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Figure 1: Molecular biology of hepatitis B virus (HBV). (A) Scaled depiction of the HBV (genotype ayw) genome. Internal circle shows genomic position relative
to EcoRI site at position 1. Partially double-stranded genome is depicted with attached RNA primer and polymerase protein. Open reading frames (ORFs)
are indicated by the thicker, colored lines. The outermost black circles represent the viral transcripts with the shared polyadenylation site; (B) schematic
representation of the overlapping nature of the HBV ORFs; (C) the mature HBV virion (Dane particle) consists of two main parts: a nucleocapsid (or core
particle) consisting of a partially double-stranded DNA genome bound to polymerase (P) and encapsidated by dimers of core protein, and a viral envelope
consisting primarily of S-HBsAg (S), with an intermediate amount of M-HBsAg (M) and lower levels of L-HBsAg (L)
overlapping ORFs [Figure 1a]. The largest ORF encodes Transcription of HBV RNAs is driven from specific
the viral polymerase, which also has reverse transcriptase promoter sequences within the viral genome. At least
(RT) activity that generates the first strand of the DNA some of the hepatotropic restriction of HBV can be
genome from an RNA intermediate. The second largest attributed to transcriptional activation by hepatocyte-
ORF encodes the three viral envelope proteins: large specific transcription factors. For example, activation
(L-), middle (M-), and small (S-) surface antigen (HBsAg). of the Enhancer I/HBx promoter is a required first step
Another ORF encodes precore, also referred to as HBV in viral transcription, as this is believed to enhance
E antigen (HBeAg), and the core protein, which makes transcription from downstream promoters. A number
up the viral capsid. Finally, the smallest ORF encodes of the transcription factors that have been mapped
the HBV X protein (HBx), a small regulatory protein that to the EN1/HBx promoter are liver specific, including
has been shown to be required for HBV replication both hepatocyte nuclear factor (HNF) 1, HNF3, and HNF4.
in vitro and in vivo. [25-29] The viral ORFs are encoded in Many of the transcription factor binding sites that have
distinct capped and polyadenylated RNAs that can be been identified within the 4 promoter regions of HBV
divided into genomic and subgenomic transcripts. The are for transcription factors that are activated by HBV
subgenomic transcripts act only as templates for HBV proteins, oftentimes HBx, implying a specific cascade of
proteins and consist of the 0.7 kb transcript, which transcription. Transcription factor-mediated regulation
[32]
encodes HBx, and the 2.1 kb and 2.4 kb HBsAg transcripts of HBV transcription has been reviewed in more detail
encoding M- and S-HBsAg, and L-HBsAg, respectively. The elsewhere. [11,33]
genomic transcripts act as mRNAs for precore, core, and
polymerase. The genomic transcript that encodes both HBV PROTEINS
core and polymerase is multifunctional and referred to
as pregenomic RNA (pgRNA). The pgRNA is the template The HBV genome encodes seven proteins: HBx, core,
for HBV replication and is reverse transcribed to generate polymerase, L-, M-, and S-HBsAg, and precore/HBeAg
the HBV DNA genome. As the viral genome is only 3.2 kb [Figure 1a]. Of these proteins, HBx is a non-structural
and the pgRNA is 3.5 kb, the pgRNA is a greater than unit regulatory protein, HBeAg is not incorporated into
length, terminally redundant copy of the viral genome. virions and is independently secreted from the cells, the
All HBV RNA transcripts share the same polyadenylation polymerase is responsible for genome replication, and
site, and each of the smaller transcripts makes up the 3’ the core and HBsAg proteins form the structural aspects
end of each of the larger transcripts. This means that the of the virion. Each of these will be discussed in further
[11]
sequence of the HBx transcript is contained at the 3’ end detail below.
of all HBV mRNA transcripts, while the largest transcript
is the only viral transcript to contain sequence that is not E antigen
shared with the other transcripts. [11,30,31] HBeAg is the final product of post-translational processing
Hepatoma Research | Volume 2 | July 1, 2016 165