Chimeric Rhinoviruses Obtained via Genetic Engineering or Artificially Induced Recombination Are Viable Only if the Polyprotein Coding Sequence Derives from the Same Species

Schibler, Manuel; Piuz, Isabelle; Hao, Weidong; Tapparel, Caroline

doi:10.1128/jvi.03668-14

Cited by 15 publications

(23 citation statements)

References 44 publications

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“…As hypothesized for the Hepatitis C virus and EVs including PV, the recombination of at least some plus strand RNA viruses is thought to be biphasic and to involve the generation of initial nonhomologous recombinants which evolve into homologous recombinants through subsequent genomic rearrangements, which can be considered intramolecular recombination events [ 6 , 7 , 9 , 90 ]. Indeed, most natural cVDPVs described so far are homologous recombinants [ 21 , 29 – 32 , 35 – 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…Two driving forces are implicated in the variability of RNA viruses: high mutation rates, which generate a population of related sequences named quasispecies, and genomic RNA recombination [ 1 – 3 ]. By allowing the exchange of genetic information and incorporating viral RNA fragments into new genomic contexts, recombination can eliminate lethal mutations or other genetic alterations [ 4 – 9 ], and increase viral pathogenicity [ 10 – 12 ] and fitness [ 7 , 8 , 13 , 14 ]. Genetic recombination has shaped the genetic diversity of RNA viruses and in particular that of enteroviruses (EVs), which often show mosaic genomes [ 15 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Evolution and Emergence of Enteroviruses through Intra- and Inter-species Recombination: Plasticity and Phenotypic Impact of Modular Genetic Exchanges in the 5’ Untranslated Region

et al. 2015

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Genetic recombination shapes the diversity of RNA viruses, including enteroviruses (EVs), which frequently have mosaic genomes. Pathogenic circulating vaccine-derived poliovirus (cVDPV) genomes consist of mutated vaccine poliovirus (PV) sequences encoding capsid proteins, and sequences encoding nonstructural proteins derived from other species’ C EVs, including certain coxsackieviruses A (CV-A) in particular. Many cVDPV genomes also have an exogenous 5’ untranslated region (5’ UTR). This region is involved in virulence and includes the cloverleaf (CL) and the internal ribosomal entry site, which play major roles in replication and the initiation of translation, respectively. We investigated the plasticity of the PV genome in terms of recombination in the 5’ UTR, by developing an experimental model involving the rescue of a bipartite PV/CV-A cVDPV genome rendered defective by mutations in the CL, following the co-transfection of cells with 5’ UTR RNAs from each of the four human EV species (EV-A to -D). The defective cVDPV was rescued by recombination with 5’ UTR sequences from the four EV species. Homologous and nonhomologous recombinants with large deletions or insertions in three hotspots were isolated, revealing a striking plasticity of the 5’ UTR. By contrast to the recombination of the cVDPV with the 5’ UTR of group II (EV-A and -B), which can decrease viral replication and virulence, recombination with the 5’ UTRs of group I (EV-C and -D) appeared to be evolutionarily neutral or associated with a gain in fitness. This study illustrates how the genomes of positive-strand RNA viruses can evolve into mosaic recombinant genomes through intra- or inter-species modular genetic exchanges, favoring the emergence of new recombinant lineages.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evolution and Emergence of Enteroviruses through Intra- and Inter-species Recombination: Plasticity and Phenotypic Impact of Modular Genetic Exchanges in the 5’ Untranslated Region

et al. 2015

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“…This kind of recombination was first demonstrated to occur in experiments with pairs of segments originating from poliovirus genomes disrupted in either the 5= UTR or the RdRP-encoding region (189,190). Subsequently, it was observed in other picornaviruses (191,192) as well as in flaviviruses (193)(194)(195)(196). As discussed elsewhere (197), this mechanism may also be responsible for certain earlier observed cases of recombination between alphaviruses (198) and rubiviruses (199) (both belonging to the Togaviridae family) and hence appears to be a general phenomenon.…”

Section: Insertions Deletions and Replacementsmentioning

confidence: 91%

Emergency Services of Viral RNAs: Repair and Remodeling

Agol

Gmyl

2018

Microbiol Mol Biol Rev

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Reproduction of RNA viruses is typically error-prone due to the infidelity of their replicative machinery and the usual lack of proofreading mechanisms. The error rates may be close to those that kill the virus. Consequently, populations of RNA viruses are represented by heterogeneous sets of genomes with various levels of fitness. This is especially consequential when viruses encounter various bottlenecks and new infections are initiated by a single or few deviating genomes. Nevertheless, RNA viruses are able to maintain their identity by conservation of major functional elements. This conservatism stems from genetic robustness or mutational tolerance, which is largely due to the functional degeneracy of many protein and RNA elements as well as to negative selection. Another relevant mechanism is the capacity to restore fitness after genetic damages, also based on replicative infidelity. Conversely, error-prone replication is a major tool that ensures viral evolvability. The potential for changes in debilitated genomes is much higher in small populations, because in the absence of stronger competitors low-fit genomes have a choice of various trajectories to wander along fitness landscapes. Thus, low-fit populations are inherently unstable, and it may be said that to run ahead it is useful to stumble. In this report, focusing on picornaviruses and also considering data from other RNA viruses, we review the biological relevance and mechanisms of various alterations of viral RNA genomes as well as pathways and mechanisms of rehabilitation after loss of fitness. The relationships among mutational robustness, resilience, and evolvability of viral RNA genomes are discussed.

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“…The capsid genes and nonstructural genes of viruses within each species group evolve separately due to the distinct functions and selective pressures associated with these gene cassettes (8). Recombinant viruses arise most frequently from intraspecies recombination (13), although interspecies recombination occurs, as well (14). Moreover, recombination dynamics reveal subgroups within species (15).…”

mentioning

confidence: 99%

Poliovirus Polymerase Leu420 Facilitates RNA Recombination and Ribavirin Resistance

Kempf

Peersen

Barton

2016

J Virol

107

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RNA recombination is important in the formation of picornavirus species groups and the ongoing evolution of viruses within species groups. In this study, we examined the structure and function of poliovirus polymerase, 3D pol , as it relates to RNA recombination. Recombination occurs when nascent RNA products exchange one viral RNA template for another during RNA replication. Because recombination is a natural aspect of picornavirus replication, we hypothesized that some features of 3D pol may exist, in part, to facilitate RNA recombination. Furthermore, we reasoned that alanine substitution mutations that disrupt 3D pol -RNA interactions within the polymerase elongation complex might increase and/or decrease the magnitudes of recombination. We found that an L420A mutation in 3D pol decreased the frequency of RNA recombination, whereas alanine substitutions at other sites in 3D pol increased the frequency of recombination. The 3D pol Leu420 side chain interacts with a ribose in the nascent RNA product 3 nucleotides from the active site of the polymerase. Notably, the L420A mutation that reduced recombination also rendered the virus more susceptible to inhibition by ribavirin, coincident with the accumulation of ribavirin-induced G¡A and C¡U mutations in viral RNA. We conclude that 3D pol Leu420 is critically important for RNA recombination and that RNA recombination contributes to ribavirin resistance. IMPORTANCE Recombination contributes to the formation of picornavirus species groups and the emergence of circulating vaccine-derived polioviruses (cVDPVs).The recombinant viruses that arise in nature are occasionally more fit than either parental strain, especially when the two partners in recombination are closely related, i.e., members of characteristic species groups, such as enterovirus species groups A to H or rhinovirus species groups A to C. Our study shows that RNA recombination requires conserved features of the viral polymerase. Furthermore, a polymerase mutation that disables recombination renders the virus more susceptible to the antiviral drug ribavirin, suggesting that recombination contributes to ribavirin resistance. Elucidating the molecular mechanisms of RNA replication and recombination may help mankind achieve and maintain poliovirus eradication. Picornaviruses are widespread in nature. Based on their ancient origins (1) and shared molecular features (2), picornaviruses are taxonomically organized by order, family, genus, species, and virus. Viruses in the family Picornaviridae are classified within 29 genera and 50 species groups. The genus Enterovirus, with 12 species groups (enterovirus species A to J and rhinovirus species A to C), contains the vast majority of medically important picornaviruses, including the polioviruses (PV), coxsackieviruses, enteroviruses, echoviruses, and rhinoviruses. These viruses, which possess single-stranded positive-sense RNA genomes, replicate via RNA intermediates in the cytoplasm of infected cells. A virus-encoded RNA-dependent RNA polymerase, 3D pol...

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Chimeric Rhinoviruses Obtained via Genetic Engineering or Artificially Induced Recombination Are Viable Only if the Polyprotein Coding Sequence Derives from the Same Species

Cited by 15 publications

References 44 publications

Evolution and Emergence of Enteroviruses through Intra- and Inter-species Recombination: Plasticity and Phenotypic Impact of Modular Genetic Exchanges in the 5’ Untranslated Region

Evolution and Emergence of Enteroviruses through Intra- and Inter-species Recombination: Plasticity and Phenotypic Impact of Modular Genetic Exchanges in the 5’ Untranslated Region

Emergency Services of Viral RNAs: Repair and Remodeling

Poliovirus Polymerase Leu420 Facilitates RNA Recombination and Ribavirin Resistance

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