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HEVs have a high rate of mutation and recombination because they co-circulate in human and animal hosts; rapidly evolving to create new variants. This rapid evolution is evident from the abundance of variants identified annually.
HEV serotypes are defined by neutralizing epitopes of the virus capsid proteins, particularly VP1 as well as VP2 and VP3 (Oberste et al., 1999a). The VP1 protein is the outermost viral capsid protein and contains the major neutralization sites thus an ideal target for vaccine development (Oberste et al., 2006). Besides being a major neutralization site, several other determinants have been mapped to the VP1 including: determinants of virulence, virion thermo stability, altered host range, in vitro cell tropism, persistent infection and plaque morphology (Muir et al., 1998). The VP1 partial genome sequence is sufficient to identify all serotypes and has been routinely used in enterovirus serotype characterization (Oberste et al., 2006; Zhou et al., 2009; Kosakovsky et al., 2005a). Partial sequencing of the HEV VP1 gene revealed that strains belonging to groups A, B and C were in co-circulation in Kibera, Kenya during the study period (2009 – 15). The HEV serotypes reported in this study include Coxsackievirus A24, A13 and A20; Echovirus E12, E13, E25 and E9 as well as HEV A76 and C99.
CV-A20 is associated with aseptic meningitis, herpangina, myocarditis and Bornholm diseases (Yin-Murphy et al., 1996). HEV-A76 is a recently reported HEV serotype classified genetically as group A EV (EV-A) and associated with viral encephalitis (Sapkal et al., 2009). Although HEV-76 is not among the most commonly reported HEV serotypes (Nasri et al., 2007) it has caused various enterovirus outbreaks including the viral encephalitis outbreak that occurred in northern India in 2006 (Sapkal et al., 2009).
Nucleotide and amino acid homology results confirmed the serotypes by ≥75% nucleotide and ≥85% amino acid identity to serotype prototypes and variant strains (Oberste et al., 2006). Evolution and genomic diversity of the various HEV circulating strains is important in identifying recombination and mutations that may contribute to the pathogenesis of various serotypes (Oberste et al., 1999a). Serotype diversity presents an environment for intra-serotype recombination that would determine the molecular characteristics of the virus population. It is also possible that both multi-serotype infections as well as the evolution of viral antigenicity are responsible for epidemics (Behura et al., 2013).
The VP1 gene harbors the BC and DE – loops which are important immunogenic regions associated with HEV infectivity (L’Huillier et al., 2015). Amino acid substitutions in these loops can significantly alter the host’s neutralizing response to the virus. An example is the Echovirus 9 where cytolytic capabilities of lytic clone-derived Echovirus 9 in human pancreatic islets have been reported to be modified by a single amino acid substitution (T81A) in the capsid protein VP1(Paananen et al.,2013). We found that the ECHO-E9 strain identified in this study had the T81A amino acid substitution suggesting a cytolytic state that could possibly result in necrosis of the human pancreatic islets. Amino acid substitutions have in some cases resulted in changes in viral antigenicity (e.g., a single amino acid alanine at position 107 in the VP1 protein, when changed to threonine in the CCA strain, dramatically diminished EV71 replication as a result of impaired maturation cleavage of the VP0 protein during EV71 assembly and subsequent viral uncoating (Zhang et al.,2017). A single amino acid change at codon position 103 observed in HEV – A76 translated to a change from glutamine to methionine. Further in vitro studies could elucidate the impact of this amino acid substitution.
Negative selection plays an important role in maintaining the long-term stability of a virus by removing deleterious mutations. This form of selection ensures that any improved structures are maintained (Kosakovsky et al., 2005b). The numerous amino acid substitutions in our study serotypes suggest that the viruses are undergoing negative selection. This is confirmed by FEL and SLAC analysis of HEV – A76 (Table 4) that suggested purifying selection and correlated well with a previous study (Opanda et al., 2016) that also suggested negative selection of circulating enteroviruses in the same age group in Kenya.
Negative and positive selection were observed in CV – A20 suggesting that both purifying and pervasive pressures are at play in this serotype strain (Linsuwanon et al., (2012).
BUSTED found significant evidence (LRT, p-value = 0.000 ≤ .05) of gene-wide episodic diversifying selection in test branches of study ECHO – E25 phylogeny. There was evidence that at least one site on at least one test branch had experienced diversifying selection in ECHO – E25 serotype (Murrell et al., 2015). Positive selection in CV – A20 and ECHO – E25 suggested a tendency of the virus to escape from stabilizing selection by positively mutating some residues in the antigenic epitope, in particular the residue located on the surface BC and DE loops, and further resulting divergence from other homologous HEV serotypes (Zhou et al., 2016). Selection analyses conducted on the VP1 amino acid sequences in several studies revealed that most of the positively selected codons are found in the BC and DE loop regions (Zhou et al., 2016). This suggests that positive selection identified in CV – A20 and other strains in this study could have an antigenic effect.
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