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Members of the Orthohepevirus genus infect mammals and birds. They share a common genome organisation with a short 5′-untranslated region, a long ORF1 followed by the overlapping and shorter ORF2 and ORF3, with a poly-A tail at the end of ORF2.
Infected individuals typically develop antibodies directed against the capsid protein. Cross-reactivity has been demonstrated between the capsid proteins of isolates of Orthohepevirus A and Orthohepevirus B (Haqshenas et al., 2002), and antibodies raised against the capsid from dromedary camels, expressed in baculovirus, exhibited antigenic cross-reactivity against several Orthohepevirus A genotypes as well as rat and ferret HEVs (Zhou et al., 2015). Given the diversity of hosts from which hepeviruses have now been described, reports of serological reactivity to hepatitis E virus antigens in novel host species are difficult to interpret without corresponding virus sequence information. Vaccines capable of protecting against human infection with HEV have been produced using portions of the capsid protein (Purdy et al., 1993, Tsarev et al., 1997) and tested in Nepal (Shrestha et al., 2007), and China (Zhu et al., 2010). Xiamen Biotech has a vaccine that is licenced in China, but that is not currently licensed for use in other countries. A vaccine comprising part of the Orthohepvirus B capsid protein has been shown to protect chickens against infection (Guo et al., 2007).
HEV is associated in humans with outbreaks and sporadic cases of acute hepatitis. The virus is considered endemic in tropical and subtropical countries of Asia, and Africa, as well as Mexico, but antibody prevalence studies suggest a global distribution for this virus. Large outbreaks that may involve thousands of cases of acute hepatitis occur in endemic regions. Sporadic cases are more common in industrialized countries. Human-to-human transmission seems rare in hepatitis E epidemics although infections can be transmitted by blood transfusion from acutely infected donors (Huzly et al., 2014, Hewitt et al., 2014). Members of Orthohepevirus A have been assigned to 7 different genotypes, HEV-1 to HEV-7. Recently a new HEV genotype (HEV-8) was proposed for viral variants isolated from Bactrian camels (Woo et al., 2016). Of these genotypes; HEV-1, HEV-2, HEV-3 and HEV-4 are most commonly associated with HEV infection in humans. Genotypes 1 and 2 are restricted to humans, whereas genotypes 3 and 4 have a broader host range and are zoonotic. Interspecies transmission of genotypes 3 and 4 hepatitis E virus between swine and non-human primates has been demonstrated experimentally. Pig handlers in both developing and industrialized countries are at increased risk of HEV infection. Human isolates from southern Asia typically belong to HEV-1 and are epidemically transmitted faecal-orally. Isolates of HEV-1 in Western Europe are usually associated with recent travel to southern Asia or Africa. Very few isolates of HEV-2 have been described, but these comprise a range of locations (Mexico and Africa) and are associated with epidemic faecal-oral transmission. Genotypes HEV-3 and HEV-4 have been isolated from humans, pigs and deer in Western Europe, South America, Northern America and Eastern Asia, with human infection presumed to result from the consumption of raw or undercooked pig meat or products although a direct link has seldom been proven. Exceptions are the consumption of figatellu sausage in France (Colson et al., 2010) and raw deer liver in Japan (Tei et al., 2003, Takahashi et al., 2004). Recent studies have expanded the host range of HEV-3 to include goats (Di Martino et al., 2016) and bottlenose dolphins (Montalvo Villalba et al., 2017), and of HEV-4 to include cattle (Hu and Ma 2010, Huang et al., 2016) and sheep (Wu et al., 2015). A variant of HEV-3 found in rabbits has distinctive insertions in ORF1 (Zhao et al., 2009) and has also been isolated from a human (Izopet et al., 2012). HEV-5 and HEV-6 have only been isolated from wild boar in Japan (Takahashi et al., 2014). HEV-7 has been isolated from dromedary camels (Woo et al., 2014) with one report of human infection (Lee et al., 2016). HEV-8 has only been isolated from Bactrian camels in China (Woo et al., 2016).
Human infection with HEV is typically self-limiting and frequently asymptomatic; studies of blood donors in several European countries report that there are typically no or minor symptoms with infrequent mild elevation of liver enzymes (Vollmer et al., 2012, Juhl et al., 2014, Tedder et al., 2016). The incubation period for hepatitis E ranges from 15 to 40 days. Symptoms include diarrhoea, epigastric pain, nausea, hepatomegaly, splenomegaly and vomiting. The icteric phase of illness begins with jaundice, dark urine and clay-coloured stools. Extrahepatic manifestations are associated with the brain, central nervous system, muscle tissue, kidney, pancreas and placenta (Bose et al., 2014, Dalton et al., 2011, Kamar et al., 2013). Mortality ranges from 0.4% to 2% among immunocompetent individuals, although it may be as high as 20 to 30% among women in the second or third trimester of pregnancy.
Exposure to HEV infection is widespread with serological evidence of infection in a majority of individuals by the age of 20-40 (Izopet et al., 2015). Following acute infection with HEV any symptoms usually resolve and the virus is cleared in a little over 6-7 weeks (Tedder et al., 2016). However, chronic infection has been described in immunosuppressed individuals (Kamar et al., 2008, Haagsma et al., 2008). In recent years it has been recognized that a proportion of infected individuals suffer from neurological symptoms (Dalton et al., 2016).
In pigs, infections with HEV are asymptomatic. Viremia lasts for 1-2 weeks, with faecal viral shedding occurring 1-2 weeks after infection and persisting for up to 8 weeks. Hepatic changes are minimal; sites of extrahepatic replication have been identified in the small intestine, colon, and hepatic and mesenteric lymph nodes (Williams et al., 2001).
Orthohepevirus B includes isolates of avian hepatitis E virus detected in chickens (Haqshenas et al., 2001, Haqshenas et al., 2002, Payne et al., 1999, Huang et al., 2002). Infection in chickens is widespread with approximately 71% of chicken flocks and 30% of chickens in the United States positive for IgG antibodies to the virus (Huang et al., 2002). Infection has also been reported in wild birds (Zhang et al., 2016) and can be experimentally transmitted to turkeys but not monkeys, mice or pigs. The clinical disease in infected chickens has been referred to as big liver and spleen (BLS) disease, and hepatitis-splenomegaly (HS) syndrome. Disease in infected chickens is associated with increased mortality and decreased egg production. Virus replication occurs in the liver as well as extrahepatic tissues, including the gastrointestinal tract. Orthohepevirus B isolates have been divided into 4 genotypes that differ from each other by 18% in complete nucleotide sequence (Bilic et al., 2009, Banyai et al., 2012). These genotypes have different geographical distributions; genotype 1 is restricted to Australia, genotypes 2 and 3 have been isolated in the USA and Europe, and genotype 4 in Hungary.
Serological reactivity to Orthohepevirus C has been detected in 25% of brown rats (Rattus norvegicus) from Germany, with virus detected in 10% of animals (Johne et al., 2010, Johne et al., 2012); a higher frequency of seroreactivity was reported in rats from the USA (Purcell et al., 2011). Genetically similar viruses have been detected in a variety of other host species; genotype C1 in rodents (Rattus sp, Bandicota indica) and eulipotyphlids (musk shrew) while genotype C2 has been detected in mustelids (ferret and mink). Isolates of this species appear similar to those of Orthohepevirus A in EM structure and hepatotropism, although following experimental transmission liver enzymes levels were unaltered (Purcell et al., 2011, Johne et al., 2010); other biological features are unknown.
Orthohepevirus D has a global distribution in bats with no evidence of transmission to humans (Drexler et al., 2012).
Four species have been demarcated on the basis of phylogenetic analysis of complete coding region nucleotide sequence and of partial amino acid sequence from the methyltransferase, helicase and RNA polymerase domains (Smith et al., 2015). The four species also have distinct host ranges; members of Orthohepevirus A have been isolated from mammals including humans (human hepatitis E virus), pigs (swine hepatitis E virus), deer, rabbits, camels, cattle, sheep, goats, mongooses, and bottlenose dolphins. Isolates of Orthohepevirus B are restricted to birds, primarily chickens, and have been allocated to several genotypes, although these are more closely related to each other than are those within Orthohepevirus A. Orthohepevirus C includes isolates from rodents, eulipotyphlids and mustelids. Bats remain the only source from which isolates of Orthohepevirus D have been reported. Related but distinct viruses have been reported from moose, fox, kestrel and little egret, and these are likely to represent additional species.
Orthohepevirus A: genus name followed by letter in order of discovery.
moose hepatitis E virus
moose (Alces alces)
fox hepatitis E virus
fox (Vulpes vulpes)
kestrel hepatitis E virus
common kestrel (Falco tinnunculus)
red-footed falcon (Falco vespertinus)
little egret hepatitis E virus
little egret (Egretta garzetta)
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