The role of latency-associated viral miRNAs during human cytomegalovirus latent infection

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Human cytomegalovirus (HCMV) establishes a latent infection in CD34+ progenitor cells and their monocyte derivatives. We have previously shown that major changes occur in cellular gene expression in latently infected cells due to expression of viral proteins encoded by a sub-set of latency-associated viral genes. Whilst we have identified a number of functions of latency-associated viral proteins, little is known about the role of virally encoded miRNAs or long non-coding RNAs during latent infection - yet, HCMV is known to encode at least 17 mature miRNAs and 3 long non-coding RNAs (lncRNA). We have recently analysed the viral miRNAome during latent infection and identified a number viral miRNAs expressed to high levels in latency models using both primary myeloid cells as well as established myeloid cell lines.One of these is the viral miRNA UL22A. Initial analyses have identified one target of UL22A to be the p110delta subunit of Phosphoinositide 3-kinase (PI3K).This project will analyse the effect of UL22A-mediated down-regulation of p110delta on the establishment and maintenance of latent infection to help identify the rationale for viral-specific targeting of this cellular kinase.Importantly, studies of acute myeloid leukaemia have shown that cells with low levels of p110delta display increased sensitivity to induction of cell death by topoisomerase inhibitors such as etoposide and this predicts that latently infected cells could be targeted by such inhibitors. Consequently, the project will not only aim to understand the role of p100delta down-regulation during latent infection but translate the effects of expression of this viral miRNA, on the cell, to novel therapies to target latency - a key aim of our ongoing research.Similarly, we also will analyse the role, if any, of the viral 4.9kb lncRNA which has been postulated to be involved in maintenance of repression of viral lytic gene expression during latency. We will generate models of HCMV latency in which expression of the 4.9kb lncRNA is knocked down to establish the effect of lack of expression of this viral gene latent carriage.