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.

Predicting Intraserotypic Recombination in Enterovirus 71

“…All of our current understanding of recombination in the generation of new strains of enteroviruses are based upon retrospective phylogenetic analysis which shows us that recent intra-and intertypic EV-A71 recombination events are limited to members of the same species group (13,14,16,42). In addition, the production of chimeric enterovirus genomes in other studies indicates a high level of plasticity (45)(46)(47). This plasticity, however, seems to be limited to intraspecies members, since no recent evidence for interspecies enterovirus recombination has been documented.…”

Viral chimeras decrypt the role of enterovirus capsid proteins in viral tropism, acid sensitivity and optimal growth temperature

“…Intertypic intraspecies recombination is a frequent event in nature, especially in non-RV EVs. While viable recombinants within the EV-A, -B and -C species have been reported to occur (both in vitro as well as in nature [ 24 , 25 ]), no similar observation has been reported for EV-D. To explore the role of capsid proteins in EV pathogenesis, we created several variants of capsid-chimeras, containing either the full capsid, full capsid and 2A, or VP1 alone. Out of all the constructs, only the exchange of the entire EV-D68 P1 region within the genomic framework of EV-D94 was as viable and fit as the parental viruses.…”

Development of a new oral poliovirus vaccine for the eradication end game using codon deoptimization

“…The level of viral fitness can thereby be modulated by varying the number of engineered synonymous changes. The capsid was targeted for modification because poliovirus is known to recombine with other human enteroviruses, and often only the capsid is retained 6,32 . Securing the modifications within the capsid region safeguards the attenuated phenotype even in recombinants, preventing further spread of Sabin-derived capsid vulnerable to reversion in the field.…”