Reemergence of Enterovirus 71 in 2008 in Taiwan: Dynamics of Genetic and Antigenic Evolution from 1998 to 2008

Abstract

In recent years, enterovirus 71 (EV71) has been a cause of numerous outbreaks of hand-foot-and-mouth disease, with severe neurological complications in the Asia-Pacific region. The reemergence in Taiwan of EV71 genotype B5 in 2008 resulted in the largest outbreak of EV71 in Taiwan in the past 11 years. Phylogenetic analyses indicated that dominant genotype changes from B to C or C to B occurred at least three times between 1986 and 2008. Furthermore, antigenic cartography of EV71 by using neutralization tests revealed that the reemerging EV71 genotype B5 strains formed a separate cluster which was antigenically distinct from the B4 and C genotypes. Moreover, analyses of full-length genomic sequences of EV71 circulating in Taiwan during this period showed the occurrence of intra-and interserotypic recombination. Therefore, continuous surveillance of EV71 including the monitoring of genetic evolution and antigenic changes is recommended and may contribute to the development of a vaccine for EV71.The genus Enterovirus ([EV] family Picornaviridae) contains numerous viruses that are pathogenic to humans. Human EVs (HEVs) have been classified into four species, HEV-A, HEV-B, HEV-C, and HEV-D, based on their sequence homologies (48). In contrast to other etiological agents of hand-foot-and-mouth disease that tend to cause mild and self-limiting disease, EV71 infection is often associated with other clinical manifestations including acute neurologic symptoms, such as poliomyelitis-like paralysis, encephalitis, aseptic meningitis, shock, and cardiac dysfunction (32).Since 1969, when EV71 was first isolated in California, EV71-associated outbreaks have been reported worldwide (42). EV71 infection reached epidemic proportions, causing sporadic cases or outbreaks and then becoming prevalent around the AsiaPacific region including Australia, Malaysia, Singapore, Japan, China, and Taiwan for the past 12 years (1, 16-18, 20, 25, 26, 28, 46, 53). Phylogenetic studies have classified EV71 into genotypes A, B, and C, which can be further subdivided into subgentotypes B1 to B5 and C1 to C5 (7,8,17,20,22,25,28,41,45,52,53). These reports indicated that the dominant EV71 strains circulating in the Asia-Pacific region varied genetically, suggesting that the virus was evolving.Intertypic or intratypic recombination of EV71 has been reported to occur frequently in the region encoding the nonstructural proteins and could potentially influence the replication, tissue tropism, and virulence of EV71 (10,11,18). These studies emphasized the importance of full-genome sequencing for the surveillance of EV71 evolution. Therefore, to analyze the evolution of EV71, we performed phylogenetic analysis of the Taiwan isolates from 1986 and from 1998 and 2008 based on the complete genomic sequences. In addition, neutralizing activities of human antiserum against the various subgenotypes of EV71 were investigated to evaluate the antigenic changes of EV71. We found evidence for intertypic and intratypic recombination and demonstrated variation in anti...

Structures of the Procapsid and Mature Virion of Enterovirus 71 Strain 1095

“…3D). This region at the 5-fold vertex represents a functional "hot spot," since these residues have been implicated in receptor binding and have been shown to determine virus virulence and affect positive selection (4,(10)(11)(12)18).…”

“…However, EV71 infection may lead to severe neurologic diseases, including meningitis, poliomyelitis-like disease, and fatal cases of encephalitis (3). Since first reported, EV71 has been implicated in an increasing number of outbreaks throughout the world and is now classified as an emerging infectious disease with pandemic potential (4,5). A thorough structural and mechanistic understanding of the virus and its interactions with host cells will support efforts to develop antiviral therapies, and we focus here on establishing a structural basis for this knowledge.…”

“…The mature capsid is built of 60 structural subunits or protomers, which are comprised of four structural proteins, VP1 to VP4 (VP1-4). Several key residues that map to the 5-fold symmetry vertex, VP1 98 and 145, have been linked to positive selection, virulence, and receptor binding (4,(10)(11)(12).…”

Antigenic and Receptor Binding Properties of Enterovirus 68

“…It was previously reported that the reemergence of B5 genotype resulted in a large EV71 outbreak in Taiwan, and detected B5 strains were shown to possess genetic and antigenic diversity compared to previously circulating strains (16). Similarly, the emer-gence of strains with different antigenicity might have been involved in the worldwide occurrence of EV68 outbreaks in recent years.…”

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“…There were reports of shifts of sub-genotype dominance in Taiwan and Japan, from B-sub-genotypes to C-sub-genotypes [22,23]. In more recent years, three new genotypes were discovered; one in India (designated as genotype D), one in Central Africa (designated as genotype E) and another from Madagascar (designated as genotype F) by sequencing the VP1 and VP2 regions of clinical isolates [24].…”