MicroRNA function in murine cytomegalovirus

Viruses require host proteins to enter a cell, replicate and spread in an animal. In the last decade, a new class of molecules has been discovered, microRNAs, which regulate the precise concentration of host proteins in a cell. We developed a global functional screening assay to determine whether this class of molecule could influence the ability of viruses to replicate. We found that manipulating the expression level of specific microRNAs inhibited the replication of members of all three herpesviral subfamilies, as well as Semliki forest virus, a single stranded RNA virus. We then showed that these antiviral microRNAs directly target host genes that are required by diverse viruses for replication. Our findings suggest that the down-regulation of specific combinations of host proteins by a microRNA can inhibit virus replication. Since the antiviral effects of a microRNA relate to regulation of host gene expression, rather than direct targeting of the virus, these molecules could be effective as broad-spectrum antivirals. Interestingly, we found that cytomegaloviruses encode molecules that interfere with these antiviral microRNAs. We identified a specific transcript produced by murine cytomegalovirus that binds to miR-27, an antiviral cellular microRNA, and mediates its degradation. Our findings demonstrate a new mode of virus-host interaction where a viral messenger RNA targets a cellular microRNA for degradation. This work suggests that other animal viruses may also target cellular microRNAs during infection and this mechanism could be a new therapeutic target.