Changes in the EV-A71 Genome through Recombination and Spontaneous Mutations: Impact on Virulence

Abstract

Enterovirus 71 (EV-A71) is a major etiological agent of hand, foot and mouth disease (HFMD) that mainly affects young children less than five years old. The onset of severe HFMD is due to neurological complications bringing about acute flaccid paralysis and pulmonary oedema. In this review, we address how genetic events such as recombination and spontaneous mutations could change the genomic organization of EV-A71, leading to an impact on viral virulence. An understanding of the recombination mechanism of the poliovirus and non-polio enteroviruses will provide further evidence of the emergence of novel strains responsible for fatal HFMD outbreaks. We aim to see if the virulence of EV-A71 is contributed solely by the presence of fatal strains or is due to the co-operation of quasispecies within a viral population. The phenomenon of quasispecies within the poliovirus is discussed to reflect viral fitness, virulence and its implications for EV-A71. Ultimately, this review gives an insight into the evolution patterns of EV-A71 by looking into its recombination history and how spontaneous mutations would affect its virulence.

Keywords: EV-A71; epidemiology; quasispecies; recombination; spontaneous mutations; virulence.

Figure 1

Schematic representation of the EV-A71 genome (7.4 Kb). The position of the VPg primer is shown at the 5′ NTR end of the genome; the Open Reading Frame (ORF) contains the structural viral protein P1 which is cleaved to yield VP1, VP2, VP3 and VP4, and non-structural viral proteins P2 (cleaved to yield 2A, 2B and 2C) and P3 (cleaved to yield 3A, 3B, 3C and 3D). The 3′ NTR end of the genome contains the poly (A) tail.

Figure 2

Illustration showing the two events of recombination of HEV-B (CBV16, E1, E12 and X) using similarity plots. CBV-16, E12, E1 and X refer to the designated names of four ancestral strains of four different serotypes. The white arrows indicate the recombination events between the two ancestral strains (CBV-16 and E12) and further recombination with E1.

Figure 3

Comparison of the nucleotide sequence between the Wild Type Poliovirus, Poliovirus Sabin Strain 1, 2 and 3 and EV-A71 strain 41(GenBank: AF316321). PV Sabin 1, PV Sabin 2 and PV Sabin 3 contain altered nucleotides in the 5′-NTR of ssRNA. Shaded areas in different shades of grey indicate the location where the altered nucleotides are.

Figure 4

Comparison of a fatal (AF316321.2) and a non-fatal (AF 352027.1) strain isolated from the HFMD outbreak in Singapore (2000). Highlighted in grey shows the difference of a single nucleotide (A) was observed at nucleotide position 5262 (amino acid residue 1506) in the 3A non-structural region of the fatal strain [50].