Role of Virus-Encoded microRNAs in Avian Viral Diseases

*Venugopal Nair and Yongxiu Yao*

## **Abstract**

To survive in the host cells, viruses have to adapt various strategies, which include the modulation of microRNA (miRNA) pathway through virus-encoded miRNAs to modulate the host cellular environment. It has been shown that several avian viruses, mostly herpesviruses, encode a number of miRNAs. These include 26 miRNAs encoded by the highly oncogenic Marek's disease virus-1, 36 miRNAs encoded by avirulent Marek's disease virus-2, 28 miRNAs by herpesvirus of turkeys, 10 miRNAs by infectious laryngotracheitis virus, 41 miRNAs by duck enteritis virus, and 2 miRNAs by avian leukosis virus subgroup J. Although locations of some of the miRNAs are conserved within the repeat regions of the genomes among some of the antigenic and phylogenetic closely related herpesviruses, there are no sequence conservation of miRNAs encoded by different avian herpesviruses. Moreover, some of the virus-encoded miRNAs have the same seed sequence as host miRNAs serve as functional orthologs. For example, mdv1-miR-M4-5p, a functional ortholog of gga-miR-155, is critical for the Marek's disease virus in inducing tumors. In this review, we describe the advances in our understanding on the role of the herpesvirus-encoded miRNAs in avian diseases. Additionally, we also describe the potential association of avian leukosis virus subgroup J encoded E (XSR) miRNA in the induction of myeloid tumors in certain genetically distinct chicken lines.

**Keywords:** avian viruses, microRNAs, MDV, DEV, ILTV and ALV

## **1. Introduction**

MicroRNAs (miRNAs) are small RNA molecules of ~22-nucleotide that profoundly affect gene expression by targeting the 3'UTR (untranslated region) of the targeted mRNA (messenger RNA). Ever since the first discovery of miRNA in *Caenorhabditis elegans* [1], the identification of miRNAs, of which some are evolutionarily conserved [2–4], has proceeded at a quick pace. It is well known now that miRNAs are key regulators of gene expression in many species including mammals, plants, flies, worms, as well as in a number of viruses. Out of 38,589 miRNAs identified so far, 530 are encoded by viruses (www.miRbase.org). Most of the viral miRNAs are encoded by DNA viruses, with members of the family *Herpesviridae* encoding for the vast majority suggesting the importance of miRNAmediated gene regulation in the biology of herpesvirus infections. Long-term survival as latent infections in different cell types are characteristic feature of virus-host interactions in herpesviruses. This requires sophisticated survival strategy to avoid detection by the innate and adaptive immune mechanisms of the host. Herpesviruses achieve this using a variety of mechanisms through translational

control, epigenetic control of viral/host gene expression, and restricted gene expression [5, 6]. The miRNAs, with the small size along with the ability for specific repression of multiple transcript targets, make them ideal tools for herpesviruses to reshape the gene expression to favor viral replication in an infected cell. Hence, it is of no surprise that herpesviruses encode 91% of virus-encoded miR-NAs identified so far. The number of miRNAs encoded by different herpesviruses varies, i.e., 5 miRNAs in Bovine herpesvirus 5 and 70 in Rhesus lymphocryptovirus (miRBase V22.1). In addition to herpesviruses, some of other virus families also encode miRNAs [7, 8] including miRNAs encoded by the human Torque Teno Virus [9]. Although retroviruses have not been widely documented to exploit the miRNA pathway [10], demonstration of E (XSR) miRNA encoded by avian leukosis virus subgroup J (ALV-J) using the canonical miRNA biogenesis pathway [11], and a conserved cluster of RNA polymerase III (pol III)-transcribed miRNAs from the bovine leukemia virus (BLV) genome [12, 13] showed that retroviruses also exploit the miRNA pathway.
