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of the translated precore ORF [Figure 1a and b]. As one is glycosylated in nearly half of all S-protein moieties. [39]
of the proteins encoded by a genomic transcript, the Once budding of the membrane occurs, these epitopes
genomic promoter drives its expression. The HBeAg are on the outer surface of the viral particles. The
ORF encodes an endoplasmic reticulum (ER) targeting topology of M is identical to that of S, except for the
sequence that co-translationally traffics the peptide to presence of preS2 within the ER lumen. [40]
the ER, where the protein is processed to the final 15 kD
HBeAg that is secreted from HBV-infected cells. [34] A major characteristic of L is that it exists in two
conformations that vary in the localization of the
The function of HBeAg remains incompletely defined. N-terminal domain. In the first conformation of L, the
Multiple groups have hypothesized that HBeAg can preS1 and preS2 domains are present in the cytosol. This
facilitate HBV immune evasion, and studies with HBc/ conformation of L is essential for binding of capsids and for
HBeAg-transgenic (tg) mice crossed with T cell receptor the assembly of HBV virions. In the second conformation
(TCR)-Tg mice expressing receptors for the HBc/ of L, the N-terminus is located in the ER lumen and, as
HBeAgs specifically suggest that a function of HBeAg a result, exposed on the surface of viral particles. Thus,
is to suppress the immune response to the HBV core this conformation of L plays a role in the infection of
protein. [35,36] The secretion of a viral marker that is not hepatocytes. The conformational change is facilitated by
present in the HBV infectious virion may help to dampen interactions of molecular chaperones Hsc70/Hsp40 and
the neutralizing immune response by diverting this BiP with L; however, the exact details of the mechanism
response away from infectious viral particles. From underlying this step are not yet understood. The preS1
[11]
[11]
a diagnostic perspective, HBeAg is an important marker domain contains the receptor-binding region for HBV, [41,42]
of HBV replication, and the levels of serum HBeAg are thus it needs to be exposed out of the cell. A myristylated
generally considered to correlate with viral titer. In fact, peptide containing a portion of the N-terminal preS1
[41]
HBeAg seroconversion is considered an important aspect region is sufficient to inhibit infection and is currently
of the transition to the inactive carrier state of infection being developed as a therapeutic. [43]
(described below). [37]
The main function of the surface antigen proteins is to form
Surface antigens the HBV envelope. Three different forms of viral particles
HBV encodes three envelope proteins, or surface antigens, are secreted from an HBV-infected cell as a result of the
that make up the viral envelope: large (L), middle (M), and unequal expression of each of the three surface antigens.
small (S) surface antigen [Figure 1a and c]. The smallest S-HBsAg is the highest expressed of the three envelope
envelope protein, or S (24 kD), is 226 amino acids (aa) in proteins and makes up the majority of the viral envelope.
length and makes up a shared C-terminal region of the two Intact, infectious HBV virions, called Dane particles,
longer envelope proteins. The M protein (31 kD) contains also include M-HBsAg and L-HBsAg. In addition, an HBV-
the S sequence with a 55aa N-terminal extension known infected cell produces non-infectious subviral particles
as preS2. Expression of the M- and S-encoding mRNA is (SVP) made primarily of S-HBsAg containing varying
driven by the S promoter, with translation initiating from (but much lower) amounts of M-HBsAg and little to no
an upstream (M) or downstream (S) AUG. The L protein L-HBsAg. These SVPs can reach a concentration 10,000-
(39 kD), the largest of the envelope proteins, contains fold higher than infectious HBV particles in the serum
S, preS2, and an additional 108aa or 119aa (depending of an infected individual. [44,45] SVPs are produced in two
on the genotype) N-terminal extension known as preS1. forms: 25 nm spheres, which are almost exclusively made
L-HBsAg is encoded by its own mRNA transcript that is up of S-HBsAg, and 22 nm filaments, which are made up
controlled by the preS1 promoter. primarily of S-HBsAg, with some M-HBsAg and potentially
small amounts of L-HBsAg. It is currently unknown why
The envelope proteins are synthesized at the ER, where HBV produces SVPs in such excess compared to the level
they attain their transmembrane configuration. Because of infectious virions, but multiple hypotheses have been
all three proteins contain an identical C-terminal proposed. For example, it has been suggested that the
sequence, the transmembrane topology of this region excess SVPs act to divert neutralizing antibodies away
is the same across all three proteins. Specifically, an from infectious particles and that SVPs play a role in
N-terminal signal sequence initiates insertion of S into inducing the immune tolerance required to sustain a long-
the ER membrane, followed by another signal that term chronic infection. A study of DHBV SVPs showed
pushes the downstream peptide sequence into the ER that the SVP-to-infectious-particle ratio plays a role in
lumen. The sequence upstream of this signal remains determining the efficiency of hepatocyte infection, with
in the cytosol, with the signal domain itself acting as a SVPs acting to either enhance or inhibit infection based
transmembrane anchor domain. This orientation forms on the ratio of SVP-to-infectious-particles. [46]
two loops; one loop, between aa 23-79, remains on the
cytosolic side, while the other loop, between aa 99-169, Core protein
remains in the ER lumen. [38] Importantly, the luminal loop The 21 kD HBV core protein, or HBcAg, is the organizing
contains the major conformational epitope of HBsAg and framework for the virion [Figure 1c]. When expressed in
166 Hepatoma Research | Volume 2 | July 1, 2016