Small Animal Models of Hepatitis E Virus Infection

Abstract

Novel hepeviruses have been recovered from many different animal species in recent years, increasing the diversity known to exist among the Hepeviridae, which now include two genera, Piscihepevirus and Orthohepevirus Multiple viral genotypes in the Orthohepevirus A species are able to replicate and cause acute hepatitis E in humans, and thus represent an important public health problem in industrialized as well as developing countries. Although hepatitis E virus (HEV) infections typically result in acute and self-limited hepatitis, immunocompromised and transplant patients are vulnerable to prolonged infections and to chronic hepatitis. Cell culture systems have been established for several HEV strains and offer new opportunities for the study of HEV biology. Similarly, a variety of new small animal models have been developed, using either nonhuman hepeviruses in their cognate hosts as surrogates for human HEV, or human HEV infection of immunodeficient mice with chimeric livers engrafted with human hepatocytes. These new models provide several advantages over previous nonhuman primate models of hepatitis E infection and will facilitate studies of pathogenicity, cross-species infection, mechanisms of virus replication, and vaccine and antiviral agent development. This article reviews the current understanding of small animal models for HEV.

Figure 1.

Phylogenetic tree based on complete genomic sequences of hepeviruses recovered from fish, humans, monkey, swine, wild boar, deer, rabbit, mongoose, camel, ferret, rat, moose, kestrel, little egret, and avian sources. Sources of hepatitis E virus (HEV) strains follow GenBank accession numbers. Sequence alignment was performed with ClustalW. Orthohepevirus species assignments are indicated on the right (see also Smith and Simmonds 2018).

Figure 2.

Experimental infection of ferrets with ferret hepatitis E virus (HEV). Animals were inoculated orally with virus recovered from the supernatant fluids of infected PLC/PRF/5 cells. (From Li et al. 2016a; adapted, with permission, from Elsevier © 2016.)