2)8 The implication of the recently identified “macro domain” wi

2).8 The implication of the recently identified “macro domain” within the ORF1 polyprotein that encodes a poly(ADP-ribose)-binding polypeptide is unclear.9 The ORF2 protein consists of three linear domains and forms homodimers, which act as capsomeres and form the viral capsid (Fig. 2).10 Truncated versions of the ORF2 protein expressed in insect cell or bacterial systems assemble into empty virus-like particles (VLPs), which have been used Torin 1 in vivo as candidate vaccines.11, 12 The ORF3 protein is required for HEV replication in the host, but not in vitro; in addition, it has pleiotropic

effects on host cell pathways and plays a role in viral egress from infected cells.13 The understanding about the replication cycle of HEV is based largely on analogy to other positive-strand RNA viruses. The cellular receptor and mode of entry of HEV into the cell are not known, but heparan sulfate proteoglycans are required for HEV attachment and Barasertib in vivo infection of target cells.14 It is proposed that after uncoating, the positive-strand viral RNA is translated into nonstructural (i.e., ORF1) proteins, which, in turn, help produce a negative-strand RNA intermediate. The latter serves

as a template to produce several positive-strand genomic RNAs (gRNA) and a subgenomic RNA, which is translated into the ORF2 and ORF3 proteins. The ORF2 capsid protein packages the gRNA into new virions, which

egress through an unexplained pathway that utilizes the ORF3 protein and cellular lipids.15 Inefficient in vitro propagation of HEV has been a bottleneck in virological studies. Genotype 3 and 4 viruses from human specimens with high HEV titers were selleck chemicals recently propagated in human liver and lung epithelial cells.16 Another genotype 3 virus was recently adapted to grow in HepG2 (i.e., human liver) cells.17 Reliable culture systems and the ability to generate virions from transfected infectious molecular clones should pave the way for much-needed virological studies on HEV. Nonhuman primates, such as chimpanzees and various macaque species, have played a major role in the discovery of HEV, subsequent molecular and pathogenetic studies, and vaccine development.18 The discovery of swine HEV has provided specific pathogen-free pigs as an alternate animal model for genotype 3 and 4 HEV. The recent discovery of rat and rabbit strains of HEV may allow the development of a reliable small animal model.19, 20 Studies in two human volunteers, patients with epidemic hepatitis E and experimentally infected primates have provided a composite picture of pathogenesis, including viral replication and shedding, antibody responses, and liver damage during hepatitis E (Fig. 3). Viremia and fecal shedding begin 1-2 weeks before and last 2-4 weeks after the onset of symptoms.

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