Phylogenetic evidence for the improved RNA higher-order structure in internal ribosome entry sequences of HCV and pestiviruses

The strong requirement for a small segment of the 5'-proximal coding sequen ce of hepatitis C virus (HCV) is one of the most remarkable features in the internal initiation of HCV mRNA translation. Phylogenetic analysis and RNA folding indicate a common RNA structure of the 5' untranslated region (UTR ) of HCV and the animal pestiviruses, including HCV types 1-11, bovine vira l diarrhea (BVDV), border disease virus (BDV) and hog cholera (HoCV), Altho ugh the common RNA structure shares similar features to that proposed for t he internal ribosome entry sequence (IRES) of picornavirus, phylogenetic ev idence suggests four new tertiary interactions between conserved terminal h airpin loops and between the terminal hairpin loop of F2b and the short cod ing sequence for HCV and pestiviruses, We suggest that the higher-order str uctures of IRES cis-acting elements for HCV and animal pestivirus are compo sed of stem-loop structures B-C, domains E-H, stem-loop structure J and fou r additional tertiary interactions. The common structure of IRES elements f or these viruses forms a compact structure by these tertiary interactions a nd stem stacking. The active structural core is centered in the junction do main of E-H that is also conserved in all members of picornaviruses. Our mo del suggests that the requirement for a small segment of the 5' coding sequ ence is to form the distinct tertiary structure that facilitates the cis-ac ting function of the HCV IRES in the internal initiation of the translation al control.