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and in situ adenosine to inosine substitutions in mature miRNAs can also alter
targeting (Wightman et al. 1993; Doench and Sharp 2004; Kawahara et al. 2007).
Finally, the miRNA sequence outside the seed region has been found to play a role
in subcellular localization of miRNAs (Hwang et al. 2007).
Eleven years after the discovery of miRNAs, the first virally encoded miRNAs
were reported (Pfeffer et al. 2004). As most algorithms for the identification of
miRNAs rely on conservation of sequence, viral miRNA prediction was particu-
larly difficult due to the absence of significant homology to known miRNAs. By
sequencing of a small RNA library from a Burkitt's lymphoma cell line latently
infected with Epstein Bar Virus (EBV), Tuschl and colleagues identified five
miRNAs that originated from the EBV (Pfeffer et al. 2004). Subsequently, many
groups, including our own, have contributed to the identification of miRNAs
encoded by other human herpesviruses. Additionally, many nonhuman herpesvirus
miRNAs have been identified, providing animal models in which to study the func-
tion of virally encoded miRNAs. Thus far, 106 of the 108 mature viral miRNAs
species in the miRNA registry are encoded by herpesviruses (Griffiths-Jones 2004,
2006; Griffiths-Jones et al. 2006). Currently, it is known that HCMV expresses 14
mature miRNAs from 11 precursor miRNAs (Fig. 1).
A herpesvirus is a large dsDNA virus that replicates in the nucleus of the host cell,
and after an initial lytic replication cycle establishes latent infection for the life of the
host. Reactivation from latency and initiation of secondary lytic replication occurs
periodically. Betaherpesviruses, which include HCMV and herpesvirus-6 and -7, can
replicate in a wide variety of cell types, but exhibit strict species specificity. The
complex life cyle of herpes viruses illustrates the need for distinctive gene regulation
mechanisms that viral miRNAs provide. Utilization of miRNA offers the virus, which
possesses limited coding capacity, a means to alter gene expression with relatively
minimal impact on genome size; maintenance of latent infection requires limited,
nonimmunogenic gene expression; tissue tropism implies an array of gene products
suited to the exploitation of specific host-cell types. As such, it is not surprising that
the first virally encoded miRNAs were discovered in a herpesvirus, EBV.
miRNA Biogenesis
The progress made in understanding miRNA biogenesis (Fig. 2) stands in stark
contrast to the limited understanding of miRNA-mediated regulatory networks.
While many fundamental questions about regulation of miRNA biogenesis still
need to be addressed, significant progress has been made concerning the process of
miRNA maturation.
Many of the subtleties and details concerning miRNA biogenesis are beyond
the scope of this review. Rather, it is our aim to provide an overview of the
biogenesis process as an aid to understanding HCMV miRNA. There is little
evidence to suggest that viral miRNA biogenesis differs from that of cellular
miRNAs. Recently, however, aspects of miRNA biogenesis such as substrate
