Submitted May 22, 2006
Accepted September 29, 2006
Kaposi sarcoma herpesvirus-encoded vFLIP and vIRF1 regulate antigen presentation in lymphatic endothelial cells
Dimitrios Lagos, Matthew WB Trotter, Richard J Vart, Hsei-Wei Wang, Nick C Matthews, Amy Hansen, Ornella Flore, Frances Gotch, and Chris Boshoff*
Wolfson Institute for Biomedical Research, University College London, United Kingdom
National Yang Ming University, Taiwan
Imperial College, United Kingdom
New York University School of Medicine
* Corresponding author; email: c.boshoff{at}ucl.ac.uk.
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 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 interferon 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
B and stimulates T-cell proliferation, revealing a mechanism to prevent uncontrolled viral dissemination. In contrast, vIRF1 inhibits basal, IFN- and vFLIP-induced MHC-I transcription and surface expression through its interaction with the transcriptional co-activator 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.
