Classification and Genomic Diversity of Enterically Transmitted Hepatitis Viruses
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Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Classification and Genomic Diversity of Enterically Transmitted Hepatitis Viruses Donald B. Smith1,2 and Peter Simmonds2 1Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom 2Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, United Kingdom Correspondence: [email protected] Hepatitis A virus (HAV) and hepatitis E virus (HEV) are significant human pathogens and are responsible for a substantial proportion of cases of severe acute hepatitis worldwide. Genetically, both viruses are heterogeneous and are classified into several genotypes that differ in their geographical distribution and risk group association. There is, however, little evidence that variants of HAVor HEV differ antigenically or in their propensity to cause severe disease. Genetically more divergent but primarily hepatotropic variants of both HAVand HEV have been found in several mammalian species, those of HAV being classified into eight species within the genus Hepatovirus in the virus family Picornaviridae. HEV is classified as a member of the species Orthohepevirus A in the virus family Hepeviridae, a species that additionally contains viruses infecting pigs, rabbits, and a variety of other mammalian species. Other species (Orthohepevirus B–D) infect a wide range of other mammalian species including rodents and bats. epatitis Avirus (HAV) and hepatitis E virus ease in humans. However, the two viruses are H(HEV) show moderate genetic diversity, quite distinct in terms of their replication strat- both being classified into several genotypes in- egy, virion structure, and taxonomy (see Kenney fecting humans, and several additional species and Meng 2018; McKnight and Lemon 2018). infecting a wide range of other mammalian HAV is classified as a member of the Hepatovi- hosts. The genetic diversity of both viruses has rus genus in the large family Picornaviridae (Zell been extensively used as a tool to investigate et al. 2017). Although HAV is spread by the www.perspectivesinmedicine.org their molecular epidemiology and transmission. fecal–oral route, it is not known whether HAV Further studies have sought to determine the replicates within tissues of the gastrointestinal existence of differences between genotypes in tract, and its disease manifestations arise from their clinical presentations and pathogenicity the spread of virus infection to the liver. and will be reviewed. HEV is classified as a member of the Ortho- hepevirus genus in the family Hepeviridae (Em- erson and Purcell 2003; Purdy et al. 2015). Vi- CLASSIFICATION rions of hepeviruses are structurally distinct HAV and HEV are positive-stranded RNA vi- from picornaviruses (see Kenney and Meng ruses that share a propensity to cause liver dis- 2018) and their structural proteins are translated Editors: Stanley M. Lemon and Christopher Walker Additional Perspectives on Enteric Hepatitis Viruses available at www.perspectivesinmedicine.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a031880 Cite this article as Cold Spring Harb Perspect Med 2018;8:a031880 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press D.B. Smith and P. Simmonds from a separate subgenomic RNA expressed nucleotide sequence divergence ranges from during virus replication rather than as part of 3.8% among members of Hepatovirus A to a single polyprotein as in the picornaviruses. 29% among members of Hepatovirus G (mean Although there is detectable homology between intraspecies divergence of 16%), compared with the RNA-dependent RNA polymerase and heli- 30%–42% among members of different species case genes of picornaviruses and hepeviruses, (mean, 38%). The respective amino acid se- they have been assigned to different RNA virus quence divergence ranges are 0.8%–26% supergroups (I and III, respectively) (Koonin (mean, 11.6%) compared with 31%–48% 1991), indicating an extremely distant evolu- (mean, 41%). tionary relationship between them. Members of these new hepatovirus species share a number of genome characteristics with HAV, such as low G+C content (37.0%–37.8% DIVERSITY AND TAXONOMY OF HAV within HAV genotypes) compared with 33.7%– AND RELATED VIRUSES 39.3% in members of the new species. They also share the massive suppression of CpG dinucleo- Hepatovirus Species tide frequencies (10%–34% of frequencies ex- Until very recently, the genus Hepatovirus in- pected from their G+C content). Although there cluded a single species, HAV, whose members is some variability in genome length and posi- comprise a group of viruses known to infect tions of cleavage sites for the different structural humans and various nonhuman primate spe- and nonstructural proteins, members of all hep- cies. The species was renamed Hepatovirus A atovirus species generally show comparable ge- in 2014 for consistency with nomenclature nome organization and features. The latter in- conventions adopted elsewhere in the picorna- cludes their universal possession of internal virus family. Since 2015, however, a wide range ribosomal entry sites (IRES) in the 50-untrans- of further, genetically divergent hepatoviruses lated region (50UTR), of which most resemble have been described in seals (Anthony et al. the type III IRES of HAV in sequence and pre- 2015), shrews, and hedgehogs (order Eulipoty- dicted structure (Anthony et al. 2015; Drexler phla), several different rodent (Rodentia) and et al. 2015; Yu et al. 2016). However, viruses bat (Chiroptera) host species (Drexler et al. belonging to Hepatovirus C and Hepatovirus E 2015), and, most recently, woodchucks (Yu (infecting a bat and rodent species, respectively) et al. 2016; and see Sander et al. 2018). Collec- possessed a type IV IRES (Drexler et al. 2015), tively, these viruses are substantially more diver- structurally resembling those of certain other gent from each other and from HAV than are picornavirus genera (e.g., Tremovirus, Duck hep- www.perspectivesinmedicine.org existing human and nonhuman primate HAV atitis virus, and Sapelovirus). Hepatovirus spe- strains, consistent with them being assigned to cies are hepatotropic (Drexler et al. 2015), infect several additional species. Using translated se- a wide range of hosts, but show limited evidence quences from the structural gene region, VP2, for host specificity. Although members of the variants showing >7% divergence from all other species Hepatovirus A are restricted to humans variants might be assigned to as many as 13 and primates (macaques and African green new species (Drexler et al. 2015). In 2017, the monkey), related hosts such as hedgehogs and ICTV accepted the proposal to create new spe- shrews (order Eulipotyphla) are infected with cies to classify those hepatovirus variants for members of other hepatovirus species (Hepato- which (near-) complete genome sequences virus H and Hepatovirus I), as are rodents and were available and that clustered separately on bats. Conversely, members of a single species phylogenetic analysis. Accordingly, the genus (Hepatovirus H) can infect three quite different Hepatovirus now includes nine species (Hepato- hosts—hedgehogs (Erinaceus europaeus), tupias virus A–I) based on phylogenetic groupings (Tupaia belangeri chinensis), and bats (Eidolon (Fig. 1). Although distance thresholds have not helvum). Although the distribution of hepatovi- been specified in the current species definition, rus species is consistent with frequent jumps 2 Cite this article as Cold Spring Harb Perspect Med 2018;8:a031880 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press A Phylogeny SubgenotypesGenotypes Species Host EF406357 LC049342 JQ425480 EU526089 EU131373 A HM769724 X75216 X75214 LC128713 I HQ246217 M20273 KX088647 KY003229 B Hepatovirus A KX228694 AY644676 A II AY644670 B AB300205 B 0.5 AB279734 FJ227135 AB973400 A III AB279732 FJ360732 FJ360730 KT819575 D00924 V EU140838 KT452637 KT452641 Hepatovirus D KT452644 KT452685 KT229611 Hepatovirus F KT229612 KT452742 Hepatovirus C KT452735 Hepatovirus E KT452729 Hepatovirus G KT452730 KR703607 Hepatovirus B KT877158 KT452714 KT452691 Hepatovirus H KT452695 KT452698 KT452658 Hepatovirus I KT452661 B Sequence divergence 5′UTR VP4 VP2 VP3 VP1 2A 2B 2C 3A3B 3C 3D 3′UTR 1 Within genotype 0.9 Between genotype Hepatovirus B 0.8 Hepatovirus C Hepatovirus D 0.7 Hepatovirus E Hepatovirus F Hepatovirus G 0.6 Hepatovirus H Hepatovirus I 0.5 0.4 Amino acid sequence divergence 0.3 0.2 0.1 0 www.perspectivesinmedicine.org 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 7500 Genome position Figure 1. Phylogeny and sequence divergence of hepatitis A viruses (HAVs). (A) Phylogenetic analysis of the complete coding sequences of representative variants of HAV (species A) and of all available sequences of other nonhuman hepatoviruses infecting other mammalian species, labeled as in the key. (The coding region spans positions 723–7407 in the HAV-MBB sequences, M20273 [Paul et al. 1987].) The tree was constructed by maximum likelihood using an optimal substitution model (general time reversible and γ distribution). Robustness of branches was indicated by bootstrap resampling supported by ≥70 from 100 replicate samples. The tree was rooted using sequences from the most closely similar