Molecular organization and replication of hepatitis E virus (HEV)

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Abstract
The recently characterized fecal-orally transmitted agent of hepatitis E (formerly known as enterically transmitted non-A, non-B hepatitis) has been determined to be a new type of positive strand RNA virus. The complete sequencing of four different geographic isolates of the hepatitis E virus (HEV) has confirmed a similar genetic organization not previously recognized in nonenveloped positive strand RNA viruses. The ~7.5 kb RNA genome (including polyA tail) has nonstructural genes located at the 5′ end and structural genes at the 3′ end. Expression of these viral genes occurs in at least 3 different forward open reading frames. The largest open reading frame begins 27 nucleotides (nt) downstream of the apparent noncoding 5′ end and extends 5,079 nt. Multiple nonstructural gene motifs/domains have been recognized in this 5′ ORF1 including a methyltransferase, a papain-like protease, a helicase and the RNA-dependent, RNA polymerase. The second major ORF2 begins 37 nt downstream of ORF1 and extends 1980 nt before terminating 65 nt upstream of the polyadenylation site. A third ORF of only 369 nt was identified by immunoscreening experiments as encoding an immunogenic epitope of the virus. Expression of the downstream ORF2 may occur through internal subgenomic RNA initiation at a sequence element found to have homology to internal RNA initiation sequences in Sindbis virus. This element in the HEV genome maps near the apparent 5′ end of one of two identified subgenomic messages. The genomic organization and expression of HEV will be discussed and a hypothesis presented regarding the viral replication strategy.