Hepatitis E virus: An overview
History of Discovery
In 1981 the Soviet virologist M.S. Balayan made an experiment of self-infection, ingesting the infectious material collected from 9 soldiers with hepatitis of unclear origin. On 37th day from the infection time point he manifested typical symptoms of acute viral hepatitis. Laboratory testing revealed no markers of already known viral hepatites A or B. Nevertheless, immune electron microscopy of fecal specimens demonstrated the presence of novel hepatitis virus. This way hepatitis E virus (or HEV) was discovered.
Meanwhile, some previous epidemics of fecal-orally transmitted hepatites were later proven to be hepatitis E disease. For instance, it was documented for New Delhi outbreak of 1955 (India), where 29,000 cases of hepatitis with jaundice were registered after sewage contamination of the drinking water supply.
Hepatitis E virus (HEV) pertains to Hepeviridae family, genus Orthohepevirus, and species Orthohepevirus А. This virus has 4 genotypes.
Genotypes 1 and 2 are the solely human pathogens; genotypes 3 and 4 are isolated from humans and various animal species (swine, boars, rabbits, deers, etc.)
Other members of genus Orthohepevirus infect only animals (zoonotic viruses).
Structure of HEV
HEV is a 27-34 nm spherical particle with icosahedral symmetry, containing a linear single-stranded (+) RNA genome. It is naked virus without lipid envelope.
Three genetic regions of HEV (open reading frames, ORFs) encode viral proteins. One ORF codes for viral enzymes (RNA-polymerase, protease and helicase); two others encode viral capsid protein – major HEV antigen, and phosphoprotein, participating in viral infection.
Only 1 serotype of virus is determined.
Generally HEV is less stable than hepatitis A virus. It is inactivated by heating at 60°C for 15-30 minutes. Also HEV is destroyed by chlorine-containing disinfectants and formaldehyde. Nonetheless, the stability of HEV virions is quite enough for fecal-oral transmission.
Viral Replication Cycle
Virus attachment is performed via capsid protein binding to hepatic heparan sulfate and heat shock protein receptors. Viruses enter hepatocytes by endocytosis. All cycle of virus propagation takes place in cytoplasm of infected cells.
Viral uncoating is followed by genomic (+) RNA translation, which results in early proteins synthesis (e.g., viral enzymes). Newly formed viral RNA polymerase (replicase) catalyzes viral (+) RNA replication through the stage of negative-sense RNA intermediate, which serves as template for viral genome synthesis. Later the structural proteins of HEV are translated.
Viral self-assemblage depends on capsid proteins; viral phosphoprotein facilitates virion translocation and egress. After complete maturation the progeny viruses are released from hepatocytes by budding.
Pathogenesis, Clinical Findings and Immunity of Hepatitis E
Hepatitis E demonstrates 2 basic clinical forms, depending on viral genotype.
HEV of 1-2 genotypes cause mass outbreaks of the disease in developing countries of Southeast Asia, Africa, and Latin America. This is mainly related with poor drinking water supply and sanitary control burdened with common deficiency of water resources. Less intensive outbreaks of infection may be registered in many countries all over the world.
HEV of 3 and 4 genotypes cause sporadic cases of hepatitis E worldwide. Last 15 years a steady growth of this infection is observed in many developed world regions (United States, European countries, Russia, Japan, New Zealand, etc.) Now it is generally ascertained that this variant of the disease is typical zoonotic infection transmitted by alimentary route.
Hence, hepatitis E caused by HEV of 1-2 genotypes is the disease with waterborne transmission. The sources of infection are humans.
And hepatitis E caused by HEV of 3-4 genotypes is zoonotic infection with alimentary (foodborne) transmission primarily via ingestion of contaminated meat. The sources of infection are various animal species (mostly swine or boars).
Incubation period lasts from 2 to 6 weeks. The details of pathogenesis of hepatitis E are not completely elucidated. HEV enters the liver via portal vein and replicates in hepatocytes. Damage of liver cells is predominantly mediated by cellular autoimmune response directed against virus-infected host cells.
The virus actively discharges from the body with feces especially in early stages of infection. Epidemic hepatitis E caused by HEV of 1-2 genotypes predominantly affects young individuals. Only 40% of patients display jaundice; the course of infection is usually moderate or mild. Lethality of epidemic outbreaks doesn’t exceed 1%. Complete recovery occurs in most cases; chronicity is not observed.
However, in case of infection of pregnant women at third trimester of pregnancy, severe and fulminant forms of the disease can develop with expected high fatality rate (20-30% and even more). The mechamisms of this clinical condition are not well-elucidated yet.
Sporadic alimentary hepatitis E caused by HEV of 3-4 genotypes affects mainly elder persons with substantial comorbidity or under immunosuppression. The disease generally demonstrates more active course with jaundice in 75% of patients. If the patient had preliminary chronic liver disease (chronic hepatitis or cirrhosis), the fatality of HEV infection may be high (up to 70% in 1 year from infection onset). Chronic forms of hepatitis E can be observed in these patients.
HEV infection confers both cellular and humoral post-infectious immunity. The protection maintains for several years. However, the levels of specific antibodies gradually decline, and HEV reinfection becomes possible.
Serological testing is primarily used for HEV laboratory diagnosis. Anti-HEV IgM antibodies are determined in patient’s sera by ELISA indicating acute disease.
Molecular genetic tests (e.g. reverse transcriptase PCR) detect HEV RNA in patient’s feces. PCR and genetic sequencing identify genotypes of hepatitis E viruses.
Prophylaxis and Treatment of HEV Infection
In most cases viral hepatitis E needs only supportive symptomatic treatment. Ribavirin and interferon are used in immunocompromised patients.
For specific prophylaxis several HEV recombinant vaccines were developed, based on viral capsid protein. One of them is registered in China for mass vaccination.