Genus: Hepatovirus


Genus: Hepatovirus

Distinguishing features

In contrast to those of other picornaviruses, protein 1A of hepatitis A virus (HAV) is extremely small (~23 aa) and does not appear to be myristoylated at its N-terminus (Tesar et al., 1993). A significant fraction of RNA containing particles possess uncleaved 1AB. Immature HAV may contain uncleaved 1D-2A (pX) precursor protein (Anderson and Ross 1990, Wang et al., 2015, Graff et al., 1999). HAV is non-cytopathogenic and egress of virus is poorly understood, but particles are released within membranous structures ("cloaked particle", "enveloped HAV", eHAV) containing one to four virions with processed 1AB and uncleaved pX (Feng et al., 2013). Membranes are thought to be removed when eHAV is shed through the bilary tract into intestine. During final morphogenesis step, pX is cleaved off VP1 by an unknown host protease. 

Virion

Morphology

No surface morphology is visible by EM. The crystal structure of HAV has been resolved (Wang et al., 2015).

Physicochemical and physical properties

Viruses are very stable, resistant to acid pH and elevated temperatures (60°C for 10 min). Buoyant density in CsCl is 1.32-1.34 g cm-3.

Nucleic acid

Length of genome (Cohen et al., 1987b, Cohen et al., 1987a, Anthony et al., 2015, Drexler et al., 2015, Yu et al., 2016): c. 7,487 nt (5'-UTR: c. 734 nt; ORF: 6,684-6,693, nt; 3'-UTR: 53-59 nt).

Although the IRES is distantly related to the type II IRES, it has been designated as type III. The 5′-UTR contains a 5′-terminal hairpin, two putative pseudoknots, and a short (c. 40 nt) pyrimidine-rich (i.e. not a pure poly-C) tract upstream of the IRES. The cre is located in the 3D region. Nucleotide sequence identity between different HAV strains is generally greater than 80%.

Genome organization and replication

Genome layout:

VPg+5'UTRIRES-III[1A-1B-1C-1D-2A/2B-2C/3A-3B-3C-3D]3'UTR-poly(A)

The deduced polyprotein has a length of 2,227-2,230 amino acids. The polyprotein contains only a single proteinase (3Cpro). There is no clearly defined L protein, and 2A has no proteolytic activity. The primary cleavage of the polyprotein occurs at the 2A/2B junction, and is catalyzed by 3Cpro. The 1D/2A cleavage may be directed by an unknown cellular protease, or the VP1 protein may be subject to C-terminal trimming as in cardioviruses. Replication in cell culture occurs slowly, with little CPE, and with low yields of virus compared to most other picornaviruses. The IRES differs from those of other picornaviruses in that its activity is dependent on intact eIF-4G.

Antigenicity

Members of Hepatovirus A belong to a single serotype and are highly conserved in their antigenic properties. Most antibodies are directed against a single, conformationally defined immunodominant antigenic site that is comprised of aa residues of the VP3 and VP1 proteins on the surface of the virion. eHAV which circulates in host blood is protected from neutralization by a cell-derived envelope. No serological data are available on phopiviruses (Hepatovirus B).

Biology

HAV infects epithelial cells of the small intestine and hepatocytes of primates. Virus is predominantly replicated within the liver, excreted via the bile and present in feces in high titer. Viral shedding is maximal shortly before the onset of clinical signs of hepatitis, which probably represents immunopathologically-mediated liver injury. Clinical manifestations are fever, jaundice, light stools, abdominal pain, and occasionally diarrhea. HAV generally establishes a persistent infection when inoculated on to any of a wide range of primate cells in vitro, but persistent infection does not occur in vivo, and the viruses are not associated with chronic hepatitis. HAVs can be divided into two distinct biotypes that are phylogenetically distinct and have different preferred hosts (all species of primates: humans, chimpanzees, owl monkeys and marmosets, for one biotype, versus green monkeys and cynomolgus monkeys for the other). These two biotypes share cross-reacting antigens, but have biotype-specific epitopes that can be distinguished by monoclonal antibodies. Little biological data are available on phopiviruses; RNA of these viruses have been detected in fecal samples, liver and other tissue samples of various small mammals (seals, woodchucks, various bat species, hedgehogs, rodents, shrews and tupajas).

Species demarcation criteria

Members of a species of the genus Hepatovirus share a common genome organization.

The divergence (number of differences per site between sequences) of known Hepatovirus species ranges from 0.18-0.40 for P1 and 0.19-0.49 for 3CD.

Thirteen types have been classified by means of phylogenetic clustering (HepV-B1 [PhV], HepV-C1, HepV-D1, -D2, HepV-E1, HepV-F1, -F2, HepV-G1, -G2, HepV-H1 to -H3, HepV-I1). Human variants of HAV have been classified into a total of 6 genotypes (IA, IB, IIA, IIB, IIIA and IIIB) that display some differences in geographical distributions and risk group associations. Clinical outcomes of infection with different HAV type, where investigated, are similar.

Member species

SpeciesVirus name(s)Exemplar isolateExemplar accession numberExemplar RefSeq numberAvailable sequenceOther isolatesOther isolate accession numbersVirus abbreviationIsolate abbreviation
Hepatovirus Ahepatitis A virusHM-175M14707NC_001489Complete genomeHAV
Hepatovirus BphopivirusNew England/USA/2011KR703607NC_027818Complete genomePhV
Hepatovirus Chepatovirus C; bat hepatovirusSMG18528Minmav2014KT452742Complete genomeHepV-C
Hepatovirus Dhepatovirus D; rodent hepatovirusRMU101637Micarv2010KT452637NC_028363Complete genomeHepV-D
Hepatovirus Ehepatovirus E; rodent hepatovirusCIV459Lopsik2004KT452735Complete genomeHepV-E
Hepatovirus Fhepatovirus F; rodent hepatovirusKEF121Sigmas2012KT452685Complete genomeHepV-F
Hepatovirus Ghepatovirus G; bat hepatovirusBUO2BF86Colafr2010KT452730Complete genomeHepV-G
Hepatovirus Hhepatovirus H; hedgehog hepatovirusIgel8Erieur2014KT452691NC_028365Complete genomeHepV-H
Hepatovirus Ihepatovirus I; shrew hepatovirusKS121232Sorara2012KT452658NC_028364Complete genomeHepV-I

Virus names, the choice of exemplar isolates, and virus abbreviations, are not official ICTV designations.

Derivation of names

Hepato: from Greek hepatos, "liver"