Genetic evolution of enterovirus 71: epidemiological and pathological implications

Bible, Jon M.; Pantelidis, Panagiotis; Chan, Paul K.S.; Tong, C. Y. William

doi:10.1002/rmv.538

Cited by 138 publications

(95 citation statements)

References 67 publications

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“…However, the VP1 gene is considered to be the most informative and robust region for evolutionary study due to a high degree of diversity and lack of involvement in recombination (Bible et al, 2007). To date, three EV71 genogroups (A, B and C) have been described (Brown et al, 1999), with genogroups B and C further divided into five subgenogroups, B1-B5 and C1-C5, respectively.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of enterovirus 71 and coxsackievirus A16 using the 5′ untranslated region and VP1 region

Zhou

Kong

Wang

et al. 2011

Journal of Medical Microbiology

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Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are members of the species Human enterovirus A, and are both major and independent aetiological agents of hand-foot-and-mouth disease. The human enterovirus (HEV) 59 untranslated region (UTR) is fundamentally important for efficient virus replication and for virulence, whilst the VP1 region correlates well with antigenic typing by neutralization, and can be used for virus identification and evolutionary studies. A comparison was undertaken of the 59UTR and VP1 nucleotide sequences of five EV71 clinical isolates and 10 CVA16 clinical isolates from one laboratory with the 59UTR and VP1 sequences of 104 EV71 strains and 45 CVA16 strains available in GenBank. The genetic relationships were analysed using standard phylogenetic methods. The EV71 phylogenetic analysis showed that the VP1 sequences were clustered into three genogroups, A, B and C, with genogroups B and C further divided into five subgenogroups, B1-B5 and C1-C5, respectively. All EV71 strains were clustered similarly in the 59UTR and VP1 trees, except for one Taiwanese strain, which demonstrated different clustering in the two trees, suggesting a recombination event in the phylogeny. The CVA16 phylogenetic analysis showed that the VP1 sequences were clustered into two genogroups, A and B, with genogroup B further divided into B1 (B1a and B1b), B2 and a possible B3; and that a similar pattern and grouping of all strains were displayed in the 59UTR tree. This study demonstrated that comparing the two regions provides evidence of epidemiological linkage of HEV-A strains, and that mutation in the two regions plays a vital role in the evolution of these viruses. The combination of molecular typing and phylogenetic sequence analysis will be beneficial in both individual patient diagnosis and public health measures. INTRODUCTIONEnterovirus 71 (EV71) and coxsackievirus A16 (CVA16), members of the species Human enterovirus A in the genus Enterovirus, family Picornaviridae, are both major and independent aetiological agents of large outbreaks of handfoot-and-mouth disease (HFMD). In contrast to CVA16, EV71-associated HFMD is more frequently associated with serious neurological complications and fatalities (McMinn et al., 2001b). Initial EV71 isolates were identified in the USA and Australia in the early 1970s, and in HFMD outbreaks in Sweden and Japan (Wong et al., 2010). Since 1997, the Asia-Pacific region has had several large EV71 epidemics, including in the Chinese mainland, Taiwan, Singapore, Malaysia and Japan. Several outbreaks have also been recorded in Australia (Gilbert et al., 1988;Sanders et al., 2006;McMinn et al., 2001b). Co-circulation of EV71 and CVA16 has contributed to serious HFMD outbreaks in China in (Zhang et al., 2009), Taiwan in 1998(Lin et al., 2003), and Malaysia in 1997(Podin et al., 2006.The enterovirus genome is a positive ssRNA molecule of approximately 7500 nt, comprising a single ORF flanked 59Abbreviations: CVA16, coxsackievirus A16; EV71, enterovirus 71; HEV, human enterovirus; ...

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Section: Discussionmentioning

confidence: 99%

Molecular characterization of enterovirus 71 and coxsackievirus A16 using the 5′ untranslated region and VP1 region

Zhou

Kong

Wang

et al. 2011

Journal of Medical Microbiology

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“…Another significant member of the Enterovirus genus is enterovirus 71 (EV71), which has caused large outbreaks in South East Asia in recent years. Infection with EV71 can result in hand-foot-and-mouth disease, but patients -especially children under 5 years of age -in severe cases develop a potentially fatal central nervous system disease [5]. Currently, there are no approved antiviral drugs to treat enterovirus infections.…”

Section: Introductionmentioning

confidence: 99%

Coxsackievirus mutants that can bypass host factor PI4KIIIβ and the need for high levels of PI4P lipids for replication

et al. 2012

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RNA viruses can rapidly mutate and acquire resistance to drugs that directly target viral enzymes, which poses serious problems in a clinical context. Therefore, there is a growing interest in the development of antiviral drugs that target host factors critical for viral replication, since they are unlikely to mutate in response to therapy. We recently demonstrated that phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) and its product phosphatidylinositol-4-phosphate (PI4P) are essential for replication of enteroviruses, a group of medically important RNA viruses including poliovirus (PV), coxsackievirus, rhinovirus, and enterovirus 71. Here, we show that enviroxime and GW5074 decreased PI4P levels at the Golgi complex by directly inhibiting PI4KIIIβ. Coxsackievirus mutants resistant to these inhibitors harbor single point mutations in the non-structural protein 3A. These 3A mutations did not confer compound-resistance by restoring the activity of PI4KIIIβ in the presence of the compounds. Instead, replication of the mutant viruses no longer depended on PI4KIIIβ, since their replication was insensitive to siRNA-mediated depletion of PI4KIIIβ. The mutant viruses also did not rely on other isoforms of PI4K. Consistently, no high level of PI4P could be detected at the replication sites induced by the mutant viruses in the presence of the compounds. Collectively, these findings indicate that through specific single point mutations in 3A, CVB3 can bypass an essential host factor and lipid for its propagation, which is a new example of RNA viruses acquiring resistance against antiviral compounds, even when they directly target host factors.

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“…Although large outbreaks of human enterovirus 71 (EV-71) have been reported worldwide since the 1960s, the prevalence of severe EV-71 infections is currently higher in the Asia-Pacific region (Bible et al, 2007;Schmidt et al, 1974). Neurological cases with a high case fatality rate were first recorded in Bulgaria in 1975, where they were mainly associated with poliomyelitis-like paralysis, and in Hungary in 1978 (Chumakov et al, 1979;Nagy et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

Phylogenetic evidence for a recent spread of two populations of human enterovirus 71 in European countries

Mirand

Schuffenecker

Henquell

et al. 2010

Journal of General Virology

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Human enterovirus 71 (EV-71) is a cause of seasonal epidemics of hand, foot and mouth disease, and of less common but severe neurological manifestations. Uncertainty persists regarding the circulation of virus populations in several geographical areas and the timescale of their dissemination. We determined EV-71 sequences at loci 1D (VP1 capsid protein) and 3CD (nonstructural proteins) in 86 strains recovered in Austria, France and Germany and performed an evolutionary genetic study of extant virus populations. Phylogenetic analyses positioned 78 of the 86 sequences within two clades among subgenogroups C1 and C2. A minor sequence cluster was assigned to subgenogroup C4. Analyses incorporating the available sequences estimated the substitution rate in genogroup C at 3.66¾10 "3 and 4.46¾10 "3 substitutions per site year "1 for loci 1D and 3CD, respectively, assuming a relaxed molecular-clock model for sequence evolution. Most of the 'European' strains belonged to clades C1b and C2b, which originated in 1994 [95 % confidence interval (CI), 1992.7"1995.8] and 2002 (95 % CI, 2001.6"2003, respectively. Estimates of divergence times for locus 3CD were consistent with those measured for locus 1D. Intertwining between clades representing EV-71 subgenogroups and clades corresponding to other enterovirus types (notably early coxsackievirus A prototype strains) in the 3CD phylogeny is highly indicative of ancestral recombination events. Incongruent phylogenetic patterns estimated for loci 1D and 3CD show that a single tree cannot model the epidemic history of circulating EV-71 populations. The evolutionary timescale of genogroup C estimated for both loci was measured only in decades, indicating recent dissemination.

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Genetic evolution of enterovirus 71: epidemiological and pathological implications

Cited by 138 publications

References 67 publications

Molecular characterization of enterovirus 71 and coxsackievirus A16 using the 5′ untranslated region and VP1 region

Molecular characterization of enterovirus 71 and coxsackievirus A16 using the 5′ untranslated region and VP1 region

Coxsackievirus mutants that can bypass host factor PI4KIIIβ and the need for high levels of PI4P lipids for replication

Phylogenetic evidence for a recent spread of two populations of human enterovirus 71 in European countries

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