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in tissue culture. Characterizing the contribution that the remaining HCMV miRNAs
(mir-UL22A-1, mir-UL36 and mir-US25-1) make to virus growth in tissue culture
awaits the generation of novel recombinant virus.
HCMV is the only betaherpesvirus in which miRNAs have been described, and
several aspects of HCMV miRNAs are unique. Firstly, unlike the miRNAs identi-
fied in alpha- and gammaherpesviruses, HCMV miRNAs are not found clustered in
small regions of the genome, but can be found up to 195 kb apart (Fig. 3). Secondly,
due to the diversity of cells permissive to HCMV infection, it is possible to study
the expression of viral miRNAs in a number of cell types. Thirdly, because of the
lack of a simple in vitro model for HCMV latency, all of the HCMV miRNAs
identified in the experiments above have been in cells lytically infected with
HCMV. Thus far, all miRNAs identified in prototypic human alpha-(herpes simplex
virus 1 [HSV-1] and gamma-Kaposi's sarcoma associated herpesvirus [KSHV] and
EBV) herpes viruses have been found in regions of the genome that are transcrip-
tionally active during latent infection. The similarities and differences between
HCMV miRNAs and other herpesvirus miRNAs, in terms of their genomic arrange-
ment, expression and conservation will be discussed below.
HCMV miRNA Conservation
Multiple ORFs are conserved throughout the herpesvirus family, which are referred
to as core herpesvirus ORFs. As none of the miRNAs identified thus far are con-
served among the human herpesviruses, it can be inferred, just as it is for the non-
core herpesvirus ORFs, that these miRNAs impart functions unique to the identity
and lifestyle of each virus.
Our lab was the first to show the conservation of miRNAs between primate her-
pesviruses of the same genera, HCMV and chimpanzee cytomegalovirus (CCMV)
(Dunn et al. 2005). For purposes of this review, we have extended our analysis to
include all HCMV miRNAs identified to date and we report here that at least five
of the HCMV miRNAs are 100% conserved in CCMV (Fig. 4). Related herpesvi-
ruses are expected to have diverged with their host species. Chimpanzee and human
are thought to have diverged approximately 5 million years ago and as such, CCMV
is the closest relative of HCMV (Davison et al. 2003).
Similar analysis of the conservation of miRNAs between EBV and the closely
related rhesus lymphocryptovirus (rLCV) revealed that at least seven of the EBV
miRNAs are conserved in rLCV (Cai et al. 2006). The strength of this report lies in
the fact that bioinformatics were not used to identify rLCV miRNAs. Rather, rLCV
miRNAs were cloned from infected cells prior to sequence analysis. Interestingly,
the rLCV miRNAs that have sequence identity with EBV BART miRNAs possess
identical synteny with EBV BART miRNAs (Cai et al. 2006).
Two human herpesviruses, HSV-1 and HSV-2, exhibit close homology. Eight of the
miRNAs predicted for HSV-1 were conserved in HSV-2 (Pfeffer et al. 2005; Cui et al.
2006). Of the eight, two of the precursor miRNAs were conserved in HSV-2 (Pfeffer
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