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Function and mechanism of viral miRNAs in cytomegalovirus infection

Final Activity Report Summary - CMV MIRNAS (Function and mechanism of viral miRNAs in cytomegalovirus infection)

This research has focused on a virus, cytomegalovirus (CMV), that harmlessly infects healthy people, but has devastating and often fatal consequences for immune suppressed patients, especially those undergoing transplantation. Human CMV (HCMV) is also the leading cause of congenital infection in humans, resulting in severe central nervous system damage. Accordingly, there is a need to understand the fundamental biology of the virus in order to develop anti-viral therapeutics and ultimately a vaccination. This project was aimed at addressing the role of small ribonucleic acids (microRNAs) in CMV pathogenesis and the mechanism by which a microRNA can influence the outcome of viral infection.

Viral-encoded microRNAs were first discovered in Epstein-Barr virus (EBV) in 2004 and have been shown to regulate host cell genes involved in the immune response as well as viral genes important for latency. Reports to date have been limited to in vitro observations; a true understanding of viral microRNA function requires analysis in an intact physiological system. Towards this goal, the first objective here was to identify microRNAs in MCMV, where the natural virus can be examined in its natural host.

Operating under the assumption that MCMV would encode these small RNAs (based on bioinformatic predictions and reports with human CMV), we set out to identify these RNAs using cloning and bioinformatic analysis. The small RNAs identified were then validated in multiple cell types and characterized to determine when in the viral life cycle they are expressed (published in the Journal of Virology).

This has laid the groundwork for further in vitro and in vivo analysis of MCMV microRNA function and we are currently analysing the targets of a subset of the highly expressed MCMV microRNAs. The MCMV microRNAs also possess some unusual regulatory properties that merit further analysis and may shed light on microRNA regulation relevant to various disease processes.