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doi:10.3748/wjg.14.4725
EDITORIAL
Hepatitis G virus
Abstract
A number of new hepatitis viruses (G, TT, SEN) were
discovered late in the past century. We review the
data available in the literature and our own findings
suggesting that the new hepatitis G virus (HGV),
disclosed in the late 1990s, has been rather well
studied. Analysis of many studies dealing with HGV
mainly suggests the lymphotropicity of this virus. HGV
or GBV-C has been ascertained to influence course
and prognosis in the HIV-infected patient. Until now,
the frequent presence of GBV-C in coinfections,
hematological diseases, and biliary pathology gives
no grounds to determine it as an accidental tourist
that is of no significance. The similarity in properties of
GBV-C and hepatitis C virus (HCV) offers the possibility
of using HGV, and its induced experimental infection,
as a model to study hepatitis C and to develop a
hepatitis C vaccine.
2008 The WJG Press. All rights reserved.
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GBV-B
Volume 14
Number 30
HGV
GBV-C
1a
1b
Proteins (x
103 daltons)
E1
E2
NS2
ab
NS3
20
70
NS4 NS5a
ab
28
55
NS5b
3'
57
HCV
315
GBV-A
2a
2b
Figure 1 Affinity of HCV, GBV-C, GBV-A, and GBV-B (From Robertson BH,
2001)[5].
GBV-C structure
The genome of the virus is represented by singlechain RNA with positive polarity [13] . The GBV-C
genome is similar to hepatitis C virus (HCV) RNA in
its organization, i.e. the structural genes are located at
the genomic 5' region and non-structural genes are at
the 3' end (Figure 2)[14]. The untranslated region at the
5' end may serve as an internal ribosomal embarkation
site, which ensures translation of a RNA coding
region[15]. The extent of the genome in different viral
isolates ranges from 9103 to 9392 nucleotides[16,17]. An
open reading frame carries information on the virusspecific polypeptide consisting of 2873-2910 amino acid
residues. GBV-C RNA codes for two structural proteins
(E1 and E2) which are envelope proteins. Unlike HCV,
the proportion of glycosylated E2 is much lower in
GBV-C. It has a total of three potential N-glycosylation
sites as compared with HCV E2, which has eleven sites.
The complete structure of viral nucleocapsid is still to
be determined as the genomic region coding for core
proteins has not been identified yet[18].
Five non-structural proteins: NS2, NS3, NS4b, NS5a,
and NS5b with molecular weights of 20, 70, 28, 55,
and 57 kDa, respectively, have been found[19,20]. These
proteins perform the function of protease, helicase, and
RNA-dependent RNA-polymerase. The sequencing
of the E1 and E2 regions has shown that they are not
hypervariable unlike the respective regions of HCV[12].
Of interest are the data obtained while studying the
buoyant density of GBV-C particles in a saccharose
gradient before and after treatment with the nonionic
detergent Tween-80. These data suggest that there is a
lipid envelope in the virus whose association with lipids
reduces antibody formation.
4727
Markers of GBV-C
The basic marker used to diagnose GBV-C is RNA
that is detectable by the amplification technique with
a preliminary stage of reverse transcription in which
cDNA is synthesized [reverse-transcriptase polymerase
chain reaction (RT-PCR)]. Data on the sequence of the
RNA region coding for helicase (NS3) and the NS5A
region are used to synthesize oligonucleotide primers.
This choice is made due to the high (83%-99%) stability
of this region in various viral isolates (the sensitivity was
as high as 200 copies/mL).
Further investigations indicated that there might
be false negative results in the testing of some samples
despite the fact that the latter contained the virus. By
taking this into account, primers with the information
coded in the 5'-untranslated region (the sensitivity was
as high as 100 copies/mL) came into additional use for
the designing of diagnostic kits[10]. The above primer
kits had a high sensitivity, but also a rather high level of
errors due to the incomplete conservatism of respective
viral RNA regions.
An alternate primer kit for the region coding for E2
has been developed. These primers had 100% specificity
for this RNA region; however, their sensitivity was not
greater than 76.6%. Recent investigations propose the
use of the two different primer kits (for viral RNA NS3,
NS5A, 5'UTR, or E2 regions) for the accurate diagnosis
of GBV-C RN[21].
GBV-C RNA has been detected in hepatocytes[19,20,22],
peripheral blood lymphocytes and monocytes [23,24],
vascular endothelial cells[25], and other tissues[7]. GBV-C
viremia may persist for a few years. The infection is
accompanied by the formation of specific antibodies
against the envelope protein E2 (anti-E2). These
antibodies have a long survival and may prevent the
body from reinfection.
An enzyme immunoassay has been developed to
detect serum GBV-C antibodies. The envelope E2
antigen (glycoprotein) was used as a viral antigen.
Analysis of the sera from healthy individuals and
patients with hepatitis demonstrated that most antiE2-positive sera were GBV-C RNA negative, which
enabled anti-E2 to be regarded as a marker of previous
infection[8,26-28]. As a rule, GBV-C antibodies and RNA
are not simultaneously encountered in a patient despite
the fact that HCV, the nearest relation of GBV-C, is
Anti-E2 (%)
3.0
4.9
42.1
13.7
4.9
23.6
Epidemiology of GBV-C
Infection with HGV is common in the world. The
detection rate of GBV-C in the population averages 1.7%.
GBV-C, like other parenteral hepatitide viruses, occurs
universally, but nonuniformly (Table 1)[8,11,33-41].GBV-C is
detectable in all ethnic groups. Analysis of the results of
examining 13610 blood donors described in 30 reports
revealed viral RNA in 649 (4.8%) of cases. These included
Caucasians (4.5%), Asians (3.4%), and Africans (17.2%)[42].
The authors propose to test blood samples due to the
high risk of infection with GBV-C[42,43].
An investigation of the prevalence of HGV among
north-eastern Thai blood donors carrying HBsAg
and anti-HCV revealed the high frequency of GBV-C
RNA (10% and 11%, respectively) in the co-infected as
compared with the controls (0%)[44].
The development of an anti-E2 detection method
has promoted a complete definition of the prevalence
of GBV-C. E2 antibodies are several times more
frequently detectable than RNA in blood donors
(Table 2)[8,33,38,40,41,45].
GBV-C is a parenterally transmitted infection[28-30].
The first verification of this fact were the experiments
dealing with inoculation of primates with the blood
of the surgeon who fell ill in 1966[2]. Cases of acute
posttransfusion hepatitis along with the enhanced
activity of serum aminotransferases and the detection
of blood GBV-C RNA in the absence of other markers
of viral hepatitides has been documented[3,31,32]. Indirect
evidence that HGB is parenterally transmitted lies in
its more frequent detection in the groups at higher risk
for infection with hepatitis viruses by similar routes
of transmission (Table 3)[8,11,34,36,38,41,46-51], as well as the
increased risk for infection in patients treated with
multiple hemodialysis procedures and higher units of
transfused blood products[33-35].
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Risk group
Patients on hemodialysis
Patients on hemodialysis
Drug abusers
Patients with hemophilia
Recipients of immunoglobulins
Drug abusers
Patients on hemodialysis
Patients on hemodialysis
Renal or hepatic posttransplantation patients
Patients on hemodialysis
Patients on hemodialysis
Patients on hemodialysis
Patients on intravenous drug injection
Patients with hemophilia
Patients on hemodialysis
Drug abusers
Patients on hemodialysis
GBV-C tropism
GBV-C predominantly replicates in peripheral blood
mononuclear cells, mainly in B and T (CD4+ and CD8+)
lymphocytes and bone marrow[23-25,60]. The mechanism
responsible for the development of GBV-C-induced
hepatitis is not clear so far. Despite the described cases of
acute and chronic hepatitis G, its hepatotropicity remains
controversial. Table 4[11,27,28,61-74] shows data that both
confirm and rule out viral tropism to liver tissue.
Viral hepatotropicity is supported by the detection of
GBV-C RNA in hepatocytes and by the development of
acute and fulminant hepatitis following the transfusion
of infected blood and its products. Lang et al reported
interesting data on the immunohistochemical detection
of GBV-C NS5 Ag in the liver biopsy specimens taken
from patients with various liver diseases[68]. Like RNAcontaining HCV, GBV-C does not integrate into the
genome of an infected cell, but it is located in its
cytoplasm and the positive cells are diffusely arranged.
The indirect evidence for the liver tissue GBV-C
replication is a considerable reduction in the serum
content of viral RNA after liver transplantation (12.4
3.9 107 copies/mL vs 2.8 0.7 107 copies/mL)[69].
Primary replication of HGV in the hepatocytes
has been questioned. Thus, the level of GBV-C RNA
in the serum was higher than that in the liver tissue
(there is an inverse correlation for HCV). In a third
of serum-positive patients, RNA was undetectable in
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No hepatotropicity
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9.0
98
53
25
28
35
3.1
3.0
16
3.6
5.7
Histological changes
Fibrosis of the portal tract without lymphoid-cell
infiltration[96], steatosis and insignificant inflammatory
infiltration of the portal tract[67,97,98] were detectable in
isolated persistent GBV-C infection. The histological
activity index in patients infected with GBV-C alone was
observed to be much lower than that in patients with
HCV+GBV-C or HCV[37,99,100]. In GBV-C monoinfected
patients, moderate or mild focal portal hepatitis was
prevalent with slight periportal infiltration and lobular
components being found in single cases. The bile tract
displayed epithelial fragmentary swelling and flattening
and no nuclei in some epitheliocytes. Some bile ducts
demonstrated partially desquamated epithelium in the
case of higher activities[99,101].
Intraoperative biopsies from GBV-C positive patients
with cholelithiasis who were monoinfected with GBV-C,
indicated that they had mild chronic hepatitis and, in
some cases, viral RNA in the liver tissue and gallbladder
mucosa. It is suggested that GBV-C may play a role in
the production of lithogenic bile and in the development
of cholelithiasis[102].
Coinfection of HGV with hepatitis B, C, and
D viruses is significantly more frequently detected
than monoinfection [103]. In patients with acute viral
hepatitis A (HAV), -B (HBV), -C (HCV), the detection
rate of GBV-C RNA was 2.9%-25%, 19%-32%,
and 20%-48.3%, respectively[88,89]. GBV-C RNA was
detectable in 8%-16% of patients with chronic hepatitis
(CH) B[30,77,100], 5.6%-21% of CH C[30,77,100], and 58% of
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S- Editor Zhong XY
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