019288:Herpesvirus 8, Human / Q000737:chemistry* / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000276:immunology*; D016328:NF-kappa B / Q000502:physiology; D014158:Transcription, Genetic / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015395:Histocompatibility Antigens Class I; D050835:Interferon Regulatory Factors; D016328:NF-kappa B; D014764:Viral Proteins; C413486:viral interferon regulatory factors; D018799:Intercellular Adhesion Molecule-1