Hepatitis E Virus (HEV) - An Overview

 

Table of Contents

• Structure of Hepatitis E Virus
• Genome of Hepatitis E Virus
• Epidemiology and Transmission of Hepatitis E Virus
• Replication of Hepatitis E Virus
• Pathogenesis of Hepatitis E Virus
• Pathogenesis of fulminant Hepatitis
• Clinical Manifestations of Hepatitis E Virus
• Laboratory Diagnosis of Hepatitis E Virus
• Treatment of Hepatitis E Virus
• Prevention and Control of Hepatitis E Virus 

Structure of Hepatitis E Virus

You can find an illustration showing the structure of both non-enveloped and quasi-enveloped Hepatitis E Virus (HEV) particles, as well as an enveloped virus in the provided image. The theoretical model for the quasi-enveloped HEV virion incorporates the ORF3 product into its outer layer. This inclusion of pORF3 has been substantiated through the use of anti-pORF3 antibodies to capture quasi-enveloped HEV virions. Furthermore, the prediction of a potential transmembrane region in the N-terminal portion of pORF3 provides additional support for this model.

Source: Link to the source 

• Hepatitis E Virus (HEV) shares structural characteristics with calciviruses, leading to its classification within the Calciviridae family. Nevertheless, it is worth noting that HEV stands alone as the exclusive member of the Hepeviridae family.
• This virus lacks an outer envelope, presenting itself as a non-enveloped (naked) particle. It takes on an icosahedral shape with a diameter ranging from 27 to 30 nm.
• The genetic material of HEV consists of a single-stranded RNA genome with a positive polarity, measuring approximately 7.2 kb in length.

Genome of Hepatitis E Virus

• The genetic makeup of Hepatitis E Virus (HEV) consists of a single-stranded RNA molecule with a positive-sense orientation, measuring 7.2 kb in length.
• This genomic RNA is polyadenylated and comprises three Open Reading Frames (ORFs).
• ORF1 is responsible for encoding nonstructural proteins, ORF2 encodes the capsid protein, and ORF3 encodes a compact, multifunctional protein.
• Both ORF2 and ORF3 proteins are produced from a single, bicistronic mRNA.
• ORF1, situated close to the 5′-end, generates a non-structural polyprotein featuring numerous functional domains, such as methyltransferase, protease, helicase, and polymerase.
• The viral capsid protein (CP), denoted as ORF2, is encoded towards the 3′-end.
• ORF3, overlapping with the other two ORFs, is responsible for producing an immunogenic protein with an unknown function.
• ORF3 generates a phosphoprotein consisting of either 113 or 114 amino acids, depending on the virus's genotype.
• HEV-CP, the capsid protein from ORF2, is comprised of a total of 660 amino acid residues.
• Positioned at the N terminus of HEV-CP is a signal peptide, followed by an arginine-rich domain that may play a role in encapsulating viral RNA during the virus assembly process.
• HEV-CP serves as a crucial antigen that triggers the host's immune response, and researchers have identified six antigenic domains within it.
• One specific region for neutralization has been identified between amino acids 452 and 617 within the polypeptide structure.

Epidemiology and Transmission of Hepatitis E Virus

• The initial reports of HEV infection emerged from the Indian subcontinent and subsequently spread to various regions, including Asia, the Middle East, Central and South America, Africa, Central Europe, and Russia.
• Travelers visiting countries with a high prevalence of the virus are therefore exposed to the risk of infection during their journeys.
• In areas where HEV is endemic, adult populations are generally susceptible, and epidemics often result in a high rate of infection.
• The primary mode of transmission for the hepatitis E virus is through the fecal-oral route, primarily due to fecal contamination of drinking water or the consumption of undercooked meat or meat products sourced from infected animals.
• Other modes of transmission include vertical transmission from a pregnant woman to her fetus and the receipt of infected blood products through transfusion.

Replication of Hepatitis E Virus

Diagram: Suggested Hepatitis E Virus Replication Process. Source: LINK HERE

• Our understanding of the mechanisms governing HEV replication remains limited.
• It is believed that the HEV capsid protein plays a role in initiating viral entry and subsequent replication by binding to a cellular receptor.
• Peptide-binding experiments related to ORF2 have suggested that the C-terminal region of ORF2 might be responsible for virus entry by interacting with heat shock cognate protein 70 (HSC70) found on the cell surface.
• Furthermore, attachment receptors known as Heparan Sulfate Proteoglycans (HSPGs) have been identified on the cell surface.
• Once the virus gains entry into permissive cells, the precise mechanisms involved in the uncoating of HEV genomic RNA remain undisclosed.
• Following uncoating, the virion releases the positive-sense genomic RNA into the cell's cytoplasm.
• This positive-sense genomic viral RNA then acts as a template for translating the ORF1 nonstructural polyprotein within the cytoplasm.
• The viral RNA-dependent RNA polymerase (RdRp) synthesizes an intermediate negative-sense RNA from the positive-sense genomic RNA, which serves as a template for generating positive-sense progeny viral genomes.
• Subgenomic, positive-stranded RNA is responsible for the translation of ORF2 and ORF3 proteins. The ORF2 capsid protein packages the genomic viral RNA and assembles new virions.
• Newly formed virions are transported to the cell membrane.
• The ORF3 protein facilitates the trafficking of these virions, which are eventually released from infected cells through cell lysis.

Pathogenesis of Hepatitis E Virus

• The precise mechanisms underlying the development of hepatitis E are not well comprehended.
• Given the presumed fecal-oral transmission of HEV, there is uncertainty about how the virus gains access to the liver.
• Evidence suggests that HEV undergoes replication at sites beyond the liver.
• It is plausible that the virus replicates within the intestinal tract before migrating to the liver.
• Negative strands of HEV RNA, indicative of viral replication, have been identified in various locations, including the small intestine, lymph nodes, colon, and liver of pigs, signifying extra-hepatic replication of HEV.
• Subsequently, HEV replication occurs within the cytoplasm of hepatocytes, with viral particles being released into both the bloodstream and bile.
• Liver damage induced by HEV infection might be mediated by the immune response, involving cytotoxic T cells and natural killer (NK) cells, as HEV itself is not directly cytopathic.
• The virus is excreted in feces.
• Patients typically exhibit a serological response against HEV at the onset of illness.
• Anti-HEV IgMs are detectable during the early stages of clinical illness and can persist for several months.
• Anti-HEV IgG antibodies become evident shortly after the IgM response and can endure for several years.
• The presence of a single serotype allows for potential cross-protection.

Pathogenesis of fulminant Hepatitis

• The precise factors contributing to the development of fulminant hepatitis E infection remain unclear.
• Both Th1 and Th2 immune responses may be involved in triggering liver failure.
• It appears that host-related factors, rather than virus genotype, variations, or specific amino acid substitutions, are responsible for the onset of fulminant hepatitis.
• In cases of fulminant hepatitis, there is an elevated presence of anti-HEV IgM and IgG antibodies, along with increased levels of cytokines such as IFN-γ, TNF-α, IL-2, and IL-10.
• Notably, the liver contains a higher frequency of CD4+ T cells, and there's evidence of CD8+ T cells infiltrating the livers of individuals with fulminant hepatitis E. This suggests that cytotoxic CD8+ T cells might play a crucial role in the development of fulminant hepatitis.
• Women experiencing acute liver failure (ALF) exhibit reduced expression of toll-like receptors (TLR) 3, TLR7, and TLR9.
• Impaired function of monocytes and macrophages in pregnant women with ALF could contribute to an insufficient innate immune response, thereby impacting the development and severity of ALF.
• Elevated concentrations of certain cytokines (such as TNF-α, IL-6, IFN-γ, and TGF-β1) may also be associated with adverse pregnancy outcomes.
• Pregnant women with fulminant hepatic failure (FHF) resulting from HEV infection tend to have higher levels of estrogen, progesterone, and β-human chorionic gonadotrophin compared to HEV-negative pregnant FHF cases.
• In vitro studies have demonstrated that serum from pregnant women, particularly those in the third trimester, can enhance HEV replication by inhibiting estrogen receptor and type I IFN expression.

Clinical Manifestations of Hepatitis E Virus

• The majority of HEV infections often progress without noticeable clinical symptoms.
• In cases where symptoms do manifest, the incubation period typically spans from 2 to 8 weeks, with an average duration of around 40 days.
• Initial signs of acute hepatitis E infection are generally non-specific and may include flu-like symptoms such as muscle pain, joint pain, weakness, and vomiting.
• Some patients may experience jaundice, itching, pale stools, and darkened urine, along with elevated levels of liver enzymes, bilirubin, alkaline phosphatase, and γ-glutamyltransferase.
• Hepatitis E infection can result in more severe acute liver diseases, particularly in pregnant women and individuals with pre-existing chronic liver conditions, and may, in rare instances, progress to fulminant hepatic failure.
• Transplant recipients, including liver and kidney transplant patients, have been known to develop chronic HEV infections, characterized by persistent increases in alanine aminotransferase levels, significant histological activity, and fibrosis.
• Individuals with HIV infection are more likely to test positive for anti-HEV antibodies compared to those without HIV infection.
• Extrahepatic manifestations of HEV infection have been observed, including muscular weakness and pyramidal syndrome in a kidney transplant recipient with ongoing HEV infection.
• Neurological disorders, such as polyradiculopathy, Guillain–Barré syndrome, bilateral brachial neuritis, encephalitis, or proximal myopathy, have been reported in patients with both acute and chronic HEV infections.

Laboratory Diagnosis of Hepatitis E Virus

• Samples: Blood, serum, feces
• The conclusive diagnosis of hepatitis E infection typically relies on identifying the presence of specific IgM and IgG antibodies against the virus in an individual's blood.
• Supplementary tests involve the use of reverse transcriptase polymerase chain reaction (RT-PCR) to detect hepatitis E virus RNA in both blood and stool samples.

Treatment of Hepatitis E Virus

• There is no targeted treatment available to modify the progression of acute hepatitis E.
• Typically, the condition resolves on its own, being self-limiting.
• Hospitalization is necessary for individuals facing fulminant hepatitis, and it should also be contemplated for pregnant women displaying symptoms.
• Immunosuppressed individuals dealing with chronic hepatitis E can experience positive outcomes through specific treatment involving the use of ribavirin, an antiviral medication.
• In select cases, interferon has also shown success as a treatment option.

Prevention and Control of Hepatitis E Virus

At a population level, the transmission of HEV and hepatitis E disease can be mitigated through the following measures:

• Maintaining rigorous quality standards for public water sources.
• Implementing proper systems for the safe disposal of human feces.

At the individual level, the risk of infection can be diminished by:

• Adhering to hygienic practices, including thorough hand-washing with clean water, particularly before handling food.
• Refraining from consuming water or ice of uncertain purity and following safe food practices as recommended by the World Health Organization (WHO).

It's worth noting that hepatitis E is preventable through vaccination. HEV239 (Hecolin) is a recombinant HEV vaccine designed to target genotype 1 and 4. It has demonstrated more than 95% effectiveness in protecting against the virus and has been deemed safe for use during pregnancy. This vaccine is currently accessible in China.