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

Abstract

Enterovirus 71 (EV71) is responsible for frequent large-scale outbreaks of hand, foot, and mouth disease worldwide and represent a major etiological agent of severe, sometimes fatal neurological disease. EV71 variants have been classified into three genogroups (GgA, GgB, and GgC), and the latter two are further subdivided into subgenogroups B1 to B5 and C1 to C5. To investigate the dual roles of recombination and evolution in the epidemiology and transmission of EV71 worldwide, we performed a largescale genetic analysis of isolates (n ‫؍‬ 308) collected from 19 countries worldwide over a 40-year period. A series of recombination events occurred over this period, which have been identified through incongruities in sequence grouping between the VP1 and 3Dpol regions. Eleven 3Dpol clades were identified, each specific to EV71 and associated with specific subgenogroups but interspersed phylogenetically with clades of coxsackievirus A16 and other EV species A serotypes. The likelihood of recombination increased with VP1 sequence divergence; mean half-lives for EV71 recombinant forms (RFs) of 6 and 9 years for GgB and GgC overlapped with those observed for the EV-B serotypes, echovirus 9 (E9), E30, and E11, respectively (1.3 to 9.8 years). Furthermore, within genogroups, sporadic recombination events occurred, such as the linkage of two B4 variants to RF-W instead of RF-A and of two C4 variants to RF-H. Intriguingly, recombination events occurred as a founding event of most subgenogroups immediately preceding their lineage expansion and global emergence. The possibility that recombination contributed to their subsequent spread through improved fitness requires further biological and immunological characterization.

Molecular epidemiology of coxsackievirus type B1

“…This is comparable to those of other enteroviruses (enterovirus 71 [33], echovirus 6 [34][35][36][37], coxsackievirus A4 [38] and echovirus 3 [39]) but slightly higher than what was published for echovirus 9 and echovirus11 [23].…”

Recombinant Coxsackievirus A2 and Deaths of Children, Hong Kong, 2012

“…Although recombination was evident in the 4 CVA2 strains, lack of comparative sequences indicated that the timing of recombination events was unknown, and low overall similarity to comparison sequences suggested that these events could be distant in time. As in many studies of human enterovirus A strains, lack of complete genome sequences for most serotypes, with the possible exception of EV71, limits interpretation of results for recombination analysis ( 10 , 11 ). In the present study, only 2 complete genome sequences of CVA4 strains (prototype strain High Point and strain SZ/CHN/09) were included in recombination analysis.…”

Enterovirus 71–associated Hand, Foot, and Mouth Disease, Southern Vietnam, 2011

“…Subgenogroup C4 has been found in the region since 1998 ( 8 ), and viruses from our study cluster with recent C4 viruses from the People’s Republic of China. Emergence of novel subgenotypes, often related to recombination events in noncoding regions ( 9 ), and switches of dominant subgenotypes are common and may be associated with large outbreaks. Most outbreaks reported in the Asia-Pacific region during the last decade were caused by previously undefined EV71 subgenogroups ( 10 ), but there is no evidence of differences in virulence.…”