The recent discovery of miRNAs of viral origin has dramatically changed our view on virus-host interaction. Viral miRNAs have been shown to regulate genes of both cellular and viral origin, contributing to a favorable environment for the virus. However, the real importance of virus-encoded miRNAs during infection of their hosts remains elusive. This paper reports the first functional phenotype of a miRNA knock-out mutant of the mouse cytomegalovirus in vivo. It shows that the mutant virus is attenuated specifically in the salivary glands of infected mice, an organ essential for long-term persistence of the virus and host-to-host spread. This attenuation revealed a striking dependence on genetic background of the mice under study. Only combined depletion of natural killer and T cells abolished the phenotype. These results indicate that, by regulating the immune system, viral miRNAs may play an important role in an efficient persistent infection.
Cytomegalovirus microRNAs Facilitate Persistent Virus Infection in Salivary Glands. (2010) PLoS Pathog 6(10): e1001150. doi:10.1371/journal.ppat.1001150
Micro (mi)RNAs are small non-coding RNAs that regulate the expression of their targets’ messenger RNAs through both translational inhibition and regulation of target RNA stability. Recently, a number of viruses, particularly of the herpesvirus family, have been shown to express their own miRNAs to control both viral and cellular transcripts. Although some targets of viral miRNAs are known, their function in a physiologically relevant infection remains to be elucidated. As such, no in vivo phenotype of a viral miRNA knock-out mutant has been described so far. Here, we report on the first functional phenotype of a miRNA knock-out virus in vivo. During subacute infection of a mutant mouse cytomegalovirus lacking two viral miRNAs, virus production is selectively reduced in salivary glands, an organ essential for virus persistence and horizontal transmission. This phenotype depends on several parameters including viral load and mouse genetic background, and is abolished by combined but not single depletion of natural killer (NK) and CD4+ T cells. Together, our results point towards a miRNA-based immunoevasion mechanism important for long-term virus persistence.