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Herpes simplex virus 1 miRNA sequence variations during productive and latent infection

It has been reported that herpes simplex virus 1 (HSV-1) encodes 29 mature microRNAs (miRNAs), the function of which is largely unknown. Although HSV-1 miRNAs have been discovered more than 10 years ago, the discrepancies in their sequences in different data sets compared to the reference sequences in miRBase are frequently reported, which hampers functional analyses. To shed light on the peculiarities of the HSV-1 miRNA processing and importance of their sequence variations, we analyzed 35 small-RNA deep-sequencing data sets from different laboratories. Our unbiased approach enabled us to address many basic and important questions such as the exact sequence of HSV-1 miRNA, sequence conservation between different strains, sequence variations between productive and latent infection and most importantly the reproducibility of HSV-1 miRNA discovery. Based on many criteria, we grouped HSV-1 encoded miRNAs into three distinct classes: miRNAs that satisfy all criteria for genuine miRNAs, group which partially satisfies the criteria and the ones which do not meet the criteria. In addition, we show that sequences of a subset of HSV-1 miRNAs differ from the sequences in miRBase. Interestingly, our results show that the frequency of isomiRs (sequence variations at 5’ or 3’) is significantly higher for HSV-1 miRNAs than host miRNAs. The molecular basis for this observation is not known, however, our preliminary results indicate that this is not an intrinsic property of HSV-1 pre-miRNA sequence, but rather regulated by viral gene product or cellular factors induced by infection. Furthermore, we describe a substantial neuron- specific posttranscriptional editing of certain HSV-1 miRNAs, which might significantly change the targeting of these miRNAs. These results indicate that the virus is using cellular processes to expand the repertoire of possible miRNA targets or to affect their stability. Thus, much more research is needed to reveal even the most basic properties of virus miRNAs.

Herpes simplex virus 1 ; microRNA

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