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Chapter 49 : Hepatitis E Virus

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Abstract:

The hepatitis E virus (HEV) genome encodes three proteins; polyprotein open reading frame 1 (PORF1) (replicative polyprotein), PORF3 (required for replication in vivo but dispensable in cell culture), and PORF2 (capsid protein). Serologic assays based on truncated PORF2 protein (aa 112 to 660) expressed using the baculovirus system have yielded seroprevalence rates of over 20% in blood donors from Baltimore, MD, whereas rates of less than 2% were found in Australian blood donors using the open reading frame 2.1 (ORF2.1) protein (aa 394 to 660) expressed in , yet the two assays appear to be equally sensitive when applied to samples from countries where HEV is endemic. The role of immunoglobulin A (IgA) in immunity to HEV infection is unknown, but as passive immunization with IgG appears to be sufficient for protection, it is likely that IgA is not essential. While hormonal factors may contribute to pathogenesis during pregnancy, other factors may also be important, such as the underlying general health status or chronic infection with HBV or hepatitis C virus in patients at the time of HEV infection. Conversely, in countries where HEV is endemic, it is often the most common cause of acute hepatitis. A variety of nucleic acid and serologic assays are used in research laboratories, but routine (commercial) diagnostic assays vary widely in their sensitivities and specificities. No specific symptomatic or anti-inflammatory treatments can be advised for hepatitis E.

Citation: Anderson D, Shrestha I. 2009. Hepatitis E Virus, p 1127-1143. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch49

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Figures

Image of FIGURE 1
FIGURE 1

Particles of HEV from the stools of an experimentally infected macaque, complexed with acute-phase patient serum. (Courtesy of Zhuang Hui, Beijing Medical University.)

Citation: Anderson D, Shrestha I. 2009. Hepatitis E Virus, p 1127-1143. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch49
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Image of FIGURE 2
FIGURE 2

Genome organization and major antigenic domains of HEV. The genome, of around 7,200 nt, contains a 5′ 7-methylguanosine cap and highly conserved 5′ and 3′ untranslated regions (UTRs) of 35 and 68 to 75 nt, respectively. Three ORFs, organized as 5′-ORF1-ORF3-ORF2-3′, encode the viral proteins, which may be translated from a set of subgenomic mRNA molecules, but it is not known which mRNA species may encode each protein. The PORF1 polyprotein contains protein domains consistent with replicative proteins (methyltransferase, protease, helicase, and RDRP), and PORF2 is the major capsid protein. The function of PORF3 is unknown; this protein is dispensable for replication in cell culture but essential in vivo. Linear antigenic domains have been identified by peptide scanning throughout each of the three proteins, while within PORF2 a conformational, immunodominant epitope (the ORF2.1 epitope) is found between aa 394 and 457, while a conformational, neutralizing epitope is found between aa 578 and 607.

Citation: Anderson D, Shrestha I. 2009. Hepatitis E Virus, p 1127-1143. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch49
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Image of FIGURE 3
FIGURE 3

Putative replication cycle of HEV. After oral ingestion, HEV particles reach the liver, where they attach to an unidentified receptor on the basolateral domain of hepatocytes, leading to virus penetration (step 1) and uncoating of the genome (step 2) within the cell. Translation of the input genome (step 3) yields the PORF1 polyprotein, which is cleaved at unknown sites to yield the replicative proteins, which copy the input genome to yield full-length negative-strand RNAs (step 4), followed by subgenomic positive-strand mRNAs and full-length positive-strand RNAs (new viral genomes) (step 5). These subgenomic RNAs are translated to yield further molecules of PORF1, PORF2 (capsid), and PORF3 (regulatory) proteins (step 6). PORF2 and new viral genomes assemble into virions (step 7); it is not known whether virions contain full-length or truncated PORF2 products, and the role of membranes in assembly is unclear. Release of progeny virus through basolateral domains of the infected cell (step 8) may result in viremia and infection of distal hepatocytes, and/or infection of neighboring hepatocytes, but transmission to new hosts through the environment is achieved via release of progeny through the apical domain (step 9) to the bile canaliculi (BC) and ultimately the feces.

Citation: Anderson D, Shrestha I. 2009. Hepatitis E Virus, p 1127-1143. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch49
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Image of FIGURE 4
FIGURE 4

HEV-specific IgM levels in patients with acute, sporadic hepatitis in Kathmandu, Nepal. All patients seen at the Siddhi Polyclinic with symptoms and biochemical markers consistent with acute hepatitis during 1997 were tested using a prototype IgM ELISA based on the ORF2.1 antigen, and the results are shown as a frequency histogram of the ratio of sample to cutoff for patient samples (A). Almost 60% of patients tested positive in the HEV IgM ELISA, but with two distinct patterns of reactivity (low positive [ ] and high positive [ ]). White bars indicate patients who tested negative. (B) The level of IgM reactivity did not correlate with patient age, sex, or levels of biochemical markers, but patients with highly positive results were more likely to present during the peak (wet) season. (Data from our laboratories.)

Citation: Anderson D, Shrestha I. 2009. Hepatitis E Virus, p 1127-1143. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch49
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Image of FIGURE 5
FIGURE 5

Course of HEV infection and characteristic humoral immune responses. After reaching high levels during the acute phase, HEV PORF2-specific IgG declines rapidly over 6 to 12 months and might not persist at protective levels for life. The serologic responses to the PORF2 protein as shown are those which probably occur in most patients, but the detection of these responses varies widely among different assays. Conversely, the responses to PORF3 appear to be highly variable (not illustrated), with a proportion of patients mounting no detectable response to the antigen, while others maintain reactivity to PORF3 for many years. (Modified from reference with permission.)

Citation: Anderson D, Shrestha I. 2009. Hepatitis E Virus, p 1127-1143. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch49
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Image of FIGURE 6
FIGURE 6

Representative test results obtained with the ASSURE HEV IgM RPOC test. A sample with no detectable HEV-specific IgM (S982) shows a single line (control [C]), while samples with HEV-specific IgM (J89, J60, and J70) show both control and test (T) lines. (Data from our laboratories.)

Citation: Anderson D, Shrestha I. 2009. Hepatitis E Virus, p 1127-1143. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch49
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