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2009b). Similarly, pp14 is not essential for MDV oncogenesis and distinct miRNA expression levels were detected in MDV infected
viral replication but was thought to be involved in neurovirulence MD resistant and susceptible chickens suggesting that miRNAs
(Tahiri-Alaoui et al., 2013). expression might be associated with resistance or susceptibility
of chickens towards MD. Later, deep sequencing and microarray
miRNAs analyses studies revealed that viral and cellular miRNAs, as well
In the past several years, avian herpesviruses encoded miRNAs as cellular genes, presented differential expression, and many of
have been discovered and characterized. It has been reported that these miRNAs and genes were related to apoptosis, cell cycle
all three serotypes of MDV encode various miRNAs, including regulation and DNA repair pathways (Hicks et al., 2018).
26 MDV-1 miRNAs, 36 MDV-2 miRNAs, and 28 HVT miRNAs Apart from the expression, several studies have been under-
(Hicks and Liu, 2013). The miRNAs in MDV-1 are divided into taken to explore the biological function of MDV-1 encoded
three major clusters, first two clusters flank meq, and the third miRNAs. Among all MDV miRNAs, miR-M4 is the most exten-
cluster is located within the 3′ end of LAT (Figs. 12.2 and 12.4) sively studied. miR-M4, located within the first cluster of six
(Zhao et al., 2011). miRNAs, is an orthologue of cellular miR-155. A miR-M4 null
The miRNAs are a class of short (≈ 22 nucleotides) RNAs MDV-1 mutant virus could not transform infected T lympho-
generated from non-coding genomic regions that are involved cytes indicating it plays a critical role in MD lymphoma formation
in various regulation pathways (Hicks and Liu, 2013). These (Zhao et al., 2011). Predictions, and following validation experi-
regulatory sequences can inhibit the translation or increase the ments, demonstrated that miR-M4 of MDV-1 regulates both
degradation of mRNA by binding to complementary sequences viral and cellular genes (Muylkens et al., 2010). In addition, a
in 3′ untranslated regions (3′ UTR) of target mRNA (Croce, member of the third cluster miRNA, miR-M7-5p, which is highly
2009). The miRNAs play an important role in tumorigenesis by expressed in MSB1 cells while extremely low in infected CEF, has
regulating oncogenic and tumour suppressor pathways (Ventura been suggested to target ICP4 and ICP27, and play a role in the
and Jacks, 2009). Various miRNAs have been identified in viruses maintenance of latency, thus generating negative feedback loops
from different subfamilies under Herpesviridae, such as HSV, to control lytic replication (Strassheim et al., 2012).
MDV, human cytomegalovirus (HCMV), Epstein–Barr virus Even though the expression profiles and functional biology
(EBV), and Kaposi’s sarcoma associated herpesvirus (KSHV), studies indicate that MDV and other herpesviruses encoded
and play an important role in regulating cellular pathways and miRNAs play an important role in regulating viral transformation
viral lytic and latent infections (Piedade and Azevedo-Pereira, and cellular pathways, the diverse functions of MDV miRNAs
2016). remain to be determined.
Since the first MDV encoded miRNAs were discovered in
2006, a total of 14 pre-mature miRNA which produced a total of 26 Other unique genes
mature miRNAs have been identified within the MDV-1 genome In addition to the proteins and genes mentioned above, there are
(Hicks and Liu, 2013). In 2008, a qPCR test was developed to several other MDV unique genes, including SORF2 (MDV087)
measure the expression patterns of MDV-encoded miRNAs and vLIP (MDV010). MDV087 is located in MDV unique
miR-4, miR-8, and miR-12 in vitro and in vivo (Xu et al., 2008). short region and encodes for SORF2 protein. SORF2 was first
This study showed that these miRNAs are expressed at higher described in MDV GA strain, and deletion experiments showed
levels in MDV induced tumours than non-tumour tissues, lead- it is not essential for virus replication in cell culture (Brunovskis
ing to the hypothesis that the expression levels of these miRNAs and Velicer, 1995; Tulman et al., 2000). Unlike GA strain, MDV
can serve as biomarkers for MDV-1 induced transformation. Two Md5 encodes SORF2 and SORF2-like (MDV097) proteins
recent studies utilized advanced techniques to provide a compre- located in the IRS/TRS junction region, which share an identical
hensive understanding of expression patterns of cellular and viral 119 amino acids at the amino terminus.
miRNAs (Tian et al., 2012; Hicks et al., 2018). In 2012, Tian et MDV viral lipase (vLIP) is encoded by MDV010, which is con-
al. (2012) applied microarray screen followed by qPCR confir- served among all three serotypes of MDV. An MDV mutant was
mation to explore the expression of cellular and viral miRNAs found to have a retrovirus long terminal repeat (LTR) inserted in
in MD resistant and susceptible chickens. Results showed that MDV010 indicating that vLIP is not essential for replication in

miR-M9 miR-M5 miR-M12 miR-M3 miR-M2 miR-M4 meq miR-M11 miR-M31 miR-M1 miR-M8 miR-M13 miR-M6 miR-M7 miR-M10 ICP4

Cluster 1 Cluster 2 Cluster 3
miRNAs miRNAs miRNAs

LAT

Figure 12.4 Schematic representation of three MDV-1 encoded miRNAs clusters.

Figure 4