Replication enhancer elements within the open reading frame of tick-borne encephalitis virus and their evolution within the Flavivirus genus

Tuplin, A.; Evans, D. J.; Buckley, A.; Jones, I. M.; Gould, E. A.; Gritsun, T. S.

Previous analysis of RNA secondary structure across the Flavivirus genus led to the concept of promoter and enhancer elements that initiate assembly of the virus polymerase complex (16) (17) (18) 23, 27, 43, 44) . Enhancers were identified as RNA structures that individually produce only small biological effects on virus replication. However, the significance of enhancers as targets for the attenuation of flaviviruses to engineer live vaccines is evident from the example of dengue virus (24, 25) . Moreover, sequence and structural conservation of flavivirus enhancers is consistent with a role as key players in virus survival in the natural environment. We previously proposed that the cumulative action of several enhancer elements could contribute significantly to the overall rate of assembly of polymerase complexes, thereby enhancing virus survival across a range of natural hosts (17, 18, 23, 27, 43, 44) . In this respect, the presented experimental data indicate that SL6 belongs to the category of REEs, i.e. RNA structures that accelerate the replication of viruses (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) (56) . This eliminates the apparent contradictions between extremely high levels of SL6 conservation across divergent TBFV virus species and the redundancy of this element for the replication of laboratory-maintained TBEV strains (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) (56) . However, the specific mechanism by which SL6 functions to enhance virus replication remains to be elucidated.