Exchanges of genomic domains between poliovirus and other cocirculating species C enteroviruses reveal a high degree of plasticity

Abstract : The attenuated Sabin strains contained in the oral poliomyelitis vaccine are genetically unstable, and their circulation in poorly immunized populations can lead to the emergence of pathogenic circulating vaccine-derived polioviruses (cVDPVs). The recombinant nature of most cVDPV genomes and the preferential presence of genomic sequences from certain cocirculating non-polio enteroviruses of species C (EV-Cs) raise questions about the permissiveness of genetic exchanges between EV-Cs and the phenotypic impact of such exchanges. We investigated whether functional constraints limited genetic exchanges between Sabin strains and other EV-Cs. We bypassed the natural recombination events by constructing 29 genomes containing a Sabin 2 capsid-encoding sequence and other sequences from Sabin 2 or from non-polio EV-Cs. Most genomes were functional. All recombinant viruses replicated similarly in vitro, but recombination modulated plaque size and temperature sensitivity. All viruses with a 5′UTR from Sabin 2 were attenuated in mice, whereas almost all viruses with a non-polio 5′UTR caused disease. These data highlight the striking conservation of functional compatibility between different genetic domains of cocirculating EV-Cs. This aspect is only one of the requirements for the generation of recombinant cVDPVs in natural conditions, but it may facilitate the generation of viable intertypic recombinants with diverse phenotypic features, including pathogenicity. Recombination between viral RNA genomes is a well-known phenomenon in poliovirus (PV) and other entero-viruses (EVs). Intra-and intertypic recombination shapes the genetic diversity of these viruses, which often have mosaic genomes. Nevertheless, little is known about the permissiveness of intertypic genetic exchanges and their possible impact on phenotype. PV is the etiological agent of paralytic poliomyelitis, a disease characterized by acute flaccid paralysis due to the destruction of motor neurons following PV replication 1. The three serotypes of PV belong to Enterovirus species C (EV-C) (genus Enterovirus, family Picornaviridae). In addition to PV, the EV-C species includes more than 20 other serotypes defined according to the genomic sequence encoding their capsid proteins. EVs are small non-enveloped viruses containing a single-stranded RNA genome of positive polarity of approximately 7.5 kb in length. This genome consists of two untranslated regions (5′ UTR and 3′ UTR) flanking a single large open reading frame. The 5′ UTR and 3′ UTR contain secondary structures involved in initiating the translation and replication of the genome 2–4. The open reading frame is translated into a single polyprotein that is proteolytically processed to yield the four capsid proteins (VP1–4), which are encoded by the P1 region of the genome, and the non-structural proteins, encoded by the P2 and P3 regions. The non-structural proteins are involved in viral replication; they include proteases and the RNA-dependent RNA polymerase 3D. The World Health Organization program for the global eradication of poliomyelitis, which was launched in 1988, has been largely successful. This program has mostly been based on vaccination with the oral polio vaccine (OPV), which is composed of live attenuated strains of the three PV serotypes, the Sabin 1, 2 and 3 strains. Most of the determinants of vaccine strain attenuation, impairing replication in the nervous system, are located in the 5′ UTR and the region encoding the capsid proteins 5. Many of these determinants also confer a temperature-sensitive (ts) phenotype on the strains 6. The Sabin strains can replicate to high titers only in the digestive tract, conferring strong systemic and intestinal immunity, limiting subsequent PV replication and viral
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Scientific Reports, Nature Publishing Group, 2016, 〈10.1038/srep38831〉
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Maël Bessaud, Marie-Line Joffret, Bruno Blondel, Francis Delpeyroux. Exchanges of genomic domains between poliovirus and other cocirculating species C enteroviruses reveal a high degree of plasticity. Scientific Reports, Nature Publishing Group, 2016, 〈10.1038/srep38831〉. 〈pasteur-01415616〉

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