Abstract
Members of Picornaviridae and of the Hepacivirus, Pegivirus and Pestivirus genera of Flaviviridae all contain an internal ribosomal entry site (IRES) in the 5′-untranslated region (5′UTR) of their genomes. Each class of IRES has a conserved structure and promotes 5′-end-independent initiation of translation by a different mechanism. Picornavirus 5′UTRs, including the IRES, evolve independently of other parts of the genome and can move between genomes, most commonly by intratypic recombination. We review accumulating evidence that IRESs are genetic entities that can also move between members of different genera and even between families. Type IV IRESs, first identified in the Hepacivirus genus, have subsequently been identified in over 25 genera of Picornaviridae, juxtaposed against diverse coding sequences. In several genera, members have either type IV IRES or an IRES of type I, II or III. Similarly, in the genus Pegivirus, members contain either a type IV IRES or an unrelated type; both classes of IRES also occur in members of the genus Hepacivirus. IRESs utilize different mechanisms, have different factor requirements and contain determinants of viral growth, pathogenesis and cell type specificity. Their dissemination between viruses by horizontal gene transfer has unexpectedly emerged as an important facet of viral evolution.
Highlights
Members of Picornaviridae and of the Hepacivirus, Pegivirus and Pestivirus genera of Flaviviridae all contain an internal ribosomal entry site (IRES) in the 50 -untranslated region (50 UTR)
Base pairing of the apical GGG motif in IIId with expansion segment 7 (ES7) of 18S ribosomal RNA is critical for the affinity of the IRES-40S interaction [68] and induces a structural rearrangement in the resulting complex that likely primes it for binding of initiator tRNA and start codon recognition [69,70]
The Theiler’s murine encephalomyocarditis virus (TMEV) GDVII strain causes fatal encephalitis in mice following intercranial inoculation, but it was completely attenuated in mice following substitution of its IRES by that of the foot-and-mouth disease virus (FMDV) O1 K strain, even though substitution had little or no effect on translation in vitro and in baby hamster kidney (BHK) 21 cells, and the chimeric viral genome was infectious and the plaque size of progeny was only slightly reduced [48]
Summary
Recombination, defined as the exchange of genetic elements between parental genomes to generate novel chimeras, occurs in divers positive-sense RNA viruses [1] It can involve replicative or non-replicative mechanisms [2,3] and potentially serves functions that include the purging of deleterious mutations and the creation of advantageous novel genetic combinations to evade host immunity, gain resistance to antiviral agents, alter virulence and expand the host range [1,4,5]. In contrast to nucleotide substitution, which only allows gradual searching through evolutionary fitness space, recombination can lead to large shifts that can create beneficial genetic diversity but may disrupt favorable combinations of co-adapted alleles [1,11] This process of movement of genetic information between genomes is known as horizontal gene transfer, and it contrasts with the ‘vertical’ replicative transmission of genetic information from parents to offspring. IRESs as an example of a class of noncoding RNA element that can move between the genomes of positive-strand RNA viruses by recombination
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