How RNA viruses maintain genome integrity

Influenza virus A range of mechanisms exist to enable maintenance and restoration of genome integrity in RNA viruses. Despite their often fastidious mechanisms to ensure accurate replication initiation and termination, virus RNA-dependent RNA polymerases (RdRps) are sufficiently flexible to accommodate alternative modes of initiation and elongation, enabling terminal repair, terminal transferase activity and recombination. For any given virus, the behaviour of the RdRp at the 3′ end of a template might be impacted by the nature of the 3′-terminal sequence. It seems likely that, if the genome termini are intact and all promoter and accessory sequences required for replication initiation are present, the RdRp will engage preferentially in accurate replication initiation. However, if key terminal sequences are missing, the replicase complex might not be able to assemble correctly, releasing the RdRp to perform ‘abnormal’ actions, such as non-templated polymerization or terminal transferase activity. Once a genome has been repaired, the RdRp could revert to its ‘normal’ function of template-dependent polymerization.

Viruses that replicate in particularly harsh environments or which have no passive defences to protect their genomes may have replicases that accommodate alternative initiation mechanisms to facilitate terminal repair more readily, and fundamental differences in virus genome and replicase architecture probably affect the propensity for RNA recombination. It is striking that most examples of RNA virus genome repair involve positive-strand viruses, whose genomes might be more vulnerable than those of the double-stranded or negative-sense viruses, in which the genomes are sequestered in protein capsids during the entire cycle of infection. The data also suggest that formation of truncated genomes, whilst hindering virus replication kinetics, might allow or aid some viruses to become persistent, which ultimately could aid their propagation within the host population. Thus the capacity for genome repair could be an important factor in virus pathogenesis.

How RNA viruses maintain their genome integrity. 2010 J Gen Virol. 91(6): 1373-1387
RNA genomes are vulnerable to corruption by a range of activities, including inaccurate replication by the error-prone replicase, damage from environmental factors, and attack by nucleases and other RNA-modifying enzymes that comprise the cellular intrinsic or innate immune response. Damage to coding regions and loss of critical cis-acting signals inevitably impair genome fitness; as a consequence, RNA viruses have evolved a variety of mechanisms to protect their genome integrity. These include mechanisms to promote replicase fidelity, recombination activities that allow exchange of sequences between different RNA templates, and mechanisms to repair the genome termini. In this article, we review examples of these processes from a range of RNA viruses to showcase the diverse approaches that viruses have evolved to maintain their genome sequence integrity, focusing first on mechanisms that viruses use to protect their entire genome, and then concentrating on mechanisms that allow protection of the genome termini, which are especially vulnerable. In addition, we discuss examples in which it might be beneficial for a virus to ‘lose’ its genomic termini and reduce its replication efficiency.

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