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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Poster Session Abstract P17 C-MAF: A KSHV MICRORNA TARGET Amy Hansen 1 , Dimitris Lagos 1 , Stephen Henderson 1 , Vicky Emuss 1 Fiona Gratrix 1 , Rolf Renne 2 and Chris Boshoff 1 1 Cancer Research UK Viral Oncology Group, UCL Cancer Institute, Paul O’Gorman Building, Huntley Street, University College London, WC1E 6BT, London, U.K. Abstract MicroRNAs are small non-coding RNA molecules which post-transcriptionally regulate gene expression by either blocking translation or inducing mRNA degradation. KSHV encodes 12 microRNAs located within the latency-associated region of the genome; ten microRNAs are clustered and co-expressed. Despite being identified 3 years ago, few KSHV microRNA targets have been identified. We present microRNA profiling data which confirms the expression of viral microRNAs in our in vitro endothelial cell model of primary infection and in vivo within KS lesions. We sought to identify cellular targets of the KSHV microRNA cluster in human lymphatic endothelial cells (LECs). Gene expression microarray profiling of LECs infected with lentivirus expressing either microRNA cluster or empty vector identified cellular targets silenced by microRNA induced mRNA degradation. Several genes were significantly deregulated; amongst these was the transcription factor c-Maf, an oncogenic avian retrovirus homologue. C-maf overexpression transforms B and T cells, however its function in endothelial cells is poorly characterised. In silico prediction analysis identified several potential KSHV microRNA target sites within the c- Maf 3’UTR. We have subsequently identified miR-K12-11 and miR-K12-6 as the principle silencers of c-Maf. In addition we show that silencing is mediated by direct microRNA interaction with the c-Maf 3’UTR. This work identifies and experimentally validates c-Maf as the first endothelial-specific KSHV microRNA target. Presenting author Email: amy.hansen@wibr.ucl.ac.uk 114
The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Poster Session Abstract P18 KSHV KAPOSIN B SUPPRESSES THE HOST INTERFERON RESPONSE BY PREVENTING STAT1 PHOSPHORYLATION Christine A King, Jennifer A Corcoran and Craig McCormick Dalhousie University, Department of Microbiology and Immunology, Halifax, Nova Scotia, B3H 1X5, Canada. Abstract A central component of host antiviral defence is the interferon (IFN)-mediated antiviral pathway. Detection of virus by infected cells triggers the secretion of type I IFN (IFN-α or IFN-β) that engages specific receptors on target cells, resulting in activation of two receptor-associated tyrosine kinases, Jak1 and Tyk2. This is followed by tyrosine phosphorylation and heterodimerization of the STAT1 and STAT2 proteins. Phosphorylated STAT1 and STAT2 combine with IRF-9 to form the ISGF-3 complex, which, upon translocation to the nucleus, binds to the cis element ISRE (IFN-stimulated response element), to drive transcription of IFN responsive genes. To ensure viral persistence and productive infection, KSHV has evolved a variety of countermeasures to disrupt IFN signal transduction. Here we show that the latent KSHV kaposin B protein potently inhibits transcription from the interferon stimulated response element (ISRE) in response to IFN-α. Furthermore, primary human umbilical vein endothelial cells (HUVECs) expressing kaposin B fail to accumulate phosphorylated STAT1 in response to IFN-α and harbor decreased levels of total STAT1. Our data suggest that kaposin B interferes with the host IFN response thereby contributing to successful immune evasion by KSHV. Presenting author Email: caking@dal.ca 115
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