Detection of genome-scale ordered RNA structure (GORS) in genomes of positive-stranded RNA viruses: Implications for virus evolution and host persistence

Abstract

Discrete RNA secondary and higher-order structures, typically local in extent, play a fundamental role in RNA virus replication. Using new bioinformatics analysis methods, we have identified genome-scale ordered RNA structure (GORS) in many genera and families of positive-strand animal and plant RNA viruses. There was remarkably variability between genera that possess this characteristic; for example, hepaciviruses in the family Flaviviridae show evidence for extensive internal base-pairing throughout their coding sequences that was absent in both the related pestivirus and flavivirus genera. Similar genus-associated variability was observed in the Picornaviridae, the Caliciviridae, and many plant virus families. The similarity in replication strategies between genera in each of these families rules out a role for GORS in a fundamentally conserved aspect of this aspect of the virus life cycle. However, in the Picornaviridae, Flaviviridae, and Caliciviridae, the existence of GORS correlated strongly with the ability of each genus to persist in their natural hosts. This raises the intriguing possibility of a role for GORS in the modulation of innate intracellular defense mechanisms (and secondarily, the acquired immune system) triggered by doublestranded RNA, analogous in function to the expression of structured RNA transcripts by large DNA viruses. Irrespective of function, the observed evolutionary conservation of GORS in many viruses imposes a considerable constraint on genome plasticity and the consequent narrowing of sequence space in which neutral drift can occur. These findings potentially reconcile the rapid evolution of RNA viruses over short periods with the documented examples of extreme conservatism evident from their intimate coevolution with their hosts.

Functionally conserved architecture of hepatitis C virus RNA genomes

“…1 and 2C). These regions may be evolving under a complex mix of pressures related to maintaining highly compacted physical configurations (18,19) while evading immune recognition. HCV genomes replicate in the presence of innate immune response sensors that detect single-stranded (RNase L) and double-stranded (PKR and others) viral RNAs.…”

“…The HCV genomic RNA is physically compact (18) and highly structured (19). These features likely facilitate persistent HCV infections in humans by protecting the genome from degradation by innate antiviral defenses (20,21).…”

Large-scale screening and characterization of enteroviruses and kobuviruses infecting pigs in Vietnam

“…Although frequencies of persistence in PKV and other kobuviruses are poorly documented, genomes of all members of this genus possess structured RNA genomes (Davis et al, 2008;Simmonds et al, 2004) -a generic property associated with persistence in several other picornavirus genera and amongst other families of positive-stranded RNA viruses. High rates of detection in older pigs and …”

Diverse roles and interactions of RNA structures during the replication of positive-stranded RNA viruses of humans and animals

“…For example, an RNA structure in the 3C pro coding region of poliovirus (ciRNA) binds RNase L, competitively inhibiting its antiviral activity (Han et al, 2007;Keel et al, 2012). Many positive-stranded RNA viruses, such as HCV, exhibit extensive RNA structure designated genome-scale ordered RNA structure (GORS) (Simmonds et al, 2004). Distinct from discrete structural elements, GORS inhibits detection by cellular PRRs with its presence correlating to persistent viruses .…”