Comprehensive full-length sequence analyses of human parechoviruses: diversity and recombination

Abstract

Human parechoviruses (HPeVs) are highly prevalent pathogens among very young children. Although originally classified into two serologically distinct types, HPeV1 and -2, recent analyses of variants collected worldwide have revealed the existence of 12 further types classified genetically by sequence comparisons of complete genome sequences or the capsid (VP1) gene. To investigate the nature of HPeV evolution, its population dynamics and recombination breakpoints, this study generated 18 full-length genomic sequences of the most commonly circulating genotypes, HPeV1 and -3, collected over a time span of 14 years from The Netherlands. By inclusion of previously published full-length sequences, 35 sequences were analysed in total. Analysis of contemporary strains of HPeV1 and those most similar to the prototype strain (Harris) showed that HPeV1 variants fall into two genetically distinct clusters that are much more divergent from each other than those observed within other HPeV types. Future classification criteria for HPeVs may require modification to accommodate the occurrence of variants with intermediate degrees of diversity within types. Recombination was frequently observed among HPeV1, -4, -5 and -6, but was much more restricted among HPeV3 strains. Favoured sites for recombination were found to flank the capsid region, and further sites were found within the non-structural region, P2. In contrast to other HPeV types, the majority of the HPeV3 sequences remained monophyletic across the genome, a possible reflection of its lower diversity and potentially more recent emergence than other HPeV types, or biological and/or epidemiological constraints that limit opportunities for co-infections with potential recombination partners.

The Association of Recombination Events in the Founding and Emergence of Subgenogroup Evolutionary Lineages of Human Enterovirus 71

“…Recombination is a frequently documented phenomenon in picornaviruses and contributes to their evolutionary diversity as well as a means to acquire new phenotypic traits from acquisition of novel combination of structural and nonstructural genes and 5=-untranslated region (5=-UTR) sequences. Recombination in picornaviruses was first observed between serotypes of poliovirus in vaccine recipients (8,20,39) and more recently in a wide range of human enteroviruses (1,15,16,21,31,41,43,45,48,56), foot-and-mouth disease virus (FMDV), and teschoviruses (55) and, more recently, parechoviruses (3,4). In each virus, recombination breakpoints concentrate in the 2A region, although further sites occur in P2 and P3 genes and in the 5=-UTR (1,3,16,30,33,49,67).…”

“…Recombination in picornaviruses was first observed between serotypes of poliovirus in vaccine recipients (8,20,39) and more recently in a wide range of human enteroviruses (1,15,16,21,31,41,43,45,48,56), foot-and-mouth disease virus (FMDV), and teschoviruses (55) and, more recently, parechoviruses (3,4). In each virus, recombination breakpoints concentrate in the 2A region, although further sites occur in P2 and P3 genes and in the 5=-UTR (1,3,16,30,33,49,67). In contrast, phylogenies of the more divergent capsid-encoding genes VP1, VP2, and VP3 are congruent with each other (and correspond to their serotypic classification) (31,42,49), leading to the idea that sequence diversification in structural gene regions is largely uncoupled from that of nonstructural genes (31,32,37,55).…”

Human Parechoviruses, New Players in the Pathogenesis of Viral Meningitis

“…echovirus 9 and 30 (Antona et al, 2007;Khetsuriani et al, 2006b), and is associated with the emergence of antigenic diverse genetic lineages or novel recombinants for which the community presumably is not immune protected (McWilliam Leitch et al, 2010). However, based upon the lower evolution rate and diversity of circulating HPeV3 strains (Benschop et al, 2010b;Calvert et al, 2010), diversification of HPeV into new lineages that are antigenically distinct is unlikely. The reason for the intermittent circulation of HPeV3 thus remains unclear.…”

“…That HPeV3 infects other cell lines than for example HPeV1, is underlined by recombination studies done in our laboratory. HPeV3 recombination is highly limited, while other HPeV types frequently recombine with each other (Benschop et al, 2008d(Benschop et al, , 2010bCalvert et al, 2010). This indicates that HPeV3 rarely gets into contact with other types in the same cell where recombinants are produced during replication of the infected viruses.…”

Human Memory B Cells Producing Potent Cross-Neutralizing Antibodies against Human Parechovirus: Implications for Prevalence, Treatment, and Diagnosis

“…The primary strains HPeV3-150237, HPeV4-251176, HPeV5-552322, and HPeV6-550389 were obtained in-house (34,35). In addition, a second, more recently circulating strain, HPeV1B-10452252, was obtained in-house (36,37). For testing of cross-neutralization, the following EV strains were used: EV71, CV-B3, RV-A16, CV-A9-AMC, CV-A9-1051883, CV-A9-1052186, E9-1252784, and E9-Barty (the numbers indicate clinical strains).…”