Evolutionary trajectory of the VP1 gene of human enterovirus 71 genogroup B and C viruses

Abstract

From 1963 to 1986, human enterovirus 71 (HEV71) infections in the Netherlands were successively caused by viruses of subgenogroups B0, B1 and B2. A genogroup shift occurred in 1987, after which viruses of subgenogroups C1 and C2 were detected exclusively. This is in line with HEV71 typing in Australia, Europe and the USA, but is distinct from that in the Asian Pacific region, where HEV71 subgenogroups B3–B5 and C4–C5 have caused large outbreaks since 1997. To understand these observations in HEV71 epidemiology, the VP1-encoding regions of 199 HEV71 strains isolated in the Netherlands between 1963 and 2008 were used to study the detailed evolutionary trajectory and population dynamics of HEV71. Genogroup B viruses showed an epochal evolution, whereas genogroup C viruses evolved independently, which is in line with the co-circulation of C1 and C2 viruses in the Netherlands since 1997. Considering that strains from the Netherlands are interspersed phylogenetically with GenBank reference strains, the evolution of B1–B2, C1–C2 viruses has a global nature. Phylodynamic analysis confirmed that increased reporting of HEV71 infections in 1986 and 2007 reflected true epidemics of B2 and C2 viruses, respectively. Sequence analysis of the complete capsid region of a subset of isolates revealed several (sub)genogroup-specific residues. Subgenogroup B2-specific rabbit antiserum showed cross-neutralization of B0, B1 and B2 viruses, but not of subgenogroup C1 or C2 viruses, probably explaining the global shift to genogroup C in 1987 following a B2 epidemic. Anti-C1 rabbit serum neutralized both genogroup B and C viruses. Global herd immunity against C1 and C2 viruses possibly explains why epidemics with subgenogroups B4 and C4 are restricted to the Asian Pacific region.

Phylogenetic Patterns of Human Coxsackievirus B5 Arise from Population Dynamics between Two Genogroups and Reveal Evolutionary Factors of Molecular Adaptation and Transmission

“…Phylogenies estimated with the 1D VP1 sequences showed a pattern of continuous lineage turnover for echovirus 30 (enterovirus B species) (17) and enterovirus 71 (enterovirus A species) (18). This indicates that virus variants are continuously emerging and are replacing the earlier prevailing viruses, a pattern similar to that of influenza A virus (19).…”

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

“…4). These phylogenetic reconstructions for genogroups B and C additionally place recombination events into the differing evolutionary trajectories of GgB and GgC that have been characterized previously (61,63). GgB is characterized by a series of successive emergence and extinctions of the B1 through B5 subgenogroups over the period from 1970 to the present day, with outbreaks occurring throughout South and East Asia in a cycle of approximately every 3 years (1993, 1997, 2000, 2003, 2006, and 2008) (9,23,46,58,62).…”

“…Screening of large data sets of VP1 sequences provides little if any evidence for any sites in the capsid coding region being subjected to the positive selection that would typically be observed in sites under strong immunological pressure. Consistent with these analyses, there is little evidence from serological cross-neutralization experiments for genogroup-or subgenogroup-specific antibodies, nor indeed the existence of measurable antigenic diversity between EV71 isolates (24,26,28,40,63). However, infections with GgB variants induce higher levels of neutralizing antibodies than GgC, supporting an idea that the emergence of GgC may have been assisted by its intrinsically lower immunogenicity than GgB (40).…”

“…What is rather less clear is the underlying mechanisms and selection pressures involved in the generation of new serotypes, as this process has to date not been directly observed. In the case of EV71, it has been hypothesized that the evolution of capsid genes, particularly VP1, represents an equivalent, immunologically driven process of diversification (61,63) and that the successive appearance of novel genogroups and subgenogroups is favored by an absence of preexisting immunity to them. The genetically diverse variants of EV71 may thus be precursors in their eventual further diversification into new serotypes in the future.…”

Human picornaviruses associated with neurological diseases and their neutralization by antibodies

“…Genotypes B3, B4, B5, C1, C2, C4 and C5 contributed to recent outbreaks [129]. Interestingly, cross-neutralization of different genotypes by immune sera from animals and humans is limited, indicating that EV-A71 became antigenically diverse [130][131][132]. Furthermore, using monoclonal neutralizing antibodies, Chen et al even observed antigenic variation between isolates classified to the same genotype [133].…”