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Hepatitis G virus

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doi:10.3748/wjg.14.4725
Hepatitis G virus
Vasiliy Ivanovich Reshetnyak, Tatiana Igorevna Karlovich, Ljudmila Urievna Ilchenko
Vasiliy Ivanovich Reshetnyak, Scientific Research Institute of
General Reanimatology, Russia Academy of Medical Sciences,
Moscow 107031, Russia
Tatiana Igorevna Karlovich, Ljudmila Urievna Ilchenko,
M.P. Chumakov Institute of Poliomyelitis and Viral
Encephalitides, Russia Academy of Medical Sciences, Moscow
142782, Russia
Author contributions: Reshetnyak VI, Karlovich TI, Ilchenko
LU contributed equally to this work.
Correspondence to: Vasiliy Ivanovich Reshetnyak, Scientific
Research Institute of General Reanimatology, Petrovka str.
25-2, Moscow 107031, Russia. v_reshetnyak@yahoo.com
Telephone: +7-495-6946505 Fax: +7-495-6946505
Received: February 20, 2008 Revised: May 10, 2008
Accepted: May 17, 2008
Published online: August 14, 2008
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.
Key words: Hepatitis G virus; Markers of GBV-C;
Epidemiology; Clinical manifestations
Peer reviewers: Mario U Mondelli, Professor, Department
Infectious Diseases, Fondazione IRCCS Policlinico San Matteo
and University of Pavia, Laboratori Area Infettivologica,
Dipartimento di Malattie Infettive, Fondazione IRCCS
Policlinico San Matteo, via Taramelli 5, Pavia 27100, Italy;
Vasiliy I Reshetnyak, MD, PhD, Professor, Scientist Secretary
of the Scientific Research Institute of General Reanimatology,
25-2, Petrovka str. 107031, Moscow, Russia
Reshetnyak VI, Karlovich TI, Ilchenko LU. Hepatitis G virus.
World J Gastroenterol 2008 August 14; 14(30): 4725-4734
World Journal of Gastroenterology ISSN 1007-9327
© 2008 The WJG Press. All rights reserved.
EDITORIAL
World J Gastroenterol 2008; 14(30): 4725-4734 Available
from: URL: http://www.wjgnet.com/1007-9327/14/4725.asp
DOI: http://dx.doi.org/10.3748/wjg.14.4725
History of the discovery of
hepatitis G virus
GBV-C, or hepatitis G virus (HGV), was discovered by
two independent groups of investigators in the study of
cases of hepatitis non-A, non-B, non-E[1,2]. The discovery
of a new viral agent associated with liver diseases has
attracted considerable attention due to the fact that there
are hepatitides of unknown etiology. This determined
the urgency of investigations aimed at comprehensively
studying the properties of the virus, its association with
liver disease and infection rates in different countries of
the world.
In 1966, the 34-year-old surgeon G. Barker (GB) fell
ill with acute hepatitis of moderate enzymatic activity and
three-week icteric period. Patient blood taken on icteric
day 3 was used for intravenous inoculation of nonhuman
primates (bare-faced marmosets, the Callithricidae
family). Hepatitis was recorded in all animals when four
monkey-to-monkey passages were performed. The
findings suggested that the cause of this hepatitis was a
yet unidentified viral agent that was named GBV.
Investigations of the GB agent recommenced
25 years later when new methods for qualitative viral
analysis and recognition evolved. Serum taken in the
acute stage of hepatitis from infected marmosets
was found to contain two viral genomes: GBV-A and
GBV-B belonging to closely-related viruses of the
Flaviviridae family. Both viruses were able to replicate
in the marmosets, but only GBV-B caused hepatitis.
Attempts to detect GBV-A or GBV-B in human beings
failed. A third virus GBV-C was soon isolated from
patient material by means of specially designed primers
to the conserved part of the NS3 region of the viruses
GBV-A, GBV-B and HCV. GBV-C was assigned to the
GBV group as it was slightly similar to GBV-B protein
in immunoassays and largely identical to GBV-A in
nucleotide sequence. GBV-C proved to be genetically
related to another independent isolate that had been
originally called HGV. They are virtually indistinguishable
in the routine diagnosis by polymerase chain reaction
(PCR). Since the signs of GBV-C/HGV became more
commonly detected in patients with hepatitis and persons
at risk for parenteral hepatitis, hepatitis G was considered
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 4726 ISSN 1007-9327 CN 14-1219/R
GBV-B
3
1a
HCV
1b
2a 2b
Figure 1 Affinity of HCV, GBV-C, GBV-A, and GBV-B (From Robertson BH,
2001)[5].
to be an independent hepatotropic entity.
Experiments infecting chimpanzees with the GBV-C
RNA-containing plasma taken from patients with chronic
hepatitis G (CHG) yielded rather unexpected results. All
the infected animals developed persistent and continuing
(as long as 20 mo) viremia. However, no case showed
a rise in the levels of indicator enzymes or detectable
abnormal liver tissue changes in liver biopsy specimens
taken weekly throughout the follow-up. Javan macaques
were also observed to have viremia without signs of liver
damage. By contrast, signs of hepatitis in the form of
hyperenzymaemia and necrotic and inflammatory changes
in the liver appeared by day 30 after inoculation of the
marmosets that had received the same GBV-C-containing
materials[3].
Further serological screening-based investigations
have indicated that the GBV-C isolate is of widespread
occurrence; however, there is no evidence for an
association of viremia with the development of some
known diseases, such as hepatitis[4].
Taxonomy and genotypic variety
of GBV-C
GBV-C virus, like GBV-A, GBV-B, and HCV, belongs to
the Flaviviridae family. Comparison of the genomes of
GBV-C, GBV-A, GBV-B, and HGV has demonstrated
that their RNA does not bear a more than 32% similarity,
thereby supporting the hypothesis that these viruses are
independent (Figure 1)[5].
Five HGV genomes (the divergence between them
was 12%) have been described[6,7]. Investigations dealing
with the classification of GBV-C were conducted by
measuring restriction fragment length polymorphisms.
The isolates from West Africa are referred to as
genotype 1 wherein 2 subtypes: 1a and 1b are identified.
Genotypes 2a and 2b are more frequently detected in
North America and Europe; genotypes 3, 4 and 5 are
more common in Asia, South-Eastern Asia, and South
Africa, respectively. Phylogenetic analysis of genomic
nucleotide sequences of the 5' and NS5 regions made
by Novikov in 2000[8] has established that the GBV-C
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World J Gastroenterol August 14, 2008 Volume 14 Number 30
9392 nucleotides (ORF-2873 aa)
Genes 315
458
5' ? E1 E2 NS2 NS3    NS4 NS5a NS5b 3'
ab ab
Proteins (x
HGV 103 daltons) 20 70 28 55 57
GBV-C
Function Coat proteins Protease Protease/ NS3 RNA-dependent
UTR Helicase Cofactor? RNA polymerase UTR
Figure 2 Schematic representation of GBV-C RNA structure, coded proteins,
GBV-A
and their functions (from Kim JP, Frey KE)[14].
isolate belonging to viral genotype 2 circulates in Russia,
Kazakhstan, Kyrgyzstan, and Turkmenistan. Analysis
of GBV-C 5'-untranslated region sequences revealed a
new sixth genotype of virus in Indonesia[9]. In addition
to genomic variability in different GBV-C isolates, some
authors propose GBV-C genomic variability within
one isolate, i.e. they suggest that there are quasispecies,
thereby emphasizing their similarity with HCV[10]. But,
the opponents of this theory argue that based on the
absence of a hypervariable region in the E2 gene, the
presence of quasispecies is impossible[11,12].
GBV-C structure
The genome of the virus is represented by single-
chain 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 virus-
specific 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.
 Reshetnyak VI et al . Hepatitis G virus
Table 1 Detection rate of GBV-C RNA in blood donors
Authors, year, country GBV-C RNA (%)
Jarvis et al, 1996, United Kingdom[33] 3.2
Alter et al, 1997, USA[34] 1.7
Mikhailov, 1997, Russia[11] 3.3
de Lamballerie et al, 1997, Belgium[35] 1.1
Lefrere et al, 1997, France[36] 4.2
Guilera et al, 1998, Spain[37] 3.0
Masuko et al, 1996, Japan[38] 0.9
Novikov, 2000, Russia[8] 3.2
Kalkan et al, 2005, Turkey[39] 4.1
Mastouri et al, 2005, Tunis[40] 5.3
Grabarczyk et al, 2006, Poland[41] 3.2
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 anti-
E2-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
  4727
Table 2 Detection rate of anti-E2 in blood donors
Authors, year, country Anti-E2 (%)
Jarvis et al, 1996, United Kingdom[33] 3.0
Masuko et al, 1996, Japan[38] 4.9
Bouchardeau et al, 2000, France[45] 42.1
Novikov, 2000, Russia[8] 13.7
Mastouri et al, 2005, Tunis[40] 4.9
Grabarczyk et al, 2006, Poland[41] 23.6
typified by this an inverse correlation between anti-E2
and viremia. The presence of serum viral RNA is also
indicative of continuing infection so is that of E2
protein antibodies for clearance of viral particles from
the patient’s body. It has been shown that the production
of GBV-C antibodies and the cessation of viremia in
most (60%-75%) immunocompetent patients occur
spontaneously and they are followed by the generation
of antibodies to the envelope protein E2 [29,30]. Two
markers (RNA and anti-E2) of GBV-C have been
concurrently detected in single studies (in 5% of cases)[8].
The highest detection rates of GBV-C antibodies are
observed in individuals aged above 50 years[31,32].
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 13 610 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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 4728 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol August 14, 2008 Volume 14 Number 30

Table 3 Detection rate of HGV RNA in high infection-risk groups

Authors, year, country Risk group GBV-C RNA (%)

Mazuko et al, 1996, Indonesia[38] Patients on hemodialysis 55
Alter et al, 1997, USA[34] Patients on hemodialysis 20
Miklhailov, 1997, Russia[11] Drug abusers 35
Karayiannis et al, 1997, United Kingdom[46] Patients with hemophilia 14
Recipients of immunoglobulins 5.4
Drug abusers 13.5
Martin et al, 1999, USA[47] Patients on hemodialysis 17.1
Rubio et al, 1997, Germany[48] Patients on hemodialysis 5
Renal or hepatic posttransplantation patients 14-20
Patients on hemodialysis 5
Lefrere et al, 1997, France[36] Patients on hemodialysis 57.5
Miyakawa et al, 1997, Japan[49] Patients on hemodialysis 3.1
Patients on intravenous drug injection 16
Novikov, 2000, Russia[8] Patients with hemophilia 28
Kumar et al, 2005, India[50] Patients on hemodialysis 6
Kachko et al, 2005, Russia[51] Drug abusers 25
Grabarczyk et al, 2006, Poland[41] Patients on hemodialysis 23.7

The use of infected blood and its products promotes
the prevalence of HGV. In the USA, 18%-20% of all
blood preparations are infected with GBV-C, of them
plasma being in 33%-84%[33]. In the United Kingdom,
94%-100% of coagulation factor Ⅷ-Ⅸ preparations
are infected with this virus[34]. Despite the fact that this
persistent infection is present in a considerable number
of healthy blood donors and in more than 35% of
the human immunodeficiency virus (HIV)-infected,
the world food and drug administration considers it
unnecessary to recommend donor blood to be tested for
serum GBV-C RNA.
There may be a sexual transmission in hepatitis G,
as in hepatitis B and C. This is evidenced by the high
detection rate of GBV-C RNA in homosexuals and
prostitutes: 13.4%-63.0% [48,52] and 13.9%-24.8% [48,53],
respectively. Yeo et al [54] studied sexual transmission
risk in 161 hemophilic patients. 21% of the females in
sexual contact with them were found to be GBV-C RNA
seropositive. The more frequent detection of markers
of GBV-C in persons at increased risk for sexually
transmitted diseases is also indirect evidence for its
sexual transmission. Wachtler et al[31] revealed HGV RNA
in 27% and anti-E2 in 35% of the HIV-infected, while
in the control group these were 2% and 6%, respectively.
The vertical transmission of GBV-C from infected
mother to infant may now be considered proven[36,55-57].
There may be intranatal infection of a baby at delivery
by the maternal passage, as confirmed by the data on a
significant reduction in the infection rates of neonates
after cesarean section of their mothers[55]. There is also
postnatal GBV-C infection. On examining 288 mothers,
Lefrere et al revealed that 89% of the GBV-C-positive
babies were infected at 3 mo after birth[36].
The level of viremia is a factor that is of importance
in the transmission of the virus. By following up 24 babies
born to mothers with a GBV-C RNA level of more than
106 copies/mL, Ohto et al revealed GBV-C in 23 (96%)
of them. The viremia index in the mothers whose babies
proved to be infected was significantly higher than that in
those whose babies were seronegative (P < 0.001). Most
babies had no clinical or biochemical signs of liver disease
despite one-year HGV persistence[58]. In the opinion of
Wejstal et al, the vertical transmission of GBV-C amounts
to 75%-80% of cases and that of HCV is 2.8%-4.2%
(P < 0.001)[56]. The frequent maternal-infant transmission
of GBV-C may account for the high prevalence of the
virus among the adult population at low risk of parenteral
and sexual transmissions. The detection of GBV-C
increases with age. HGV was detectable in 9% and 28.6%
of the children under 15 years and above 16 years of age,
respectively[59].
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 RNA-
containing 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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 Reshetnyak VI et al . Hepatitis G virus
Table 4 Data on the hepatotropicity of GBV-C
Hepatotropicity
Detection of GBV-C RNA in the sera of patients with
acute hepatitis non-A-non-E[61-66]
Histological pattern of hepatitis in
GBV-C infection[27,28,66,67]
Detection of GBV-C RNA and NS5 Ag in the liver tissue[68]
A significant reduction in the serum level of GBV-C
RNA after liver transplantation[69]
the hepatocytes despite the fact that tissue had been
repeatedly taken from different lobes of the liver[73]. A
study of liver biopsy specimens from 12 GBV-C-positive
patients revealed no RNA “minus” strand responsible
for replication and a RNA “plus” strand only in half
the patients with low titers, which may be indicative of
GBV-C contamination from blood. Laskus et al reported
similar results investigating liver tissue and sera from 10
patients co-infected with HCV and GBV-C[74].
After establishing that the hepatotropicity of GBV-C
was low, the next stage of elucidating the pathogenicity
of the virus was to study its tropism to other tissues.
Handa et al determined the presence of a RNA-“minus”
strand in the vascular endotheliocytes[25]. In the authors’
opinion, isolation of GBV-C RNA from a liver biopsy
specimen may reflect viral replication in the endothelium
of the vessels located in the liver[25]. Tucker et al reported
the detection of RNA “plus” strands in all 23 study
organs taken for analysis from GBV-C-infected patients
who had suddenly died[7]. However, both RNA strands
were found only in the spleen and bone marrow.
The comparison of nucleotide sequences in the E2-
region and the lack of occurrence of mutant viral forms
during antiviral therapy with interferons suggested
that the mechanisms that are responsible for persistent
infection are different from those for HCV. Thus, during
2-year follow-up, the average amino acid sequence
replacement in the E2-region was 100 times lower in
GBV-C than in HCV[75]. Investigations indicated that
viremia in GBV-C-infected patients was low and equal to
103-104 copies/mL[76]. It has been suggested that the viral
particles that are present in the blood use low-density
lipoprotein receptors for penetration into the target cell
and generate lipid complexes similar to those seen for
HCV particles. An experiment was made on cultured
peripheral blood mononuclear cells (PBMC)[60,77].
GBV-C may replicate in PBMC and interferon-
resistant Daudi cells[60]. Experiments were carried out
to inoculate human PBMC lines and hepatocytes with
GBV-C RNA in vitro. The same lines were infected with
HCV as a control. These experiments demonstrated that
GBV-C replicates only in CD4+ cells[60,78]. Studies of
cells from different organs of GBV-C-infected patients
were conducted in parallel. They also detected traces of
RNA “minus” strand virus. Thus, the in vitro and in vivo
studies provide evidence that PBMC are the primary site
of GBV-C replication.
The contribution of not only the immune system,
  4729
No hepatotropicity
The equal detection rate of GBV-C RNA in donors with
normal and increased alanine aminotransferase activities
(1.7 and 1.5%, respectively)[70]
Normal aminotransferase activity values in the presence
of GBV-C RNA[11,71]
No correlation between the level of GBV-C RNA and
the activity of alanine aminotransferase[72]
The level of GBV-C RNA in the liver tissue is lower than
that in the serum[73,74]
but also genetic predisposition to prolonged viral
circulation is sug gested. HLA typing in GBV-C-
infected patients with hemophilia showed that 22% of
the RNA-positive patients and 72% of the anti-E2-
positive patients had HLA DQ7, HLA DR15 and HLA
DR8. There is also evidence for low content of CD4+
and the high level of CD8+ lymphocytes in anti-E2-
positive patients, which makes it possible to predict
GBV-C clearance[79].
HGV replication in peripheral blood monocytes
and lymphocytes, and the spleen and bone marrow,
combined with long viral persistence suggest that
GBV-C replicates predominantly in the hematopoietic
system. On examining 44 patients with non-Hodgkin’s
lymphoma, African et al revealed markers of HCV
infection in 5% of cases[80]. None of them was found to
have HGV RNA. However, meta-analysis of 178 cases
of non-Hodgkin’s lymphoma and 355 healthy volunteers
indicated GBV-C RNA in 8.4% (15/176) and 0.8%
(3/355) of the examinees, respectively, which points
to the high risk of HGV in patients with lymphoma[81].
There is evidence for the frequent detection of GBV-C
RNA in patients with leukemia as compared to those
with myeloproliferative diseases[82]. Crespo et al reported
the development of aplastic anemia in a 24-year-old male
patient with acute hepatitis G[83]. Frequent transfusions
in these patients may be one of the causes of HGV
infection.
There are higher detection rates of GBV-C RNA
(11%) and anti-E2 (17%) in autoimmune hepatitis than
in the control group (2%)[84]. Heringlake et al revealed
serum GBV-C RNA in 6.7%, 10.0% and 12.5% of the
patients with types Ⅰ, Ⅱ and Ⅲ autoimmune hepatitis,
respectively[85]. GBV-C is typified by a long-term (as long
as 16 years) persistence in human blood[86].
Clinical manifestations of GBV-C
The clinical picture of GBV-C infection is commonly
similar to that of the subclinical and anicteric types
of hepatitis with normal or low aminotransferase
a c t iv i t i e s [ 87] . G B V- C - a s s o c i a t e d h e p a t i t i s r un s
with nor mal biochemical parameters in 75% of
patients[80]. There are reports on the occurrence of acute
(Table 5) [62-65,88,89], fulminant [61,90,91] and chronic (mild
and moderate)[32,76,92,93] hepatitis and hepatic fibrosis[27,86].
Some author’s note the younger age of the GBV-C-
infected [28,37,93]. The incubation period of acute viral
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 4730 ISSN 1007-9327 CN 14-1219/R
Table 5 Detection rate of GBV-C RNA in acute nonA-nonE
hepatitis
Authors, year, country Number of patients GBV-C RNA (%)
Alter et al, 1997,
45
United Kingdom[62]
Romano et al, 2000, Italy[63] 98
Chu et al, 1999, Taiwan, China[64] 53
Parana et al, 1999, Brazilia[65] 25
Yashina et al, 1997, USA[88] 28
Uchaikin et al, 2000, Russia[89] 35
hepatitis G averages 14-20 d. The outcome of acute
hepatitis may be: (1) recovery with the disappearance
of serum GBV-C RNA and the emergence of anti-E2;
(2) development of chronic hepatitis (CH) with serum
GBV-C RNA being persistently detectable; (3) presence
of GBV-C RNA without biochemical or histological
signs of liver disease.
The alanine aminotransferase (ALT) activity in
GBV-C unlike HCV, does not correspond to the degree
of viremia and the severity of hepatic histological
changes. By examining 1075 patients with isolated
hypertransaminasemia for 6 mo, Berasain et al revealed
GBV-C RNA in 74 (6.9%) patients[94]. Only one (0.09%)
patient was monoinfected. There is also evidence for two-
fold increases in the activity of alkaline phosphatase (AP)
and γ-glutamyl transpeptidase (γ-GTP) in GBV-C
positive patients[95].
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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World J Gastroenterol August 14, 2008 Volume 14 Number 30
CH B+D[98]. No differences were found in the clinical
manifestations (including those in the chronic pattern
and outcome) of the disease, biochemical parameters, or
the severity of hepatic histological changes in patients
9.0 with HBV and/or HCV as compared in those with
HBV+GBV-C and/or HCV+GBV-C [104-106]. Patients
3.1
3.0
with CHC alone and in combination with HGV have
16 been meticulously examined. By examining 420 patients,
3.6 Tanaka et al revealed a higher ALT activity in the group
5.7 of patients coinfected with HCV and GBV-C than in
those infected with HCV[107].
By comparing histological changes in the liver
tissue of patients with HCV and HCV + GBV-C,
Moriyama et al detected more significant bile duct
damages, perivenular and pericellular fibrosis in the latter
group[108]. These data were supported by the examination
of 312 patients with CH[99]. Of them 28 (9%) patients
were found to have RNA for HCV and GBV-C.
Complaints and clinical symptoms did not differ in the
groups of patients with HCV and HCV+GBV-C. There
was no evidence for the impact of HGV on the clinical
manifestations and the course of concomitant HCV
infection. However, analysis of liver tissue morphological
changes in patients coinfected with HCV and GBV-C
revealed slightly more frequent epithelial damage in the
bile duct (89%) than in those infected with HCV (67%),
which manifested itself as lysis of the epitheliocytic
nuclei, as well as flattening, destruction, and swelling of
the epithelium and its lymphocytic infiltration.
Whether GBV-C influences the course of CHC and
whether therapy with interferon is effective are currently
being discussed. Most studies demonstrate no differences
in the clinical course of the disease, biochemical
parameters, or the magnitude of hepatic histological
changes in both HCV alone and in combination with
GBV-C[109-111]. A study for the therapy of HGV is based
on the evaluation of interferon treatment in patients
coinfected with HCV+GBV-C. HGV was ascertained
to be sensitive to interferon. Administration of
α-interferon (α-IFN) to patients at a dose of 3 000 000
IU thrice weekly for 6 mo resulted in ALT activity
normalization and serum GBV-C RNA clearance in
18%-40% of the patients treated with α-IFN[112,113]. Six
months after termination of a course of therapy, there
were persistent biochemical and virological responses
in 55%-57% of patients[114]. The therapeutic efficiency
was observed to depend on baseline GBV-C RNA
levels. The patients who had a low RNA titer (mean,
3.3 × 105 copies/mL) more frequently responded to
the therapy than those who had a higher one (mean,
3.5 × 108 copies/mL)[104,109]. There is now a prevailing
opinion that GBV-C has no impact on the efficiency
of α-interferon treatment for chronic hepatitis C[114,115].
At the same time some investigations suggest that
the therapy causes more frequent adverse reactions
in patients with HCV+GGV-C and that after its
ter mination, this group of patients has a higher
histological activity index[116,117].
The implications of HGV for the development of
chronic liver diseases has not been appraised to date.
 Reshetnyak VI et al . Hepatitis G virus
As for GBV-C infection, investigators could not trace
the clinical stages characteristic of HBV and HCV:
acute hepatitis-chronic hepatitis-liver cirrhosis (LC)-
hepatocellular carcinoma (HCC). A long-term (less than
16 years) follow-up of patients permitted discussion only
of the likelihood of development of chronic hepatitis.
GBV-C RNA was detectable in 8%-25.4% of patients
with chronic hepatitis non-A-non-E [118], 6%-15% of
patients with cryptogenic liver cirrhosis [119,120], and
3.1%-8.3% with HCC[121,122].
The similarity of the properties of GBV-C and
HCV offers a possibility of using HGV and its induced
experimental infection as a model to study hepatitis C.
Unlike hepatitis C, hepatitis G infection may be modeled
in nonhuman primates, which considerably reduces
the cost these studies that are in great demand for the
designing of hepatitis C vaccine.
Unexpected results were obtained while studying the
impact of GBV-C on the course of HIV infection[123,124].
Co-infection with GBV-C in the HIV-infected was
established to cause a reduction in mortality rates and
better clinical parameters of infection. Furthermore,
the efficiency of high-activity antiretroviral therapy
significantly increased. The positive effect of GBV-C
is accounted for by the fact that the envelope proteins
of this virus bind CD8l+ on T cells and induce dose-
dependent secretion of RANTES (regulated on
activation, normal T-cell expressed and secreted),
the natural ligand that binds CCR5 on the target cell,
thereby blocking the penetration of HIV[21,125]. In vitro
studies showed an increase in the expression of the
chemokines-RANTES, macrophage inflammatory
proteins (MIP-1α, MIP-1β), and stromal-cell derived
factor (SDF-1) in the blood of patients. There was also
a reduction in the expression of CCR5 onto the surface
of GBV-C-infected cells. All these factors may provide
indirect evidence for the diminished sensitivity of GBV-
C-infected cells to HIV[125-127].
A review of available data in the literature and the
authors’ own data suggest that the new HGV discovered
in the late 1990s has been rather well studied. The
structure of the virus is almost completely known;
its genotypes have been ascertained; its prevalence
(epidemiology) shown and the clinical picture of the
disease, routes of viral transmission, and the types
of coinfection described. The predominant site of
replication of the virus in the blood mononuclear cells,
spleen, and bone marrow has been indicated. The lack
of hepatotropicity of virus G (which is rarely detected
in the the liver), its frequent detection in the body
and tissues of a patient without any clinical signs of
hepatitis, and clinical improvement in the HIV-infected
patients coinfected with GBV-C cast doubt on the
appropriateness of the concept “viral hepatitis G”. The
interest shown in HGV is likely to be associated with the
similarity of its properties to those of HCV.
REFERENCES
1 Simons JN, Pilot-Matias TJ, Leary TP, Dawson GJ, Desai
SM, Schlauder GG, Muerhoff AS, Erker JC, Buijk SL,
  4731
Chalmers ML. Identification of two flavivirus-like genomes
in the GB hepatitis agent. Proc Natl Acad Sci USA 1995; 92:
3401-3405
2 Linnen J, Wages J Jr, Zhang-Keck ZY, Fry KE, Krawczynski
KZ, Alter H, Koonin E, Gallagher M, Alter M, Hadziyannis
S, Karayiannis P, Fung K, Nakatsuji Y, Shih JW, Young L,
Piatak M Jr, Hoover C, Fernandez J, Chen S, Zou JC, Morris T,
Hyams KC, Ismay S, Lifson JD, Hess G, Foung SK, Thomas
H, Bradley D, Margolis H, Kim JP. Molecular cloning and
disease association of hepatitis G virus: a transfusion-
transmissible agent. Science 1996; 271: 505-508
3 Balayan MS, Poleshchuk VF. Viral hepatitis in primates:
experimental reproduction and natural infection. Virusnye
hepatity (Viral hepatitides) 1998; 3: 3-12
4 Maidana MT, Sabino EC, Kallas EG. GBV-C/HGV and
HIV-1 coinfection. Braz J Infect Dis 2005; 9: 122-125
5 Robertson BH. Viral hepatitis and primates: historical
and molecular analysis of human and nonhuman primate
hepatitis A, B, and the GB-related viruses. J Viral Hepat 2001;
8: 233-242
6 Okamoto H, Nakao H, Inoue T, Fukuda M, Kishimoto J,
Iizuka H, Tsuda F, Miyakawa Y, Mayumi M. The entire
nucleotide sequences of two GB virus C/hepatitis G virus
isolates of distinct genotypes from Japan. J Gen Virol 1997;
78 (Pt 4): 737-745
7 Tucker TJ, Smuts HE. GBV-C/HGV genotypes: proposed
nomenclature for genotypes 1-5. J Med Virol 2000; 62: 82-83
8 Novikov DV. Molecular biological characteristics of HCV.
Abstract of dissertation for Candidate of Medical Sciences.
2000: 1-22
9 Muerhoff AS, Dawson GJ, Desai SM. A previously
unrecognized sixth genotype of GB virus C revealed by
analysis of 5'-untranslated region sequences. J Med Virol
2006; 78: 105-111
10 Viazov S, Riffelmann M, Khoudyakov Y, Fields H,
Varenholz C, Roggendorf M. Genetic heterogeneity of
hepatitis G virus isolates from different parts of the world. J
Gen Virol 1997; 78 (Pt 3): 577-581
11 Mikhailov MI. Hepatitis G: problems of studies. Virus hepat
1997; 1: 3-11
12 Stapleton JT, Williams CF, Xiang J. GB virus type C: a
beneficial infection? J Clin Microbiol 2004; 42: 3915-3919
13 Nakao H, Okamoto H, Fukuda M, Tsuda F, Mitsui T,
Masuko K, Iizuka H, Miyakawa Y, Mayumi M. Mutation
rate of GB virus C/hepatitis G virus over the entire genome
and in subgenomic regions. Virology 1997; 233: 43-50
14 Kim JP, Fry KE. Molecular characterization of the hepatitis
G virus. J Viral Hepat 1997; 4: 77-79
15 Bassit L, Kleter B, Ribeiro-dos-Santos G, Maertens G, Sabino
E, Chamone D, Quint W, Saez-Alquezar A. Hepatitis G
virus: prevalence and sequence analysis in blood donors of
Sao Paulo, Brazil. Vox Sang 1998; 74: 83-87
16 Schaluder GG, Dawson GJ, Simons JN, Pilot-Matias TJ,
Gutierrez RA, Heynen CA, Knigge MF, Kurpiewski GS,
Buijk SL, Leary TP. Molecular and serologic analysis in the
transmission of the GB hepatitis agents. J Med Virol 1995; 46:
81-90
17 Leary TP, Muerhoff AS, Simons JN, Pilot-Matias TJ, Erker
JC, Chalmers ML, Schlauder GG, Dawson GJ, Desai SM,
Mushahwar IK. Sequence and genomic organization of
GBV-C: a novel member of the flaviviridae associated with
human non-A-E hepatitis. J Med Virol 1996; 48: 60-67
18 Marmor M, Hertzmark K, Thomas SM, Halkitis PN, Vogler
M. Resistance to HIV infection. J Urban Health 2006; 83: 5-17
19 Pessoa MG, Terrault NA, Detmer J, Kolberg J, Collins M,
Hassoba HM, Wright TL. Quantitation of hepatitis G and
C viruses in the liver: evidence that hepatitis G virus is not
hepatotropic. Hepatology 1998; 27: 877-880
20 Kudo T, Morishima T, Shibata M. Hepatitis G infection. N
Engl J Med 1997; 337: 276-277
21 Souza IE, Allen JB, Xiang J, Klinzman D, Diaz R, Zhang S,
Chaloner K, Zdunek D, Hess G, Williams CF, Benning L,
Stapleton JT. Effect of primer selection on estimates of GB
www.wjgnet.com
 4732 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol
virus C (GBV-C) prevalence and response to antiretroviral
therapy for optimal testing for GBV-C viremia. J Clin
Microbiol 2006; 44: 3105-3113
22 Laras A, Zacharakis G, Hadziyannis SJ. Absence of the
negative strand of GBV-C/HGV RNA from the liver. J
Hepatol 1999; 30: 383-388
23 Kao JH, Chen W, Chen PJ, Lai MY, Chen DS. Liver and
peripheral blood mononuclear cells are not major sites for
GB virus-C/hepatitis G virus replication. Arch Virol 1999;
144: 2173-2183
24 Zampino R, Pickering J, Iqbal M, Gaud U, Thomas HC,
Karayiannis P. Hepatitis G virus/GBV-C persistence:
absence of hypervariable E2 region and genetic analysis of
viral quasispecies in serum and lymphocytes. J Viral Hepat
1999; 6: 209-218
25 Handa A, Brown KE. GB virus C/hepatitis G virus
replicates in human haematopoietic cells and vascular
endothelial cells. J Gen Virol 2000; 81: 2461-2469
26 Hwang SJ, Lu RH, Chan CY, Chang FY, Lee SD. Detection
of antibodies to E2-protein of GB virus-C/hepatitis G virus
in patients with acute posttransfusion hepatitis. J Med Virol
1999; 57: 85-89
27 Ilchenko LYu, Sharafanova TI, Shepeleva SD, Serova TI.
Antibodies to hepatitis G virus in patients with chronic liver
diseases. Hepatology 2003; 5: 4-6
28 Loginov AS, Sharafanova TI, Reshetniak VI, Il'chenko LIu,
Shepeleva SD, Serova TI, Tkachev VD. [HGV and TTV -
new hepatitis viruses] Ter Arkh 2000; 72: 9-13
29 Thomas DL, Vlahov D, Alter HJ, Hunt JC, Marshall R,
Astemborski J, Nelson KE. Association of antibody to
GB virus C (hepatitis G virus) with viral clearance and
protection from reinfection. J Infect Dis 1998; 177: 539-542
30 Yang JF, Dai CY, Chuang WL, Lin WY, Lin ZY, Chen
SC, Hsieh MY, Wang LY, Tsai JF, Chang WY, Yu ML.
Prevalence and clinical significance of HGV/GBV-C
infection in patients with chronic hepatitis B or C. Jpn J Infect
Dis 2006; 59: 25-30
31 Wachtler M, Hofmann A, Muller G, Frosner G, Nitschko
H, Karwat M, Knetsch I, Emminger C, Eichenlaub D.
Prevalence of GB virus C/hepatitis G virus RNA and
anti-E2 glycoprotein antibodies in homosexual men with
HIV coinfection. Infection 2000; 28: 297-300
32 Rey D, Vidinic-Moularde J, Meyer P, Schmitt C, Fritsch S,
Lang JM, Stoll-Keller F. High prevalence of GB virus C/
hepatitis G virus RNA and antibodies in patients infected
with human immunodeficiency virus type 1. Eur J Clin
Microbiol Infect Dis 2000; 19: 721-724
33 Jarvis LM, Davidson F, Hanley JP, Yap PL, Ludlam CA,
Simmonds P. Infection with hepatitis G virus among
recipients of plasma products. Lancet 1996; 348: 1352-1355
34 Alter HJ, Nakatsuji Y, Melpolder J, Wages J, Wesley R,
Shih JW, Kim JP. The incidence of transfusion-associated
hepatitis G virus infection and its relation to liver disease. N
Engl J Med 1997; 336: 747-754
35 de Lamballerie X, Charrel RN, Dussol B. Hepatitis GB virus
C in patients on hemodialysis. N Engl J Med 1996; 334: 1549
36 Lefrere JJ, Sender A, Mercier B, Mariotti M, Pernot F, Soulie
JC, Malvoisin A, Berry M, Gabai A, Lattes F, Galiay JC,
Pawlak C, de Lachaux V, Chauveau V, Hreiche G, Larsen
M, Ferec C, Parnet-Mathieu F, Roudot-Thoraval F, Brossard
Y. High rate of GB virus type C/HGV transmission from
mother to infant: possible implications for the prevalence of
infection in blood donors. Transfusion 2000; 40: 602-607
37 Guilera M, Sáiz JC, López-Labrador FX, Olmedo E,
Ampurdanés S, Forns X, Bruix J, Parés A, Sánchez-Tapias
JM, Jimenez de Anta, Rodes J. Hepatitis G virus infection in
chronic liver disease. Gut 1998; 42: 107-111
38 Masuko K, Mitsui T, Iwano K, Yamazaki C, Okuda K,
Meguro T, Murayama N, Inoue T, Tsuda F, Okamoto H,
Miyakawa Y, Mayumi M. Infection with hepatitis GB virus
C in patients on maintenance hemodialysis. N Engl J Med
1996; 334: 1485-1490
39 Kalkan A, Ozdarendeli A, Bulut Y, Saral Y, Ozden M,
www.wjgnet.com
August 14, 2008 Volume 14 Number 30
Kelestimur N, Toraman ZA. Prevalence and genotypic
distribution of hepatitis GB-C/HG and TT viruses in blood
donors, mentally retarded children and four groups of
patients in eastern Anatolia, Turkey. Jpn J Infect Dis 2005; 58:
222-227
40 Mastouri M, Safer IL, Pozzetto B, Bourlet T, Khedher M.
[Prevalence of hepatitis G virus among Tunisian blood
donors] East Mediterr Health J 2005; 11: 1053-1060
41 Grabarczyk P, Brojer E, Windyga J, Lopaciuk S, Klukowska
A, Mikulska M. [GBV-C/HGV and TTV infection markers
in Polish blood donors and haemophilia patients] Przegl
Epidemiol 2006; 60: 581-588
42 Wiwanitkit V. Hepatitis G virus RNA positivity among the
voluntary blood donors: a summary. Ann Hepatol 2005; 4:
43-46
43 Dencs A, Sebestyen A. Prevalence and genotypes of
hepatitis G virus/GB virus C in a multirisk group in
Hungary. Acta Microbiol Immunol Hung 2007; 54: 305-316
44 Barusruk S, Urwijitaroon Y. High prevalence of HGV
coinfection with HBV or HCV among northeastern Thai
blood donors. Southeast Asian J Trop Med Public Health 2006;
37: 289-293
45 Bouchardeau F, Laperche S, Pillonel J, Elghouzzi MH,
Maisonneuve P, Tirtaine C, Boiret E, Razer A, Girault A,
Beaulieu MJ, Courouce AM. GB virus type C/HGV markers
in HCV RNA-positive French blood donors: correlation
with HCV genotypes and risk factors. Transfusion 2000; 40:
875-878
46 Karayiannis P, Pickering J, Chiaramonte M, Thomas HC.
Hepatitis G virus infection. Lancet 1997; 349: 954
47 Martin P, Fabrizi F, Dixit V, Brezina M, Gerosa S, Russell J,
Conrad A, Gitnick G. Epidemiology and natural history of
hepatitis G virus infection in chronic hemodialysis patients.
Am J Nephrol 1999; 19: 535-540
48 Rubio A, Rey C, Sanchez-Quijano A, Leal M, Pineda JA,
Lissen E, Hess G. Is hepatitis G virus transmitted sexually?
JAMA 1997; 277: 532-533
49 Miyakawa Y, Mayumi M. Hepatitis G virus--a true hepatitis
virus or an accidental tourist? N Engl J Med 1997; 336:
795-796
50 Kumar D, Arora A, Singh NP, Kohli R, Kar P, Das BC.
Hepatitis G virus infection in hemodialysis patients from
urban Delhi. Ren Fail 2005; 27: 87-93
51 Kachko AV, Ershov AE, Gavrilova IV, Shustov AV,
Kochneva GV, Sivolobova GF, Grazhdantseva AA, Bukin
VN, Komissarova MA, Netesov SV. [The occurrence
rate of HGV/GBV-C RNA and risk factors in patients
of narcological dispensary in Novosibirsk] Zh Mikrobiol
Epidemiol Immunobiol 2005; 25-30
52 Stark K, Doering CD, Bienzle U, Pauli G, Hamouda O,
Engel AM, Schreier E. Risk and clearance of GB virus
C/hepatitis G virus infection in homosexual men: A
longitudinal study. J Med Virol 1999; 59: 303-306
53 Sawayama Y, Hayashi J, Etoh Y, Urabe H, Minami K,
Kashiwagi S. Heterosexual transmission of GB virus C/
hepatitis G virus infection to non-intravenous drug-using
female prostitutes in Fukuoka, Japan. Dig Dis Sci 1999; 44:
1937-1943
54 Yeo AE, Matsumoto A, Shih JW, Alter HJ, Goedert JJ.
Prevalence of hepatitis G virus in patients with hemophilia
and their steady female sexual partners. Sex Transm Dis
2000; 27: 178-182
55 Ohto H, Ujiie N, Sato A, Okamoto H, Mayumi M. Mother-
to-infant transmission of GB virus type C/HGV. Transfusion
2000; 40: 725-730
56 Wejstal R, Manson AS, Widell A, Norkrans G. Perinatal
transmission of hepatitis G virus (GB virus type C) and
hepatitis C virus infections--a comparison. Clin Infect Dis
1999; 28: 816-821
57 Palomba E, Bairo A, Tovo PA. High rate of maternal-infant
transmission of hepatitis G virus in HIV-1 and hepatitis C
virus-infected women. Acta Paediatr 1999; 88: 1392-1395
58 Halasz R, Fischler B, Nemeth A, Lundholm S, Sallberg M.
 Reshetnyak VI et al . Hepatitis G virus
A high prevalence of serum GB virus C/hepatitis G virus
RNA in children with and without liver disease. Clin Infect
Dis 1999; 28: 537-540
59 Mphahlele MJ, Aspinall S, Spooner R, Carman WF. Age
related prevalence of hepatitis G virus in South Africans. J
Clin Pathol 1999; 52: 752-757
60 Xiang J, Wunschmann S, Schmidt W, Shao J, Stapleton JT.
Full-length GB virus C (Hepatitis G virus) RNA transcripts
are infectious in primary CD4-positive T cells. J Virol 2000;
74: 9125-9133
61 Sheng L, Soumillion A, Beckers N, Wu CG, Verslype C,
Nevens F, Pirenne J, Aerts R, Kosala H, Fevery J, Yap SH.
Hepatitis G virus infection in acute fulminant hepatitis:
prevalence of HGV infection and sequence analysis of a
specific viral strain. J Viral Hepat 1998; 5: 301-306
62 Alter MJ, Gallagher M, Morris TT, Moyer LA, Meeks EL,
Krawczynski K, Kim JP, Margolis HS. Acute non-A-E
hepatitis in the United States and the role of hepatitis G
virus infection. Sentinel Counties Viral Hepatitis Study
Team. N Engl J Med 1997; 336: 741-746
63 Romano L, Fabris P, Tanzi E, Tositti G, Mazzotta F, Zanetti
AR. GBV-C/hepatitis G virus in acute nonA-E hepatitis and
in acute hepatitis of defined aetiology in Italy. J Med Virol
2000; 61: 59-64
64 Chu CM, Lin SM, Hsieh SY, Yeh CT, Lin DY, Sheen IS, Liaw
YF. Etiology of sporadic acute viral hepatitis in Taiwan: the
role of hepatitis C virus, hepatitis E virus and GB virus-C/
hepatitis G virus in an endemic area of hepatitis A and B. J
Med Virol 1999; 58: 154-159
65 Parana R, Vitvitski L, Andrade Z, Trepo C, Cotrim H,
Bertillon P, Silva F, Silva L, de Oliveira IR, Lyra L. Acute
sporadic non-A, non-B hepatitis in Northeastern Brazil:
etiology and natural history. Hepatology 1999; 30: 289-293
66 Cheng Y, Zhang W, Li J, Li B, Zhao J, Gao R, Xin S, Mao P,
Cao Y. Serological and histological findings in infection and
transmission of GBV-C/HGV to macaques. J Med Virol 2000;
60: 28-33
67 Loginov AS, Lvov DK, Sharafanova TI, Tikhomirov EE,
Ilchenko LY, Reshetnyak VI, Tkachev VD. Detection of
hepatitis G virus (HGV) in chronic liver diseases. Ros
Gastroenterol Zhurn 1999; 1: 23-31
68 Lang Z, Fang D, Luo Z. [Detection of HGV NS5 antigen in
liver tissue of patients with chronic liver disease] Zhonghua
Yixue Zazhi 1998; 78: 598-600
69 Berg T, Muller AR, Platz KP, Hohne M, Bechstein WO, Hopf
U, Wiedenmann B, Neuhaus P, Schreier E. Dynamics of GB
virus C viremia early after orthotopic liver transplantation
indicates extrahepatic tissues as the predominant site of GB
virus C replication. Hepatology 1999; 29: 245-249
70 Stransky J. [The discovery of hepatitis G virus] Cas Lek Cesk
1996; 135: 99-101
71 Kobayashi T, Ishii M, Niitsuma H, Kikuchi K, Suzuki C,
Gama H, Kobayashi K, Ueno Y, Toyota T. Genoepide-
miology and pathogenicity of hepatitis G virus in Japan.
Tohoku J Exp Med 1997; 183: 101-112
72 Sarrazin C, Herrmann G, Roth WK, Lee JH, Marx S, Zeuzem
S. Prevalence and clinical and histological manifestation
of hepatitis G/GBV-C infections in patients with elevated
aminotransferases of unknown etiology. J Hepatol 1997; 27:
276-283
73 Fan X, Xu Y, Solomon H, Ramrakhiani S, Neuschwander-
Tetri BA, Di Bisceglie AM. Is hepatitis G/GB virus-C virus
hepatotropic? Detection of hepatitis G/GB virus-C viral
RNA in liver and serum. J Med Virol 1999; 58: 160-164
74 Radkowski M, Wang LF, Vargas H, Rakela J, Laskus
T. Lack of evidence for GB virus C/hepatitis G virus
replication in peripheral blood mononuclear cells. J Hepatol
1998; 28: 179-183
75 Orii K, Tanaka E, Rokuhara A, Maruyama A, Ichijo T,
Yoshizawa K, Kiyosawa K. Persistent infection mechanism
of GB virus C/hepatitis G virus differs from that of hepatitis
C virus. Intervirology 2000; 43: 139-145
76 Souza IE, Zhang W, Diaz RS, Chaloner K, Klinzman
  4733
D, Stapleton JT. Effect of GB virus C on response to
antiretroviral therapy in HIV-infected Brazilians. HIV Med
2006; 7: 25-31
77 Xiang J, Wunschmann S, Diekema DJ, Klinzman D, Patrick
KD, George SL, Stapleton JT. Effect of coinfection with GB
virus C on survival among patients with HIV infection. N
Engl J Med 2001; 345: 707-714
78 Fogeda M, Navas S, Martín J, Casqueiro M, Rodríguez
E, Arocena C, Carreño V. In vitro infection of human
peripheral blood mononuclear cells by GB virus C/
Hepatitis G virus. J Virol 1999; 73: 4052-4061
79 Toyoda H, Takahashi I, Fukuda Y, Hayakawa T, Takamatsu
J. Comparison of characteristics between patients with GB
virus C/hepatitis G virus (GBV-C/HGV) RNA and those
with GBV-C/HGV E2-antibody in patients with hemophilia.
J Med Virol 2000; 60: 34-38
80 Arican A, Sengezer T, Bozdayi M, Bozkaya H, Ucgul E,
Dincol D, Uzunalimoglu O. Prevalence of hepatitis-G
virus and hepatitis-C virus infection in patients with non-
Hodgkin's lymphoma. Med Oncol 2000; 17: 123-126
81 Wiwanitkit V. Individuals with HGV-RNA are at high risk
of B cell non-Hodgkin's lymphoma development. Asian Pac
J Cancer Prev 2005; 6: 215-216
82 Pavlova BG, Heinz R, Selim U, Tuchler H, Pittermann
E, Eder G. Association of GB virus C (GBV-C)/hepatitis
G virus (HGV) with haematological diseases of different
malignant potential. J Med Virol 1999; 57: 361-366
83 Crespo J, de las Heras B, Rivero M, Lozano JL, Fabrega E,
Pons-Romero F. Hepatitis G virus infection as a possible
causative agent of community-acquired hepatitis and
associated aplastic anaemia. Postgrad Med J 1999; 75:
159-160
84 Tribl B, Schoniger-Hekele M, Petermann D, Bakos S,
Penner E, Muller C. Prevalence of GBV-C/HGV-RNA, virus
genotypes, and anti-E2 antibodies in autoimmune hepatitis.
Am J Gastroenterol 1999; 94: 3336-3340
85 Heringlake S, Tillmann HL, Cordes-Temme P, Trautwein
C, Hunsmann G, Manns MP. GBV-C/HGV is not the major
cause of autoimmune hepatitis. J Hepatol 1996; 25: 980-984
86 Kao JH, Chen PJ, Wang JT, Lai MY, Chen DS. Blood-bank
screening for hepatitis G. Lancet 1997; 349: 207
87 Alter HJ. The cloning and clinical implications of HGV and
HGBV-C. N Engl J Med 1996; 334: 1536-7
88 Yashina TL, Favorov MO, Khudyakov YE, Fields HA,
Znoiko OO, Shkurko TV, Bonafonte T, Sevall JS, Agopian
MS, Peter JB. Detection of hepatitis G virus (HGV) RNA:
clinical characteristics of acute HGV infection. J Infect Dis
1997; 175: 1302-1307
89 Uchaikin VF, Stepanov AN, Chuyelov SB. Prevalence and
clinical manifestations of virus hepatitis G in children. Ros
Zhurn Gastroenterol Gepatol Koloproktol 2000; 4: 74-76
90 Yoshiba M, Okamoto H, Mishiro S. Detection of the
GBV-C hepatitis virus genome in serum from patients with
fulminant hepatitis of unknown aetiology. Lancet 1995; 346:
1131-1132
91 Pessoa MG, Wright TL. Hepatitis G virus: what is the next
step? Liver Transpl Surg 1997; 3: 677-679
92 Di Bisceglie AM. Hepatitis G virus infection: a work in
progress. Ann Intern Med 1996; 125: 772-773
93 Il'chenko LIu, Sharafanova TI, Tsaregorodtseva TM,
Shepeleva SD, Tkachev VD. [Chronic liver diseases
associated with hepatitis G and TT viruses] Eksp Klin
Gastroenterol 2002; 66-71
94 Berasain C, Betes M, Panizo A, Ruiz J, Herrero JI, Civeira
MP, Prieto J. Pathological and virological findings in
patients with persistent hypertransaminasaemia of
unknown aetiology. Gut 2000; 47: 429-435
95 Colombatto P, Randone A, Civitico G, Monti Gorin J, Dolci
L, Medaina N, Oliveri F, Verme G, Marchiaro G, Pagni R,
Karayiannis P, Thomas HC, Hess G, Bonino F, Brunetto
MR. Hepatitis G virus RNA in the serum of patients with
elevated gamma glutamyl transpeptidase and alkaline
phosphatase: a specific liver disease? [corrected] J Viral
www.wjgnet.com
 4734 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol
Hepat 1996; 3: 301-306
96 Sáiz JC, Ampurdanés S, Olmedo E, López-Labrador FX,
Forns X, Guilera M, Tassies D, Costa J, Sánchez-Tapias JM,
Jiménez de Anta MT, Rodés J. Hepatitis G virus infection
in chronic hepatitis C: frequency, features and response to
interferon therapy. J Hepatol 1997; 26: 787-793
97 Fattovich G, Ribero ML, Favarato S, Azzario F, Donato F,
Giustina G, Fasola M, Pantalena M, Portera G, Tagger A.
Influence of GB virus-C/hepatitis G virus infection on the
long-term course of chronic hepatitis B. Liver 1998; 18: 360-365
98 Vargas HE, Laskus T, Radkowski M, Poutous A, Wang LF,
Lee R, Dodson F, Gayowski T, Singh N, Marino IR, Fung
JJ, Zhang-Keck ZY, Kim JP, Rakela J. Hepatitis G virus
coinfection in hepatitis C virus-infected liver transplant
recipients. Transplantation 1997; 64: 786-788
99 Ilchenko LYu, Karlovich TI. Clinical and virological
features of mixed hepatitis. Treatises of the MP. Mikhailov
MI, editor. Materials of Chumakov Institute of Poliomyelitis
and Viral Encephalitis, RAMS, 2007: 297-302
100 Sharafanova TI, Reshethyak VI, Ilchenko LU. Viral С
hepatitis, this is associated with others hepatotropic. Poster
board presentation 79 (abstract 1532) at the 36th Annual
Meeting of the European Association for the Study of the
Liver (EASL); 2001 April 18-22; Prague, Czech Republic. J
Hepatol 2001; 34 suppl 1: A1532
101 Ilchenko LYu, Sharafanova TI, Vinnitskaya YeV, Shepeleva
SD, Makaryeva YeD. Biliary pathology in patients infected
with hepatitis G and TT viruses. Poster board presentation
61 (abstract 174) of the 4th Russian Scientific Forum "Saint
Petersburg-Gastro-2002"; 2002 September 17-20; Saint
Petersburg, Russia. Gastrobulleten 2002; 2 (3): A174
102 Chekmazov IA, Ilchenko LYu, Karlovich TI, Khomeriki SG,
Silvestrova SYu, Morozov IA, Morozov DV. Hepatitis G
(HGV) and TT (TTV) viruses in patients with cholelithiasis
(provisional data). Hepatology 2005; 1: 37-41
103 Kumar D, Gupta RK, Anand R, Pasha ST, Rai A, Das BC,
Kar P. Occurrence &amp; nucleotide sequence analysis of
hepatitis G virus in patients with acute viral hepatitis &amp;
fulminant hepatitis. Indian J Med Res 2007; 125: 752-755
104 Kao JH, Chen PJ, Wang JT, Lai MY, Chen DS. Blood-bank
screening for hepatitis G. Lancet 1997; 349: 207
105 Fabris P, Infantolino D, Biasin MR, Benedetti P, Tositti G,
Bettini C, Marchelle G, de Lalla F. HGV/GBV-C infection
in patients with acute hepatitis of different etiology and in
patients with chronic hepatitis C. J Gastroenterol 1998; 33: 57-61
106 Bychenko DV, Cheshik SG, Malyshev NA. Diagnosis
and clinical evaluation of HGV infection in patients with
parenteral viral hepatitides-HBV, HCV and HBV/HCV. Mir
Virusnikh Gepatitov 2003; 1: 9-13
107 Tanaka E, Tacke M, Kobayashi M, Nakatsuji Y, Kiyosawa K,
Schmolke S, Engel AM, Hess G, Alter HJ. Past and present
hepatitis G virus infections in areas where hepatitis C is
highly endemic and those where it is not endemic. J Clin
Microbiol 1998; 36: 110-114
108 Moriyama M, Matsumura H, Shimizu T, Shioda A, Kaneko
M, Saito H, Miyazawa K, Tanaka N, Sugitani M, Komiyama
K, Arakawa Y. Hepatitis G virus coinfection influences the
liver histology of patients with chronic hepatitis C. Liver
2000; 20: 397-404
109 Enomoto M, Nishiguchi S, Fukuda K, Kuroki T, Tanaka M,
Otani S, Ogami M, Monna T. Characteristics of patients with
hepatitis C virus with and without GB virus C/hepatitis G
virus co-infection and efficacy of interferon alfa. Hepatology
1998; 27: 1388-1393
110 Slimane SB, Albrecht JK, Fang JW, Goodman Z, Mizokami
M, Qian K, Lau JY. Clinical, virological and histological
implications of GB virus-C/hepatitis G virus infection
in patients with chronic hepatitis C virus infection: a
multicentre study based on 671 patients. J Viral Hepat 2000; 7:
51-55
111 Quintero D, Salmerón J, Palacios A, Muñoz de Rueda P,
www.wjgnet.com
View publication stats
August 14, 2008 Volume 14 Number 30
Torres C, Rodríguez L, Caballero T, Ruiz Extremera A.
[Coinfection with hepatitis G virus in chronic hepatitis C.
Response to treatment with interferon alpha] Med Clin (Barc)
2000; 114: 726-729
112 Fujisawa T, Horiike N, Michitaka K, Onji M. Influence of
RNA titre and amino acid changes in the NS5A region of GB
virus c/hepatitis G virus on the effectiveness of interferon
therapy. J Gastroenterol Hepatol 2000; 15: 632-639
113 McHutchison JG, Nainan OV, Alter MJ, Sedghi-Vaziri
A, Detmer J, Collins M, Kolberg J. Hepatitis C and G co-
infection: response to interferon therapy and quantitative
changes in serum HGV-RNA. Hepatology 1997; 26: 1322-1327
114 García F Jr, García F, Roldán C, López I, Martínez NM,
Alvarez M, Bernal MC, Hernandez J, Maroto MC. Detection
of HCV and GBV-CHGV RNA in peripheral blood
mononuclear cells of patients with chronic type C hepatitis.
Microbios 2000; 103: 7-15
115 Orito E, Mizokami M, Yasuda K, Sugihara K, Nakamura
M, Mukaide M, Ohba KI, Nakano T, Kato T, Kondo Y,
Kumada T, Ueda R, Iino S. Interferon-alpha therapy in
patients dually infected with hepatitis C virus and GB virus
C/hepatitis G virus--virological response of HGV and
pretreatment HGV viremia level. J Hepatol 1997; 27: 603-612
116 Pramoolsinsap C, Sirikulchayanonta V, Busakorn W,
Poovorawan Y, Hirsch P, Theamboonlers A, Lerdverasirikul
P. Coinfections with hepatitis g and/or c virus in hepatitis
B-related chronic liver disease. Southeast Asian J Trop Med
Public Health 1999; 30: 741-749
117 Szaflarska-Szczepanik A, Loe E, Krenska-Wiacek A,
Chrobot A. [Chronic hepatitis C in a 12-year-old girl
coinfected with HGV] Pol Merkur Lekarski 1999; 7: 21-22
118 Al-Ahdal MN, Rezeig MA, Kessie G, Chaudhry F, Al-
Shammary FJ. GB virus C/hepatitis G virus infection in
Saudi Arabian blood donors and patients with cryptogenic
hepatitis. Arch Virol 2000; 145: 73-84
119 Jain A, Kar P, Gopalkrishna V, Gangwal P, Katiyar S, Das
BC. Hepatitis G virus (HGV) infection &amp; its pathogenic
significance in patients of cirrhosis. Indian J Med Res 1999;
110: 37-42
120 Hoofnagle JH, Lombardero M, Wei Y, Everhart J, Wiesner
R, Zetterman R, Yun AJ, Yang L, Kim JP. Hepatitis G
virus infection before and after liver transplantation. Liver
Transplantation Database. Liver Transpl Surg 1997; 3: 578-585
121 Yuan JM, Govindarajan S, Ross RK, Yu MC. Chronic
infection with hepatitis G virus in relation to hepatocellular
carcinoma among non-Asians in Los Angeles County,
California. Cancer 1999; 86: 936-943
122 Yuan JM, Govindarajan S, Gao YT, Ross RK, Yu MC.
Prospective evaluation of infection with hepatitis G virus in
relation to hepatocellular carcinoma in Shanghai, China. J
Infect Dis 2000; 182: 1300-1303
123 Tillmann HL, Heiken H, Knapik-Botor A, Heringlake S,
Ockenga J, Wilber JC, Goergen B, Detmer J, McMorrow M,
Stoll M, Schmidt RE, Manns MP. Infection with GB virus C
and reduced mortality among HIV-infected patients. N Engl
J Med 2001; 345: 715-724
124 Maidana MT, Sabino EC, Kallas EG. GBV-C/HGV and
HIV-1 coinfection. Braz J Infect Dis 2005; 9: 122-125
125 Xiang J, McLinden JH, Chang Q, Kaufman TM, Stapleton
JT. An 85-aa segment of the GB virus type C NS5A
phosphoprotein inhibits HIV-1 replication in CD4+ Jurkat T
cells. Proc Natl Acad Sci USA 2006; 103: 15570-15575
126 Xiang J, George SL, Wunschmann S, Chang Q, Klinzman D,
Stapleton JT. Inhibition of HIV-1 replication by GB virus C
infection through increases in RANTES, MIP-1alpha, MIP-
1beta, and SDF-1. Lancet 2004; 363: 2040-2046
127 Xiang J, Klinzman D, McLinden J, Schmidt WN, LaBrecque
DR, Gish R, Stapleton JT. Characterization of hepatitis G
virus (GB-C virus) particles: evidence for a nucleocapsid
and expression of sequences upstream of the E1 protein. J
Virol 1998; 72: 2738-2744
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