Complete Genome Analysis of the C4 Subgenotype Strains of Enterovirus 71: Predominant Recombination C4 Viruses Persistently Circulating in China for 14 Years

Abstract

Genetic recombination is a well-known phenomenon for enteroviruses. To investigate the genetic characterization and the potential recombination of enterovirus 71 (EV71) circulating in China, we determined the 16 complete genome sequences of EV71 isolated from Hand Foot Mouth Disease (HFMD) patients during the large scale outbreak and non-outbreak years since 1998 in China. The full length genome sequences of 16 Chinese EV71 in present study were aligned with 186 genome sequences of EV71 available from GenBank, including 104 China mainland and 82 international sequences, covering the time period of 1970–2011. The oldest strains of each subgenotype of EV71 and prototype strains of HEV-A were included to do the phylogenetic and Simplot analysis. Phylogenetic analysis indicated that all Chinese strains were clustered into C4 subgenotype of EV71, except for HuB/CHN/2009 clustered into A and Xiamen/CHN/2009 clustered into B5 subgenotype. Most of C4 EV71 were clustered into 2 predominant evolutionary branches: C4b and C4a evolutionary brunches. Our comprehensive recombination analysis showed the evidence of genome recombination of subgenotype C4 (including C4a and C4b) sequences between structural genes from genotype C EV71 and non-structural genes from the prototype strains of CAV16, 14 and 4, but the evidence of intratypic recombination between C4 strains and B subgenotype was not enough strong. This intertypic recombination C4 viruses were first seen in 1998 and became the predominant endemic viruses circulating in China mainland for at least 14 years. A shift between C4a and C4b evolutionary brunches of C4 recombination viruses were observed, and C4a viruses have been associated with large scale nationwide HFMD outbreak with higher morbidity and mortality since 2007.

Metagenomics Study of Viral Pathogens in Undiagnosed Respiratory Specimens and Identification of Human Enteroviruses at a Thailand Hospital

“…Our study produced a large set of genome sequences which contain complete coding sequences for EV-A71-B5 and EV-B of diverse genotypes in Thailand, whereas most previous genome studies in Asia focused on HFMD pathogen EV-A71 21,30. Phylogenetic and recombination analysis in the present study suggest VP1 gene is consistent with genome or CDS sequence in phylogeny-based typing of enteroviruses, whereas the more conserved protease and polymerase sequences are not suitable for genotyping due to the high recombination rate in these regions.…”

Best practices to prevent transmission and control outbreaks of hand, foot, and mouth disease in childcare facilities: a systematic review

“…6,[8][9][10][11][12] It is therefore important to distinguish EV71 from other HFMD strains during the outbreak. 13 In 2011, following the emergence of HFMD outbreaks throughout the Western Pacific Region, the HKSAR Government announced EV71 infection as one of the 47 statutorily notifiable communicable diseases under the Prevention and Control of Disease Ordinance (Central Notification Office).…”

Comprehensive safety assessment of a human inactivated diploid enterovirus 71 vaccine based on a phase III clinical trial

“…[2][3][4][5] HFMD is caused by polioviruses, coxsackieviruses, echoviruses, and enteroviruses. 1,6 Although HFMD outbreaks are more commonly associated with coxsackievirus 16 (CA16), 5 enterovirus 71 (EV71) has been reported to be significantly associated with most global outbreaks, particularly with outbreaks with high mortality, [7][8][9][10][11][12][13][14][15][16] as was also observed in China. 1,6,7,14,15 The number of reported HFMD cases has sharply increased in almost all Chinese provinces since the first EV71 infection-related outbreak in Fuyang in 1995.…”

“…1,6 Although HFMD outbreaks are more commonly associated with coxsackievirus 16 (CA16), 5 enterovirus 71 (EV71) has been reported to be significantly associated with most global outbreaks, particularly with outbreaks with high mortality, [7][8][9][10][11][12][13][14][15][16] as was also observed in China. 1,6,7,14,15 The number of reported HFMD cases has sharply increased in almost all Chinese provinces since the first EV71 infection-related outbreak in Fuyang in 1995. 1,6,8,14,15 In addition to HFMD, EV17 infection can also cause herpangina, aseptic meningitis, febrile illness, viral exanthema, and airway infection.…”

“…1,6,7,14,15 The number of reported HFMD cases has sharply increased in almost all Chinese provinces since the first EV71 infection-related outbreak in Fuyang in 1995. 1,6,8,14,15 In addition to HFMD, EV17 infection can also cause herpangina, aseptic meningitis, febrile illness, viral exanthema, and airway infection. 2,16,17 As no pharmacological intervention has been found to prevent and control EV71, a vaccine is urgently sought to control EV71 epidemics.…”