In this recent NIH study, researchers Heiss, Maximova and Pletnev demonstrate microRNAs (miRNAs) incorporated into the flaviviral genome of a chimeric tick-borne encephalitis/dengue virus (TBEV/DEN4) alter virulence in numerous cell lines and rhesus monkeys. Beginning with an in vitro analysis on Mosquito C6/36, Vero and rat neural cells, it was found that the presence of highly expressed miRNAs incorporated into the TBEV/DEN4 genome limited viral replication in developing primary neurons. They go on to illustrate the necessity of incorpated-miRNA attenuation by showing a significant decrease/abolishment of neurovirulence in mice. They illustrate sufficiency by making a single point mutation of the miRNA target sequence, restoring neurovirulence. Lastly, they conduct an analysis on viremia in rhesus monkeys, demonstrating a lower and shorter viral titer with the miRNA modified viruses.
Though they do not suggest any approaches to clinical applications, they do assert from this analysis and their experience with the mir-T9 virus, that attempts to target the flavivirus genome using microRNA would not be beneficial for vaccine development.
Brian L. Heiss, Olga A. Maximova, and Alexander G. Pletnev. Insertion of MicroRNA Targets into the Flavivirus Genome Alters Its Highly Neurovirulent Phenotype. Journal of Virology, February 2011, p. 1464-1472, Vol. 85, No. 4
- Vy Tran