Hepatitis E in High-Income Countries: What Do We Know? And What Are the Knowledge Gaps?

Abstract

Hepatitis E virus (HEV) is a positive-strand RNA virus transmitted by the fecal⁻oral route. HEV genotypes 1 and 2 infect only humans and cause mainly waterborne outbreaks. HEV genotypes 3 and 4 are widely represented in the animal kingdom, and are mainly transmitted as a zoonosis. For the past 20 years, HEV infection has been considered an imported disease in developed countries, but now there is evidence that HEV is an underrecognized pathogen in high-income countries, and that the incidence of confirmed cases has been steadily increasing over the last decade. In this review, we describe current knowledge about the molecular biology of HEV, its clinical features, its main routes of transmission, and possible therapeutic strategies in developed countries.

Keywords: Hepatitis E virus; clinical; transmission; virology; zoonosis.

Figure 1

Organization of the Hepatitis E virus (HEV) genome, open reading frames (ORFs), and proteins. Methyltransferase (Met), Y domain (Y), papain-like cysteine protease (PCP), hypervariable region (HVR), proline-rich domain (PRO), X macrodomain (X), RNA helicase (Hel), RNA-dependent RNA polymerase (RdRp), non-coding region (NCR).

Figure 2

Putative replication cycle of HEV. Step 1: HEV in the extracellular environment. Step 2: Attachment of HEV to the target cell involving heat shock protein. Step 3: Receptor binding. Step 4: Clathrin-dependent endocytosis. Step 5: Encapsidation and liberation of genomic RNA. Step 6: RNA translated into nonstructural ORF-translated protein 1 (pORF1). Step 7: Replication of RNA+ into negative-sense transcripts. Step 8a: Synthesis of subgenomic RNA. Step 8b: Synthesis of full-length positive sense transcripts. Step 9: Translation of subgenomic RNA into ORF2 and ORF3 proteins. Step 10: Capsid formation and assemblage of new virions. Step 11a and 11b: Exit of the virus via the ORF3 proteins fixed on the endoplasmic membranes or the cell wall. Step 12: Mature virions attached to ORF3 protein and lipids (quasi-enveloped form in bloodstream) or free (in bile).

Figure 3

Different clinical forms of Hepatitis E.

Figure 4

Diagram summarizing the different routes of transmission of HEV in high-income countries. Black arrows mean “confirmed transmission routes” and red arrows with “?” mean “suspected and not confirmed transmission routes”.