Recombination between Poliovirus and Coxsackie A Viruses of Species C: A Model of Viral Genetic Plasticity and Emergence

Genetic recombination in RNA viruses was discovered many years ago for poliovirus (PV), an enterovirus of the Picornaviridae family, and studied using PV or other picornaviruses as models. Recently, recombination was shown to be a general phenomenon between different types of enteroviruses of the same species. In particular, the interest for this mechanism of genetic plasticity was renewed with the emergence of pathogenic recombinant circulating vaccine-derived polioviruses (cVDPVs), which were implicated in poliomyelitis outbreaks in several regions of the world with insufficient vaccination coverage. Most of these cVDPVs had mosaic genomes constituted of mutated poliovaccine capsid sequences and part or all of the non-structural sequences from other human enteroviruses of species C (HEV-C), in particular coxsackie A viruses. A study in Madagascar showed that recombinant cVDPVs had been co-circulating in a small population of children with many different HEV-C types. This viral ecosystem showed a surprising and extensive biodiversity associated to several types and recombinant genotypes, indicating that intertypic genetic recombination was not only a mechanism of evolution for HEV-C, but an usual mode of genetic plasticity shaping viral diversity. Results suggested that recombination may be, in conjunction with mutations, implicated in the phenotypic diversity of enterovirus strains and in the emergence of new pathogenic strains. Nevertheless, little is known about the rules and mechanisms which govern genetic exchanges between HEV-C types, as well as about the importance of intertypic recombination in generating phenotypic variation. This review summarizes our current knowledge of the mechanisms of evolution of PV, in particular recombination events leading to the emergence of recombinant cVDPVs

Genetic Relationship between Cocirculating Human Enteroviruses Species C

Recombination events between human enteroviruses (HEV) are known to occur frequently and to participate in the evolution of these viruses. In a previous study, we reported the isolation of a panel of viruses belonging to the Human enterovirus species C (HEV-C) that had been cocirculating in a small geographic area of Madagascar in 2002. This panel included type 2 vaccine-derived polioviruses (PV) that had caused several cases of acute flaccid paralysis in humans. Previous partial sequencing of the genome of these HEV-C isolates revealed considerable genetic diversity, mostly due to recombination. In the work presented herein, we carried out a more detailed characterization of the genomes of viruses from this collection. First, we determined the full VP1 sequence of 41 of these isolates of different types. These sequences were compared with those of HEV-C isolates obtained from other countries or in other contexts. The sequences of the Madagascan isolates of a given type formed specific clusters clearly differentiated from those formed by other strains of the same type isolated elsewhere. Second, we sequenced the entire genome of 10 viruses representing most of the lineages present in this panel. All but one of the genomes appeared to be mosaic assemblies of different genomic fragments generated by intra- and intertypic recombination. The location of the breakpoints suggested potential preferred genomic regions for recombination. Our results also suggest that recombination between type HEV-99 and other HEV-C may be quite rare. This first exhaustive genomic analysis of a panel of non-PV HEV-C cocirculating in a small human population highlights the high frequency of inter and intra-typic genetic recombination, constituting a widespread mechanism of genetic plasticity and continually shifting the HEV-C biodiversity

Genetic exchanges between poliovirus and coxsackievirus (a new model of viral evolution, ecosystem and emergence)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Molecular typing based on full-length VP1 sequences.

<p>Molecular typing based on full-length VP1 sequences.</p

Phylogenetic relationships between Madagascan CV-A13 field strains and other CV-A13 isolates for which sequences are available in GenBank, based on 3′ one-third of the VP1 region (∼300 nt).

<p>The length of the branches is proportional to the number of nucleotide changes (percent divergence). The percentage of bootstrap replicates is indicated if higher than 70%. The field strains isolated in Madagascar are indicated by full circles if isolated in 2002, by open circles if isolated in other years. For the other isolates, the location and year of isolation are indicated in the tree. Triangles indicate the prototype strains. The CV-A11 G9 sequence was introduced for correct rooting of the tree.</p

Phylograms depicting the relationships between the studied HEV-C in different genomic regions.

<p>The percentage of bootstrap replicates is indicated at nodes if higher than 70%. The length of branches is proportional to the number of nucleotide changes (percent divergence). The sequences of CV-A10 and EV-19 (members of HEV species A and B, respectively) were introduced for correct rooting of the tree. Triangles indicate the prototype strains, circles the field strains; the VDPV strain MAD004 is labelled with open circles. Each color corresponds to a given HEV-C serotype. Below each tree, the region taken in consideration for alignment is highlighted in red in the schematic diagram of the genome.</p

Phylogenetic relationships between Madagascan HEV-C field isolates collected in 2002 and other isolates for which sequences are available in GenBank, based on full-length VP1 sequences.

<p>The length of the branches is proportional to the number of nucleotide changes (percent divergence). The percentage of bootstrap replicates is indicated for the main nodes. Each area of grey shading corresponds to a serotype. The field strains isolated in Madagascar in 2002 are indicated by circles; the isolates whose full-length genome was subsequently sequenced are indicated in bold. For the other isolates, the location and year of isolation are indicated in the tree. Triangles indicate the prototype strains.</p

Common and Diverse Features of Cocirculating Type 2 and 3 Recombinant Vaccine-Derived Polioviruses Isolated From Patients With Poliomyelitis and Healthy Children

International audienceBackground. Five cases of poliomyelitis due to type 2 or 3 recombinant vaccine-derived polioviruses (VDPVs) were reported in the Toliara province of Madagascar in 2005.Methods. We sequenced the genome of the VDPVs isolated from the patients and from 12 healthy children and characterized phenotypic aspects, including pathogenicity, in mice transgenic for the poliovirus receptor.Results. We identified 6 highly complex mosaic recombinant lineages composed of sequences derived from different vaccine polioviruses and other species C human enteroviruses (HEV-Cs). Most had some recombinant genome features in common and contained nucleotide sequences closely related to certain cocirculating coxsackie A virus isolates. However, they differed in terms of their recombinant characteristics or nucleotide substitutions and phenotypic features. All VDPVs were neurovirulent in mice.Conclusions. This study confirms the genetic relationship between type 2 and 3 VDPVs, indicating that both types can be involved in a single outbreak of disease. Our results highlight the various ways in which a vaccine-derived poliovirus may become pathogenic in complex viral ecosystems, through frequent recombination events and mutations. Intertypic recombination between cocirculating HEV-Cs (including polioviruses) appears to be a common mechanism of genetic plasticity underlying transverse genetic variability