Evidence of Recombination between Divergent Hepatitis E Viruses

Abstract

Phylogenetic and recombination analysis was performed on 32 complete hepatitis E virus (HEV) genomes from infected humans and pigs. For the first time, evidence for recombination between divergent HEV strains was obtained, with at least two strains being found to have discordant phylogenetic relationships consistent with the occurrence of intragenotype recombination. This finding confirms that humans can be dually infected with divergent HEV strains and has implications for the emergence and evolution of new HEV epidemics.Hepatitis E virus (HEV) is a causative agent of enterically transmitted hepatitis disease and, apart from infections of pregnant women, is generally associated with low mortality (11,17). Outbreaks of HEV have been described to occur in many regions of the world, including Asia, Africa, and Mexico (1, 33, 53), while sporadic cases have been documented in the United States, Africa (9), and Europe (27,37,38,60). HEV is presumed to be a zoonotic disease, as surveys of both wild and domestic animals have found evidence for human-related HEVs in rats (12, 22), pigs (2,7,21,29,32,56), deer (45), and wild boar (41). Direct animal-to-human transmission of HEV has been demonstrated, for example, from deer to human as a result of eating uncooked meat (45). Interestingly, HEV characterized from swine in countries where HEV is not endemic is usually closely related to cases of sporadic human HEVs from the same country, for example, in the United States and Japan (29,30,42,57), while in India, where HEV is endemic, human and swine HEV strains are not closely related (2). This suggests that in certain regions HEV is more established in the human population and that in other regions HEV is emerging as a result of direct contact with animal reservoirs for the virus. Divergent HEVs with no human counterparts have also been found in chickens (avian HEV). Avian HEV shares only 50 to 60% nucleotide sequence identity with HEV from humans and swine (15,16).HEV is a positive single-stranded RNA virus that is approximately 7,200 nucleotides (nt) in length. HEV's genome is capped and polyadenylated and has three open reading frames (ORF) (Fig. 1). As the organization of HEV's genome resembles that of Caliciviridae, at one time it was considered a mem-FIG. 1. Genomic organization of HEV. The scale at the bottom of the figure corresponds to nucleotides (in thousands). ORF1 encodes a nonstructural polyprotein which provides guanylyl-methyltransferase and RNA-dependent RNA polymerase activities and possibly other functions (23,25). The ORF2 and ORF3 proteins are believed to be encoded by individual subgenomic RNAs generated during replication (44, 58). ORF2 encodes the viral capsid protein; ORF3, which contains one potential phosphorylation site, encodes a very small protein of about 123 amino acids (59). ORF3 proteins partition with the cytoskeleton, and it has been suggested that an interaction between ORF2 and ORF3 is associated with the assembly of virions (47,50). ORF3 is also believed to interact with proteins involv...

Genotype-Specific Evolution of Hepatitis E Virus

“…Following exploratory analyses to determine whether recombination detection was simply an artifact of complex patterns of mutations, a sequence was deemed recombinant if three or more methods had reported it as a recombinant. In agreement with prior reports of recombination in HEV (26,76,77), we identified 14 recombinant viruses, including novel recombinants (Table 6).…”

Reassortment and Concerted Evolution inBanana Bunchy Top VirusGenomes

“…A total of 132 coding sequences from all components of BBTV and other nanoviruses, including five identified VOL. 81,2007 GENOME EVOLUTION OF BBTV 1747 …”

“…Phylogenetic network methods were developed to visualize a non-tree-like network of target sequences and are particularly useful in studying organisms with reticulate evolutionary history (34). Such methods have been incorporated in phylogenetic analysis of viruses as evidence of recombination or conflicting signals in the genomes of, for example, Dengue virus (28), primate lentivirus (61), and hepatitis E virus (81). To examine the congruence of the phylogenetic trees obtained from study of DNA 1 and 3 sequences, we conducted a preliminary screening of conflict phylogenetic signals by an incongruence length difference (ILD) test (14).…”

Consensus proposals for classification of the family Hepeviridae

“…Within species Orthohepevirus A, four genotypes are currently described that infect humans (HEV-1, HEV-2, HEV-3 and HEV-4), and assignment of complete genome sequences to these genotypes is generally unambiguous. The only exceptions are recombinant viruses, which have been documented both within and between genotypes (Chen et al, 2012;van Cuyck et al, 2005;Fan, 2009;Wang et al, 2010), although in some cases recombinant viruses may represent laboratory artefacts (Wang et al, 2010). More problematic is the designation of additional genotypes HEV-5 and HEV-6, names which have been variously assigned to avian HEV and rat HEV (here proposed to be classified as members of the species Orthohepevirus B and Orthohepevirus C, respectively) and variants isolated from wild boar (Oliveira-Filho et al, 2013; Smith et al, 2013;Takahashi et al, 2011), or by implication to variants isolated from rabbits (Geng et al, 2011;Zhao et al, 2009).…”