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cytotoxic T lymphocytes (Sullivan et al. 2005), and thus we would expect that the
miRNA mutant virus would be replicatively attenuated in vivo.
Two targets of the HSV-1 mir-LAT were recently identified. Mir-LAT targets the
3′-UTRs of TGF beta 1 and SMAD3 (Gupta et al. 2006), resulting in the disruption of
pro-apoptotic pathways (Gupta et al. 2006). Expression of a miRNA from the LAT
prompted many to attribute a role for mir-LAT in the maintenance of a latent infection.
However, to date mir-LAT has not been studied in the context of a latent infection and
its role in the maintenance of HSV-1 latency awaits further verification.
HCMV mir-UL112 has been found to target two viral open reading frames (Grey
2006). Nelson and co-workers reported that mir-UL112 targeted viral immediate
early (IE) proteins-1 and -2. IE1 and IE2 are essential for viral infection and possess
numerous reported functions, including transactivation and cell cycle inhibition
(Mocarski et al. 2007). IE1 is not essential, but a deletion mutant shows a severe
growth defect (Mocarski et al. 2007). Mir-UL112 is expressed with immediate early
kinetics. The regulation of these two viral proteins is likely to have an important role
in viral infection. Further studies are needed to address the functional importance of
mir-UL112's negative regulation of IE1 and IE2.
Future Directions
The identification of viral miRNA targets is currently the bottleneck in further
understanding the role and function of virally encoded miRNAs. It may be
expected that an understanding of HCMV miRNA function will reveal novel
mechanisms contributing to the unique replicative success of this herpesvirus.
Further, identification of HCMV miRNA targets may well illuminate fundamental
and universal components of the host response to microbial infection. Microbes
have provided the foundation for many important discoveries in molecular biology.
It is our hope that, in addition to expanding therapeutic and prevention strategies,
probing the functions of miRNA in the context of viral infection will illuminate
fundamental aspects of miRNA-mediated control of gene expression.
Acknowledgements
We thank Gerry Abenes, Kihoon Kim, Aaron To, and Eric Sanborn for help-
ful discussions and comments on the manuscript. Gratitude also goes to Kihoon Kim and Gina
Blackledge for contributions to the figures. P.J.R. was supported by a NIH predoctoral training
grant (AI007620) and E.Y. acknowledges predoctoral fellowship support from University of
California at Berkeley (Graduate Division). The research has been supported by grants from NIH.
References
Ambros V (2004) The functions of animal microRNAs. Nature 431:350-355
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell
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