The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements
The HBV genome is a circular partially double-stranded DNA molecule. It contains four overlapping open reading frames (ORFs) genes. The S (preS1, preS2) region(s) encodes the major (small), middle and large proteins (HBsAg). The C and pre-C regions encode HBcAg and HBeAg. The X region encodes a poly...
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Інститут молекулярної біології і генетики НАН України
1999
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| Цитувати: | The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements / F. Adjamian // Биополимеры и клетка. — 1999. — Т. 15, № 2. — С. 109-121. — Бібліогр.: 156 назв. — англ. |
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irk-123456789-1563232019-07-05T17:11:38Z The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements Adjamian, F. Обзоры The HBV genome is a circular partially double-stranded DNA molecule. It contains four overlapping open reading frames (ORFs) genes. The S (preS1, preS2) region(s) encodes the major (small), middle and large proteins (HBsAg). The C and pre-C regions encode HBcAg and HBeAg. The X region encodes a polypeptide expressed during HBV infection. The P region codes for a protein with several, functions in replication. Four classes of HBV mRNAs have been identified, in the HBV genome the pre-S1 promoter expresses the large protein. The pre-S2/S promoters produce both major and middle proteins. The X promoter produces 0.7 and 0.9 kb transcripts. The C and pre-C promoters produce the Core, pol(HBcAg), and the HBeAg proteins. Enhancer I and II are key regulatory elements in the transcriptional regulation of HBV. The activity of enhancer II is highly the liwr specific. Enhancer II activates the transcriptional activity of both the pre-S1 and preS2/S promoters. Two HBV enhancers strongly affect the activity of all three major HBV promoters. A box-α in the II-A and box-β in II-B elements of HBV genome, are necessary for the enhancer II function. Either box-α or box-β can regulate the activity of the Core promoter, a, b, f proteins and c, d proteins bind to box-α and box-β, respectively, and mediate the enhancer function. Геном вірусу гепатиту В людини (HBV) існує у вигляді дволанцюгових кільцевих молекул ДНК Він містить чотири фланкуючі відкриті рамки зчитування (ORFs) генів, S (preSl, preS2) регіоні и) кодує головний, середній та великий білки (HBsAg). С і preC регіони кодують HBcAg і HBeAg, X регіон кед у є поліпептид, який експресується за час HBV інфекції Р регіон кодує білок з різноманітними функціями у реплікації. Ідентифіковано чотири класи HBV мРНК. У геномі HBV pre-S1 промотор продукує великий білок, pre-S2/S виробляє головний і середній білки. X промотор кодує 0,7 і 0,9 трагскрипти. С і пре-С промотори кодують Core і pol(HBVcAg) і HBeAg білки. Ключовими регуляторними елементами HBV є енхансери І і II. Активність енхансера II є специфічною для печінки. Він активує транскрипцію обох пре-S1 і пре-S2/S промоторів. Два HBV енхансери активують основні промотори HBV. Бокс-α в І 1-А і бокс-β в ІІ-В елементах у геномі HBV необхідні для функції енхансера II. Бокси а і р можуть регулювати активацію промотора Core, білки a, b, f і білки с, d прикріплюються у боксах а і р відповідно і впливають на енхансерну функцію. Геном вируса гепатита В человека (HBV) существует в виде двухцепочных кольцевых молекуул ДНК Он содержит четыре фланкирующие открытые рамки считывания (ORF8) генов. S (преS1, преS2) регион/ы) кодирует главный, средний и большой белки (HBsAg). С и пре-С регионы кодируют HBсAg и HBeAg. X регион кодирует полипептид, экспрессирующийся в течение HBV инфекции. Р регион кодирует белок с разнообразными функциями в репликации. Идентифицированы четыре класса HBV мРНК. В геноме HBV npe-Sl промотор продуцирует большой белок, пpe-S2/S промотор производит оба (главный и средний) белка. X промотор кодирует 0,7 и 0,9 транскрипты. С и пре-С промоторы кодируют Core и pol(HBcAg) и HBeAg белки. Ключевыми регуляторными элементами в HBV являются энхансеры I и II. Активность энхансера II очень специфична для печени, Энхансер II активирует транскрипционную активность пре-S1 и пре-S2/S про моторов. Два HBV энхансера активируют основные промоторы HBV. Вокс-α в НА и бокс-β в П-В элементах в геноме HBV необходимы для функции энхансера II. Воксы α и β могут регулировать активацию Core промотора, белки a, b, f и белки с, d прикрепляются в боксах α и β соответственно и действуют на энхансерную функцию. 1999 Article The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements / F. Adjamian // Биополимеры и клетка. — 1999. — Т. 15, № 2. — С. 109-121. — Бібліогр.: 156 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00050E http://dspace.nbuv.gov.ua/handle/123456789/156323 578.2 en Биополимеры и клетка Інститут молекулярної біології і генетики НАН України |
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Обзоры Обзоры Adjamian, F. The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements Биополимеры и клетка |
| description |
The HBV genome is a circular partially double-stranded DNA molecule. It contains four overlapping open reading frames (ORFs) genes. The S (preS1, preS2) region(s) encodes the major (small), middle and large proteins (HBsAg). The C and pre-C regions encode HBcAg and HBeAg. The X region encodes a polypeptide expressed during HBV infection. The P region codes for a protein with several, functions in replication. Four classes of HBV mRNAs have been identified, in the HBV genome the pre-S1 promoter expresses the large protein. The pre-S2/S promoters produce both major and middle proteins. The X promoter produces 0.7 and 0.9 kb transcripts. The C and pre-C promoters produce the Core, pol(HBcAg), and the HBeAg proteins. Enhancer I and II are key regulatory elements in the transcriptional regulation of HBV. The activity of enhancer II is highly the liwr specific. Enhancer II activates the transcriptional activity of both the pre-S1 and preS2/S promoters. Two HBV enhancers strongly affect the activity of all three major HBV promoters. A box-α in the II-A and box-β in II-B elements of HBV genome, are necessary for the enhancer II function. Either box-α or box-β can regulate the activity of the Core promoter, a, b, f proteins and c, d proteins bind to box-α and box-β, respectively, and mediate the enhancer function. |
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Article |
| author |
Adjamian, F. |
| author_facet |
Adjamian, F. |
| author_sort |
Adjamian, F. |
| title |
The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements |
| title_short |
The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements |
| title_full |
The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements |
| title_fullStr |
The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements |
| title_full_unstemmed |
The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements |
| title_sort |
hepatitis в virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| publishDate |
1999 |
| topic_facet |
Обзоры |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/156323 |
| citation_txt |
The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements / F. Adjamian // Биополимеры и клетка. — 1999. — Т. 15, № 2. — С. 109-121. — Бібліогр.: 156 назв. — англ. |
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ISSN 0233-7657. Биополимеры и клетка. 1999. Т. 15. № 2
The hepatitis В virus: general description, physical
structure, genetic organization, gene transcripts and
genomic regulatory elements
Farzam Adjamian
Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine
150 Zabolotnoho vul., 250143, Kyiv, Ukraine
The HBV genome is a circular partially double-stranded DNA molecule. It contains four overlapping open
reading frames (ORFs) genes. The S (preSJ, preS2) region(s) encodes the major (small), middle and
large proteins (HBsAg). The C and pre-C regions encode HBcAg and HBeAg. The X region encodes a
polypeptide expressed during HBV infection. The P region codes for a protein with several functions in
replication. Four classes of HBV mRNAs have been identified. In the HBV genome the pre-Sl promoter
expresses the large protein. The pre-S2/S promoters produce both major and middle proteins. The X
promoter produces 0.7 and 0.9 kb transcripts. The C and pre~C promoters produce the Core, pol(HBcAg),
and the HBeAg proteins. Enhancer I and II are key regulatory elements in the transcriptional regulation
of HB V. The activity of enhancer II is highly the liver specific. Enhancer II activates the transcriptional
activity of both the pre-Sl and preS2/S promoters. Two HBV enlmncers strongly affect the activity of all
three major HBV promoters. A box-α in the II-A and box-β in II-B elements of HBV genome, are
necessary for the enhancer II function. Either box-α or box-β can regulate the activity of the Core promoter,
a, b, f proteins and c, d proteins bind to box-α and box-β, respectively, and mediate the enhancer function.
The study of human HBV which is one of the smallest
known for animal virus, has been severaly limited
because it only infects humans and because a tissue
culture system in which this virus can be propagated
is not available. (HBV can not be propagated in vitro).
The hepatitis B surface antigen (HBsAg) transcription
has been studied only in cell lines containing HBV
DNA integrated into chromosomes, and HBsAg-rela-
ted mRNAs 2.0 to 2.5 kb long have been described
[1—5 J.
The hepatitis B viruses, also called Hepadna-
viruses [6], represent a small group of primarily
hepatotropic enveloped DNA viruses that proceed
through reverse transcription of a RNA intermediate
[7, 8 ] in a manner analogous to that of retroviruses.
Beside the HBV of man [9 ], this family (Hapad-
naviridae) includes woodchuck hepatitis virus (WHV)
of Marmota топах [10], ground squirrel hepatitis B
virus (GSHV) of Spermophilus beecheyi [11 ], the tree
squirrel hepatitis B virus [12], duck hepatitis B virus
© F ADJAMIAN, 1999
(DHBV) of Anas domesticus [13] and other ducks,
heron hepatitis B virus in gray herons [14] and
probably others. This taxonomy is derived from the
relative hepatotropism of virus family members, their
common virion morphology, genome size, structure
and organization, and common mechanism of genome
replication. All the viruses exhibit a strict host
specificity; the human virus replicating only in man
and a small number of higher apes.
The disease state induced by infection with HBV
is manifest in varying ways characterized by the
extent of liver inflammation and damage arid viral
persistence. In a small percentage of cases, primary
infection leads to fulminant hepatitis resulting in
severe liver dysfunction with very high mortality.
Primary infection is most often resolved by complete
clearance ol the virus and development of immune
memory to counter reinfection, but 5—10 % of
infected adults develop chronic infection characterized
by the persistence of viral antigens in the serom and
accompanied by varying degrees of hepatic injury.
This disease state may continue after integration of
HBV DNA into the hepatocyte genome from which
109
ADiAMIAN F.
transcription of viral antigen genes may continue in
the absence of virion production. H BV can be detec-
ted in the hepatocyte either as a free DNA molecules
or in an integrated form [15]. ChiOnically infected
patients are predisposed to developing hepatocellular
carcinoma (HCC) [16—19] with more than 100-fold
greater probability than non-infected individuals
[20]. The presence of integrated HBV DNA in
hepatocellular carcinoma has led to the hypothesis
that viral integration may contribute to the process of
hepatocarcinogenesis [21, 22]. In hepatocytes that
have undergone malignant transformation, part of
HBV DNA are integrated into chromosomes of the
host [23—31].
However, the mechanisms of integration, res-
ponsible for Iumorigenesis and for the shutdown of
HBV gene expression and replication in hepatocellular
carcinoma remain unclear [32], but the integrated
HBV subgenomes are suspected to be carcinogenic [3,
33—37]. Hepatitis B constitutes a major worldwide
health problem with the number of chronically in-
fected people currently estimated in excess of 250
million [38—40].
HBV has a partially double stranded, open-
circular genome of 3.2 kb which contains four open
reading frames (ORFs) including the S-gene encoding
the suiiace antigen (HBsAg) and the C-gene encoding
the Core antigen (HBcAg) (Fig. I). A large ORF
encompassing most of the viral genome encodes the
viral polymerase while the fourth ORF encodes a
protein of 154-amino acid residues which has been
termed the X antigen (HBAg). Because the function
of this product in the viral life cycle is still under
intensive investigation.
Although the viral genome and RNA transcripts
can be detected in extra-hepatic tissues of HBV-
infected chimpanzees and in transgenic mice carrying
the HBV DNA [39, 41—43], liver is still the principal
site of clinical disease in which HBV actively repli-
cates.
Infected plasma contains viral particles of dif-
ferent sizes and forms. During infection of humans,
the virus (Dane particle) and the two prominent
subviral particles (filaments and 22-nm particles) are
observed in the sera of infected individuals. The
virion has a diameter of approximately 42 nm (Dane
particle) with a 27-nm core. The 22 nm diameter
particles consist of empty viral envelopes that bears
the hepatitis B surface antigen (HBsAg). Filaments
and 22 nm particles consist only of the HBsAg and
cellular lipid. Careful examination of the surface
antigen [44, 45] has indicated that it is composed of
at least three pairs of proteins: p24 and gp27; gp33
and gp36; p39 and gp42 (p: protein, gp: glycoprotein),
where the second protein in each pair is a gly-
cosylated from of the first. It is apparent from the
work of a number of investigators [5, 31, 46] that
these proteins are derived from a large open reading
frame (one of OR Fs) and originate from the first
three strongly conserved ATGs in that region. This
particular ORF consists of an «S» region that is
preceded by an in-phase reading frame, which has
been designated as «pre-surface» or «рге-S». The
pre-S region may be further subdivided into «pre-Sl»
and «pre-S2» [46—48]. The 42 nm HBV particles
(Dane particle = virion) contains three different sur-
face proteins which are referred to as «major (small)»
protein, «middle» protein and «large» protein. (The
outer envelope of the virion is arrayed by three
surface S proteins; the major (small) S, the middle S,
and the large S [17, 44, 49, 50—53)). The large
surface protein (LS) is translated from the first ATG
codon of the surface open reading frame, while the
middle and small (major) forms are translated from
in-frame ATG codons further downstream. Inside the
viral envelope, there is the 27-nm «Core» particle
formed by subunits of core proteins referred to as
HBcAg. It contains the viral polymerase and the
partially double stranded DNA molecule to which a
protein is covalently linked (for a review see [54]).
All three forms of the surface (envelope) proteins
(antigens) which are co-linear in the carboxyl-ter-
minal protein, are needed for virion production and
cotranslationally inserted into the Endoplasmic Reti-
culum (ER) as transmembrane proteins and, together
with envelope cytoplasmic core (nucleocapsid) par-
ticles, form mature virions that are secreted via the
constitutive secretory pathway [53], but an over-
production of the large form can result abnormal
particle formation that becomes inspissated in the ER
and damages the host cell [55, 56]. In addition, the
middle and/or small forms, in the absence of other
viral proteins, can bud into the lumen and be secreted
in the form of spherical and filamentous subviral
particles. LS, in contrast cannot be secreted when
expressed alone but instead is retained within the cell
in the form of intraluminal particles [55, 57, 58—60,
102 ].
If LS is coexpressed with the other forms of
surface protein, they form heteromultimers whose
phenotype depends on the relative amounts of the
various surface proteins: a small relative amount of LS
results in secretion, while a large amount results in
retention. This retention affects the secretion not only
of noninfectious subviral particles but also of the
infectious virion particles and, therefore, is delete-
rious to the viral life cycle [61 ]. Not surprisingly, in
the infected cell, LS is usually synthesized in much
110
THE HEPATITIS B VIRUS: GENERAL DESCRIPTION
Fig. 1. HBV genome organization and viral transcripts (in ayw subtype): Open reading frames are represented by arrows, and Iwxes
represented transcriptional control regions. The stars correspond to the ATG codons and the position given at the end of the arrows correspond
to those of the stop codons. Abbreviation: GRE - Glucocorticoid Responsive Element, DRI and DRIT - primary site for replication
smaller amounts than the middle and small surface
proteins. This differential regulation is achieved by
the presence of two independent promoters [62 ]. The
upstream pre-Sl promoter gives rise to transcripts
that are translated mainly into LS, while the down-
stream S promoter gives rise to transcripts capable of
translation into only the middle and small surface
protein. Since the amount of pre-Sl mRNA is nor-
mally much smaller than the amount of S mRNA,
there is insufficient LS to prevent secretion. Because
the relative ratio of LS to the middle and small
surface proteins synthesized by HBV is crucial to its
replication, it was found, that there is a feedback
mechanism to ensure a balanced synthesis of these
proteins, in that LS significantly activates the S
promoter [63]. This activation is con-elated whit the
intracellular retention of LS and is mimicked by
agents that induce ER stress [63 ], Conversely, LS
111
ADiAMIAN F.
also activates cellular promoters known to respond to
ER stress, but not irrelevant promoters. Therefore,
overexpression of LS and subsequent intracellular
particle retention appear to activate the S promoter by
an intracellular signalling pathway induced by ER
stress. This activation would in turn lead to increased
synthesis of the middle and small surface proteins
and, hence, allow secretion of both subviral and virion
particles [63]. (The pre Sl and S promoters will
explaind in other part of litis review.)
The investigation of the HBV life cycle has been
hampered by the lack of a system for HBV replication
in vitro. However, in vitro culture systems whit human
hepatoma cells that are capable of producing HBV
particles by DNA transfection have been successfully
established by various groups of investigators [64—
67, 71]; cloning and sequencing [47, 48], the use of
animal model systems [7, 68], and eukaryotic exp-
ression system [69, 70], however, have brought some
insight into the HBV gene organization and life cycle.
Different systems are now available to study HBV
gene expression. Virus multiplication and production
of surface antigens have been obtained in hepatoma
cell lines transfected by cloned HBV DNA [71 ], in
adult [72] and fetal [73] primary human hepatocytes
cultures by direct infection, This has been clone also
in vivo with the transgenic mouse system [38, 39, 43,
74, 75]. By using eukaryotic vectors, expression of
HBsAg has been demonstrated in various cultured
cells [4, 76 ]. Synthesis of HBsAg in mammalian cells
has uniformly resulted in production of this gene
product and its secretion in the form of 22 nm
particles into the culture medium, which facilitates
detection and purification [5]. So that knowledge of
the virus cycle and of its molecular biology is in
progress.
The viral surface antigen has a common group
specific determinant a and carries one member of
each of the two pairs of mutually exclusive subtype
determinants d and у [68 ] and w and r [78 ]. Thus
there are four major subtypes of HBsAg: adw,' adr,
ayw, and ayr [79]. These subtypes have been recently
classificated into group A, B, C' and D by Okamoto et
al. [80]. The groups A, B and D are homogenous
while group C is not [80]. In this later group the adw
genome is closely related to the ayr and adr genomes.
Two by two analysis of the nucleotide sequences show
some degree of divergence. The divergence is about
10 % for viruses of different subtypes and about 2 %
for viruses of the same subtype except for the ayr
subtype which diverges only 2 % from the adr
subtype. Occasionally mixed subtypes have been re-
ported in adwr, adyw, adywr and aywr. Both appa-
rently excluded determinants map to the same mole-
cule. It is not known if this represents a double
infection or an uncommon HBV strain.
Virion DNA: It has been mentioned above, that
the HBV genome is a small circular partially double-
stranded DNA molecule. This genome is accompanied
by a single stranded region of variable length (Fig.
1). The minus (-) strand is linear and of fixed length
of about 3200 nucleotides. It is the coding strand from
which the viral mRNA and the viral pregenomic RNA
are transcribed. At its 5' end, there is a protein that
serves as primer for reverse transcription. The plus
strand (+) is of variable length ranging from 50 to
100 % that of the minus strand. The maintenance of
the circular structure is assured by a short cohesive
overlap region of about 200 nucleotides at the 5' end
of the two strands. A 12 bp direct repeats (DRI and
DRII) located near the 5' end of both strands seems
to serve as a primary site for replication (Fig. 1).
The first «Т» of the sequence 5'GAATTC in the
plus strand corresponding to the unique EcoRI site
which exists in most genomes is used as reference
origin of physical map. Nucleotides numbering is from
5' to 3' in the plus strand. When the EcoRI site dose
not exist the base occupying the same position is
taken as position 1.
Physical structure and genetic organization of the
HBV genome: As a remind and completion, it is
pointing out that the hepatitis B virus genome con-
tains four overlapping open reading frames genes
encoding all known proteins of this virus. The enve-
lope open reading frame, or S region (S gene),
contains three in phase translation start codons
(ATG) defining the N-termini of three envelope
polypeptides; pre-Sl, pre-S2 and S protein (The
hepatitis B surface antigen [HBsAg]) [54, 81, 82].
Referring to the ayw subtype [47], the shortest
polypeptide (226 aa) (aa = amino acid) that contains
the group a and the subtypes ( d / у , w/r) determinants
is also called major (small) protein (HBsAg) because
of in relative abundance. It is encoded by the S region
starting from the ATG at position 158 (in the adw
subtype [83 ]). The middle envelope polypeptide con-
tains the entire amino acid sequence of the major
polypeptide plus 55 aa at the N-terminus containing
the pre-S2 antigen, starting from the ATG at position
3214 ([The P31 ATG] in adw subtype [83]). The
large protein is composed by the entire amino acid
sequence of the middle envelope polypeptide plus 158
aa at the N-terminus and bears the pre-Sl antigen
[52, 82]. The two pre-S antigens are highly immuno-
genic neutralizing epitopes, the larger one being
involved in the virus binding to cell receptors and in
the entry in the hepatocytes [82 ]. Many trans-
criptional factors are able to bind to specific sites in
112
the pre-S region of HBV DNA and could be somehow
responsible for the hepatotropism i. e. HNFl and API
[83, 84].
A glucocorticoid responsive element (GRE) has
been mapped within the S gene between positions 351
and 366 (in ayw subtype) [85 ]. This element has no
enhancer activity but act synergettically with the viral
enhancer [86 ]. Steroid hormones have been shown to
positively regulate the S gene expression in transgenic
mice [87]. (The Enhancer activity will discussed in
other part of this review.) The capside open reading
frame or region C (C gene) contains two in frame
ATG and encodes a nucleic acid binding protein,
HBcAg, that encapsidate the viral nucleic acids and a
29 aa longer polypeptide (pre-C) that is secreted as
HBeAg [88 ]. The X region (X gene) encodes a
polypeptide expressed during HBV infection and in
hepatocellular carcinoma [89]. This polypeptide has
transactivating properties on HBV and other viral and
cellular promoters [90—92 ]. The P region (P = Pol
gene) overlaps all the others. It codes for a protein
with several function in replication; (DNA poly-
merase, RNAse H, primer for DNA synthesis and
reverse transcriptase [93]). This protein as well as
reverse transcriptase activity [94, 95], binds to the
viral DNA 5' terminus of the minus strand [96 ].
Three major classes of HBV-specific message are
detected in infected hepatocytes, and 5' ends of the
RNAs are heterogeneous (Fig. 2) [41, 54, 97]: the
3.5-kb RNAs, which are slightly larger than the 3.2
kb unit length of HBV genome serve as the mRNAs
THE HEPATITIS B VIRUS: GENERAL DESCRIPTION
for expression of the core protein. It is also used for
the synthesis of viral DNA polymerase [7, 8, 98].
Because these RNAs are the only species containing
the full complement of viral genetic information, they
also serve as templates for reverse transcription
during HBV replication [8, 97, 99]. Two other
mRNAs are subgenomic in size: the 2.4 kb RNAs
encode the large envelope protein HBV surface ,anti-
gen (S-protein), and the 2.1 kb RNAs encode the
middle and major HEiV surface antigens. Expression
of these HBV-specific mRNAs is controlled by four
different promoters in the HBV genome [54]: the
Core promoter regulates expression of the 3.5 kb
RNAs, whereas the; pre-S promoter (The distal
TATA-Iike promoter (SPI)) [4, 100, 101] and the S
promoter (The proximal Simian virus 40 (SV40)-like
promoter (SPII)) regulate expression of the 2.4 and
2.1 RNAs, respectively [44, 102, 103]. Both the SPI
and the SPII promoters display a preference for
differentiated hepatoma cell lines [104]. The liver-
and differentiated state-specific transcriptional acti-
vities of the SPI promoter are controlled by the
combined action of a HNF-I binding element, lying
between 68 and 95 bp upstream of the; RNA cap site
in the SPI promoter region [98], and the HBV
enhancer, which is located downstream of the coding
sequence of the S gene [104, 105].
The liver- and differentiated state-specific trans-
criptional activities of the SPII promoter are contri-
buted mainly by the upstream flanking sequence in
the promoter region [83, 104, 106]. In addition (0.7
Fig. 2. Linear representation of the HBV genome. The numbering system of Pasek et al. [481 is used. Transcriptional control regions are
shown as boxes and are abbreviated as follows: SPJ - pre-SI promoter; SPIJ- pre-S2/S promoter, enh(I)/Xp - enhancer X/I promoter,
CpIenh(II) - Core promoter/enhancer Π
AD JAMlAM F.
[113]) 0.8 to 0.9 kb mRNA has been detected in the
in vitro expression system by the DNA transfection of
HBV DNA [107]. This transcript may be related in
some way to the expression of the X gene [99],
controlled by X-promoter. One of the two major
HBV-specific poly (A+) RN As characterized in infec-
ted livers of chimpanzees is 2.1 kb long [4, 41 ]. This
transcript codes for the major S protein and appare-
ntly for pre-S2 protein. Thus, four classes of mRNAs
have been identified so far in the process of HBV
propagation and are known to use the single poly-
adenylation signal for their termination [99 ].
Two similar major transcripts were also observed
in the infection of other hepadnaviruses, the wood-
chuck hepatitis virus (WHV) and ground squirrel
hepatitis virus (GSHV). Analysis of Ihe 5' ends of the
two major transcripts from infected woodchucks and
ground squirrels indicated that they were hetero-
geneous for all transcripts [108, 109]. For the two
major transcripts of HBV, however, use of the tran-
sient expression system of transfected HBV DNA
with HuH-7 cell made possible a similar analysis of
the heterogeneity of 5' ends of two major transcripts
[67]. It is mentioned above, thai in human, the
principal site of clinical pathology after HBV infec-
tions is the liver because HBV actively replicates only
in hepatocytes [17, 41]. Consistent with this obser-
vation, the 3.5 kb genomic transcript has been detec-
ted primarily in well-differentiated human hepatoma
cell lines transfected by the cloned HBV genome [67,
71 ], suggesting that liver-specific factors are needed
for efficient transcription of the genomic transcripts
from the core promoter, but although HBV DNA has
been found in non hepatic tissues in infected patients
and in transgenic mice [38, 39, 42, 43, 110].
Gene Transcripts: All the transcripts already
described have the same 3' end consisting on a
polyadenylation site 1916-TATAAA- 1921(111). As a
result and completion, there are four promoters that
regulate the expression of the different HBV genes;
two Surface promoters, one Core promoter, and one
X promoter. The given positions correspond to that of
the adw [48 ] HBV genome.
The pre-Sl promoter: This promoter which con-
tains a TATA box sequence was defined by in vitro
[101] and in vivo [112] studies; this promoter
initiates transcription at position 2810 (in adw),
upstream from the pre-Sl region. Low activity of this
promoter was found in the human hepatoma Ale-
xander ceil line [31 ] and in the liver of an infected
chimpanzee [4]. Using stable transformation with
cloned HBV DNA, it was shown that this TATA
box-containing promoter is not essential for the
expression of hepatitis B surface antigen [76]. Thus
the pre-Sl promoter, which is a canonical TATA
sequence, located upstream the ATG of the pre-Sl
region and, produces 2.4 kb transcripts. However, this
promoter is less functional that the other viral pro-
moters [82].
The S promoter; as a second promoter termed
the S promoter and was characterized and mapped at
the pre-S2 region. This promoter induces initiation of
transcription at three major sites, spanning some
30 bp) around the EcoRI site [4, 5, 76 ]. The position
of these three initiation sites are 5 nucleotides down-
stream from and 5 and 25 nucleotides upstream from
the EcoRI site (designated as a, b, and c, respec-
tively). Since the ATG of the pre-S2 region is
positioned between the b and с initiation sites, only
the two longest RNA species may code for p31 protein
with an extra 55 amino acids of the pre-S2 region.
The shorter species lack the p31 ATG so that the first
available ATG, at position 158 (in adw subtype), is
the transcriptional start point of the major S protein.
It was proposed that the expression of these trans-
cripts in vivo is directed by a sequence positioned
around the Fnu4HI restriction site (3165 in adw
subtype) [4] at the region where sequence similarity
to the SV40 late promoter was been shown. Thus the
S promoter is located round position 3155 (in ayw
subtype) just upstream to the translation site of the
middle protein and produces 2.1 kb transcripts [4'
The 5' ends of these transcripts are heterogeneous
and encodes both the major (small) and middle
protein. Despite the extensive mapping of S gsne
mRNA initiation sites, little is known about regu-
latory elements which modulate the S promoter.
Transient expression studies revealed that ibis
promoter is highly active in the Alexander
(PLC/PRF/5) hepatoma cell line but not in SK-Hepl
and HeLa cells. It has been determined that a distal
element of the promoter (-103 to -48) confers this
cell-type-specific behavior through a mechanism in
which the promoter activity repressed in HeLa and
SK-Hepl cell but increased in Alexander cells [83].
It has been also found an enhancer like activity
associated with a small DNA segment of the S
promoter (-27 to +30) [83]. This proximal element
actives in HeLa and SK-Hepl cells only in the
absence of the distal negative element. Finally, ana-
lysis of S promoter deletion mutants demonstrated
that the -27 to -17 region of the S promoter is crucial
for its activity [83 ].
The X promoter; has not been precisely located
[107]. It is weakly active in vivo and represent less
than 1 % of the viral transcripts. In in vitro system,
0.7 kb and 0.9 kb transcripts have been reported
[113]. This promoter seem to be more efficient out of
114
THE HEPATITIS B VIRUS: GENERAL DESCRIPTION
the whole HBV genome context. Since the HBV X
protein (pX) trans-activates many promoters [114],
including the HBV Core promoter [91 ], it is deter-
mined that pX not regulates the pre-Sl or S promoter
(pX has not trans-effect on the Surface gene pro-
moters).
The Core promoter; regulates the replication of
the virus, as the 3.5 kb C mRNA/pregenome not only
serves for translation of the Core and Pol proteins but
also represents the template for reverse transcription
[97, 115, 116]. From the second Core promoter
transcript, the pre-C mRNA, only the HBeAg precur-
sor is translated [115, 116]. The Core promoter is
composed of a minimal or basic Core promoter <BCP)
sufficient to initiate transcription and of upstream
regulatory sequences (URS) [117—119]. A short
TA-rich sequence in the BCP serves as both the
initiator and TATA box for transcription initiation of
the pre-C mRNA and C mRNA/pregenome, respec-
tively [120].
An important activating URS element is the alpha
box (see part of Regulatory Elements of HBV genome
in this review), which binds hepatocyte nuclear factor
4 (HNF4), C/EBP, or other liver-specific trans-
cription factors [110, 117, 118, 121—124]. In addi-
tion, binding sites for HNF3 and ubiquitous factors
like SPI were identified in this promoter [125, 126].
Unlike the pre-Sl promoter, the Core promoter of
wild-type HBV does not contain an HNFl binding
site [127].
Because of its crucial role in the viral life cycle,
naturally occurring sequence variation in the Core
promoter of HBV in patients is under intense inves-
tigation. Specific point mutations in the BCP were
found in HBV from patients with fulminant hepatitis
[128—131]. Similar mutation as well as different
short deletions or insertions were found in viremic
HBeAg-negative patients with chronic hepatitis B
[129—134].
Since for these patients no mutation in the C
gene could explain the lack of HBeAg expression, it
was speculated that promoter mutation may be res-
ponsible. Specific types of short deletions in the Core
promoter region were found in patients with extre-
mely low-level viremia, in some cases without any
serological marker for HBV infection [135—138].
Thus, a particular phenotype may be caused by
specific mutations in the Core promoter. However,
this speculation has not previously been substantiated
by experimental evidence [93]. At last the Core
promoter, produces transcripts of 3.5 kb. Three 5'
ends have been located upstream of the C gene: two
of them initiating downstream of the ATG of pre-C
region, coding for the major capsid antigen (HBcAg)
and the genomic viral DNA, and another one starting
ups tream region pre-C coding for the HBeAg [67 |. A
C gene specific 2.1 kb spliced transcript that represent
the 2.1 kb S transcripts has been described [1391.
A polymerase gene promoter has not been iden-
tified. The 3.5 kb transcripts that have heterogeneous
5' ends [108] could also encode the polymerase gene
products.
Regulatory Elements of HBV genome: Eukarvotic
gene expression is in large part regulated at the
transcription, level. Such regulation is governed by the
constellation of trans-acting cellular factors that bind
to specific as-acting elements and act in either a
positive or negative manner [140]. Cell-type-specific
gene activation a primary' determinant of cellular
differentiation, represents a more complex type of
interplay, as both constitutive arid tissue-restricted
trans-acting regulatory factors are involved [1,41].
The differential sequence-specific recognition of these
cis-acting elements in promoters and/or enhancer s by
their cognate factors provides a mechanistic basis for
the tissue- and differentiation-specific regulation of
gene expression. The study of model viral genes
which display distinct tissue tropism can provide
valuable insight into the intricate effects of cell-type-
specific transcription regulation on differentiation. It
has been mentioned above, that control of gene
transcription in part regulated by the presence of
cis-acting DNA elements that interact with specific
nuclear transcription factors. Enhancers, which act in
a position- and orientation-independent mannner, are
key regulatory elements in the transcriptional regu-
lation of viral and cellular genes [142, 143 ]. The
72-bp repeat of simian virus 40 (SV40) is the best-
characterized enhancer.
The SV40 72-bp enhancer, which is composed of
multiple regulatory cis-acting elements via the inter-
action whit ubiquitous and cell-type-specific trans-
criptional factors, orchestrates the expression of viral
genes in many cells [144—146]. Two regions of the
HBV genome are known to display properties of a
transcriptional enhancer (Fig. 2) [147—149]. A
transcriptional region, Enhancer I, is located between
the open reading frames of the surface antigen, within
the region P, and upstream the X region (position
1074—1234 in ayw subtype) and partially overlaps the
X promoter [147, 150]. Because activation of trans-
cription by this enhancer is greater in several cultured
hepatoma cells than in nonhepatic cells, it has lieen
suggested that this enhancer is responsible for liver-
specific gene expression of HBV [150]. It is described
the identification of a second enhancer sequence
(enhancer II) in the HBV genome: Enhancer II is
situated downstream of the previously identified en-
115
АШAMLAN F.
hancer (enhancer I), immediately upstream from the
coding region of the Core gene (initiation site of viral
major transcript) [152], overlaps with the Core pro-
moter [93], within the X open reading frame [98,
152].
Enhancer II has been mapped to nt 1636 to 1741
[123] in HBV genome. It furnishes a unique model of
use in investigating the structure and function of an
enhancer. Unlike enhancer I, the activity of enhancer
II is highly liver specific, functioning only in highly
differentiated human hepatoma cells. Furthermore,
enhancer II activity varies in different hepatoma lines,
suggesting that this enhancer is regulated according
to the differentiation state of the hepatoma line used.
Because enhancers have been shown to play a pivotal
role in the regulation of mammalian and viral gene
expression and because HBV gene expression is
tightly coupled to the step of reveres transcription in
this replication cycle, a mechanism for regulation of
HBV enhancer activity may clarify the molecular
basis for the absence of HBV replication and gene
expression in hepatocellular carcinoma [22]. With
various deletions at the 5' end of enhancer II, a
positive regulatory element was identified at nt 1636
to 1690 (the II-A element), with the 5' boundary
between nt 1636 and 1671. The II-A Element alone
did not have an enhancer function, but the enhancer
activity was been achieved by the concomitant pre-
sence of the sequence from nt 1704 to 1741 (the II-B
element). The II-B Element alone did not have
enhancer activity. These facts indicate that coope-
ration between the II-A and II-B elements is required
to exhibit the enhancer activity of enhancer II [98 ].
Two functional constituents, a 23-bp sequence box-α
in the II-A element and a 12-bp sequence box-β in
II-B element, were identified as being both necessary
and sufficient for enhancer II function [123]. Interes-
tingly, either box-a or box-/? in an upstream position
can regulate the activity of the nearly Core promoter
[119].
Examination of the box-α and box-β sequences
reveals a weak homology to the extended consensus
for a C/EBP binding site. Gel shift and footprinting
analyses indicate that multiple proteins bind to these
sequences and thus are candidate transcription factors
that mediate the enhancer function. One heat-resis-
tant protein, protein a, and one heat-sensitive pro-
tein, protein b, bind to box-α. Protein a, which bind
to box-α in a way indistinguishable from that seen
with a recombinant C/EBP, appears not to be iden-
tical to C/EBP in that the binding of protein a
requires a minimal sequence larger than the canonical
C/EBP sites.
Two box-/?-binding proteins с and d, show gre-
ater affinity for the C/EBP consensus than for
Ъох-β. However, both proteins с and d are relatively
heat sensitive and display a distinct sequence prefe-
rence from the recombinant C/EBP protein. Since the
function of enhancer II is strictly dependent on a
bipartite architecture, this system provides a unique
model for studies of how the interactions of its
binding proteins lead to the enhancer function. Fur-
thermore, proteins that display binding activities to
box-α and box-/? are found to be present in nuclear
extracts of the differentiated human hepatoma cell
line HepG2 by DNAse I footprinting and gel shift
analyses [123]. Using DNA transfection to bypass
viral entry into cells, it has been demonstrated that
the expression of HBV genes exhibits liver cell and
differentiation state specificity in the infective process
in vivo [64, 66, 67, 71, 104, 153—155]. Previous
studies show that only in the human hepatoma cell
lines HepG2 and HuH-7, which have the feature of
well-differentiated liver cells, does enhancer II have
strong enhancing activity on the simian virus 40
(SV40) early promoter [1101. In contrast, this is not
seen in the poorly differentiated HA22T/VGH cells
or the nonliver HeLa cells [98 ]. These results also
apply to the upstream regulatory effect on the bast.
Core promoter (BCP) [119]. These differentiateo
actions, therefore, may contribute at least in part to
the observed hepatotropism of HBV. It has been
mentioned above that gel shift experiments reveal a
unique box-a-binding protein, protein a, which is
present only in differentiated liver cells, where en-
hancer II is functional. The converse is true for
another box-a-binding protein, protein /, which is
present only in poorly differentiated liver cells and
nonliver cells. The simplest hypothesis that explains
these results is that protein a activates and/or protein
/ suppresses the enhancer and upstream regulator
functions.
Although C/EBP is a candidate for a trans-
cription factor that interacts with box-α or box-β,
none of the binding factors identified in the gel shift
assays, including protein a and protein /, is likely to
be C/EBP because they differ from C/EBP in heat
liability and sequence preference [117]. In addition,
enhancer II consists an upstream negative regulatory
element [98, 110, 122, 124, 152, 156]. Enhancer II
activates the transcriptional activity of both the SPl
and SPII promoters in a liver- and differentiated
state-specific manner [98 ].
It has been shown that the two HBV enhancers
strongly effect the activity of all three major HBV
promoters in human hepatoma cells and that the
activity of HBV enhancers is differentially regulated,
depending on the state of hepatocyte differentiation.
116
THE HEPATITIS B VIRUS: GENERAL DESCRIPTION
Ф. Аджаміян
Вірус гепатиту В: загальний опис, фізична структура, генетична
організація, транскрипція генів та геномні регулюючі елементи
Резюме
Геном вірусу гепатиту В людини (HBV) існує у вигляді
дволанцюгових кільцевих молекул ДНК. Він містить чотири
фланкуючі відкриті рамки зчитування (ORFs) генів. S (preSl,
preS2) регіон(и) кодує головний, середній та великий білки
(HBsAg). C і ргеС регіони кодують HBcAg і HBeAg. X регіон
кодує поліпептид, який експресується за час HBV інфекції. P
регіон кодує білок з різноманітними функціями у реплікації.
Ідентифіковано чотири класи HBV мРНК. У геномі HBV
pre-Sl промотор продукує великий білок, pre-S2/S виробляє
головний і середній білки. X промотор кодує 0,7 і 0,9 траі с-
крипти. C і пре-С промотори кодують Core і pol(HBVcAg) і
HBeAg білки. Ключовими регуляторними елементами HBV є
енхансери І і II. Активність енхансера II є специфічною для
печінки. Він активує транскрипцію обох npe-Sl і npe-S2/S
промоторів. Два HBV енхансери активують основні промото-
ри HBV. SoKC-a в II-A і бокс-β в II-B елементах у геномі HBV
необхідні для функції енхансера II. Бокси а і β можуть
регулювати активацію промотора Core, білки a, b, f і білки с,
d прикріплюються у боксах а і β відповідно і впливають на
енхансерну функцію.
Ф. Аджамиян
Вирус гепатита В: общее описание, физическая структура,
генетическая организация, транскрипция генов и геномные
регулирующие элементы
Резюме
Геном вируса гепатита В человека (HBV) существует в виде
двухцепочных кольцевых молекуул ДНК. Он содержит четыре
фланкирующие открытые рамки считывания (ORFs) генов. S
(npeSl, npeS2) регион/ы) кодирует главный, средний и боль-
шой белки (HBsAg). С и пре-С регионы кодируют HBcAg и
HBeAg. X регион кодирует полипептид, репрессирующийся в
течение HBV инфекции. P регион кодирует белок с разнообраз-
ными функциями в репликации. Идентифицированы четыре
класса HBV мРНК. В геноме HBV npe-Sl промотор продуци-
рует большой белок, npe-S2/S промотор производит оба
(главный и средний) белка. X промотор кодирует 0,7 и 0,9
транскрипты. С и пре-С промоторы кодируют Core и
Pol(HBcAg) и HBeAg белки. Ключевыми регуляторными эле-
ментами в HBV являются энхансеры I и II. Активность
энхансера II очень специфична для печени. Энхансер II активи-
рует транскрипционную активность npe-Sl и npe-S2/S про-
моторов. Два HBV энхансера активируют основные промото-
ры HBV. Бокс-α в II -A и бокс-β в Il-B элементах в геноме HBV
необходимы для функции энхансера II. Боксы а и β могут
регулировать активацию Core промотора, белки a, b, f и белки
с, d прикрепляются в боксах а и β соответственно и дейст-
вуют на энхансерную функцию.
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УДК 578.2
Received 28.10.98
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