Journal of Clinical Virology 33 (2005) 257–266

Review

GB virus C: Insights into co-infection

Mark D. Berzsenyi a,∗ , D. Scott Bowden b , Stuart K. Roberts a
aDepartment of Gastroenterology, Alfred Hospital, Commercial Road, Prahran 3181, Victoria, Australia
b Molecular Microbiology Laboratory, Victorian Infectious Diseases Reference Laboratory, 10 Wreckyn St.,
North Melbourne 3051, Victoria, Australia

Received 23 February 2005; received in revised form 22 March 2005; accepted 1 April 2005

Abstract

GB virus C (GBV-C) is a single stranded positive sense RNA virus, which is a member of the Flaviviridae. It has a close sequence
homology and genomic organisation to hepatitis C virus (HCV). However, unlike HCV it is not hepatotrophic. GBV-C replicates within cells
of the haemopoietic lineage, in particular lymphocytes. No disease has been associated with GBV-C infection but co-infection with human
immunodeficiency virus (HIV) leads to improved morbidity and mortality for the HIV infected individual and slows progression to acquired
immunodeficiency syndrome. This potential benefit of GBV-C has been demonstrated in the pre and post highly active anti-retroviral treatment
(HAART) eras. GBV-C has been found to decrease HIV replication in in vitro models. The mechanism of the beneficial effect of GBV-C
appears to be mediated by alterations in the cellular immune response, the details of which remain unclear. Despite this, there continues to
be controversy regarding the influence of GBV-C on HIV as several reports have questioned the beneficial effect. GBV-C does not appear to
influence liver related disease in subjects co-infected with HCV or hepatitis B virus (HBV). Combination of HIV and HCV leads to accelerated
liver disease. The influence of GBV-C in this situation is yet to be determined. Elucidation of the putative protective effect of GBV-C in HIV
co-infection could potentially identify novel targets for anti-HIV therapeutics and lead to the development of disease modifying vaccines.
© 2005 Elsevier B.V. All rights reserved.

Keywords: GB virus C; Human immunodeficiency virus; Hepatitis C virus; Co-infection

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
2. Epidemiology and transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
3. Molecular biology and phylogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
4. Clinical significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
4.1. Human immunodeficiency virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
4.2. Hepatitis C virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
5. Interactions of GBV-C and HIV with the host’s cellular immune response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
6. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263

1. Introduction a West African population when they were attempting to ret-

rospectively track down the causative agent of an incident of
GB virus C (GBV-C) was first identified by the Virus Dis- acute hepatitis in a Chicago surgeon (initials GB) (Simons
covery Group at Abbott Laboratories in serum samples from et al., 1995). The finding of GBV-C was fortuitous as it was
subsequently shown to be unrelated to the episode of hepatitis
∗ Corresponding author. Tel.: +61 3 92762223; fax: +61 3 92762194. experienced by the surgeon. Coincidentally, hepatitis G virus
E-mail address: M.Berzsenyi@alfred.org.au (M.D. Berzsenyi). (HGV) was independently cloned from the plasma of a patient

1386-6532/$ – see front matter © 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jcv.2005.04.002
258 M.D. Berzsenyi et al. / Journal of Clinical Virology 33 (2005) 257–266
who was subsequently found to be infected with hepatitis C
virus (HCV) (Linnen et al., 1996). Sequence comparison of
these two viruses has shown that they are different isolates of
the same virus with nucleotide and amino acid homologies
of 86% and 95%, respectively (Alter, 1996; Polgreen et al.,
2003). The virus is referred to as both GBV-C and HGV in
the literature with the current taxonomic name being GBV-
C/HGV (Polgreen et al., 2003). However, the virus does not
appear to be associated with hepatitis, so the virus will be
referred to as GBV-C for this review.
Based on comparison of genome organization and se-
quence homologies, GBV-C is the most closely related human
virus to HCV, another member of the Flaviviridae (Linnen et
al., 1996; Leary et al., 1996; Reed and Rice, 2000). In con-
trast to HCV, GBV-C does not appear to be hepatotrophic as
the virus neither replicates in hepatocytes nor causes acute or
chronic hepatitis (Alter, 1997; Laskus et al., 1997). In fact,
GBV-C is a lymphotrophic virus that is believed to repli-
cate primarily in the spleen and bone marrow (Tucker et al.,
2000). There is also some evidence that the virus replicates
in a number of different peripheral blood mononuclear cells,
including CD4 positive T cells (Xiang et al., 2000).
By itself, GBV-C infection has not been associated with
any specific disease nor does it appear to represent a substan-
tial health risk. No association has been found between GBV-
C and such conditions as hepatocellular carcinoma, lichen
planus, cryoglobulinaemia, Sjögren’s disease or various ma-
lignant or non-malignant haematological disorders (Polgreen
et al., 2003). However, in the setting of co-infection with hu-
man immunodeficiency virus (HIV), current evidence points
to GBV-C offering a benefit in terms of slower progression
for HIV related diseases and acquired immunodeficiency syn-
drome (AIDS).
This article will review the association of GBV-C with
HIV and the blood-borne hepatitis viruses as well as examine
the epidemiology, molecular biology, immunology of GBV-C
and propose possible future directions of research.
2. Epidemiology and transmission
GBV-C infection is relatively common and has a world
wide distribution. Between 1% and 4% of healthy blood
donors have GBV-C RNA detected in their sera (Moaven
et al., 1996; Alter, 1997; Stapleton, 2003). Of these, the ma-
jority of people clear the virus and develop antibodies to the
E2 envelope glycoprotein. The humoral immune response
to the E2 glycoprotein is associated with loss of GBV-C
RNA/viraemia. The prevalence of E2 antibodies (anti-E2) in
sera is found to be two to six times higher than RNA/viraemia
suggesting that spontaneous clearance of GBV-C infection is
common (Tacke et al., 1997b; Dille et al., 1997; Thomas et al.,
1998). Anti-E2 may serve as a useful marker for diagnosing
clearance of GBV-C RNA/viraemia and as such is a marker
of past infection (Tacke et al., 1997a). The development of
anti-E2 is also associated with protection from re-infection
(Tillmann et al., 1998; Thomas et al., 1998). Interestingly,
studies have shown a low seroconversion rate of 5% in a
high-risk group of children all of whom were infected with
HCV. The authors suggested that there may be a greater risk of
chronic carriage with early acquisition of GBV-C (Hardikar
et al., 1999).
There is extensive evidence that GBV-C is transmitted by
sexual and percutaneous routes in much the same way as
HIV and is frequently found in populations at risk for blood-
borne or sexually transmitted viruses (Alter et al., 1997;
Bjorkman et al., 2001; Lefrere et al., 1999a; Scallan et al.,
1998; Sawayama et al., 1999). Male to male sex has been pro-
posed to be a more effective mode of transmission of GBV-C
(Berzsenyi et al., 2005). Further to this, there is evidence that
GBV-C can be transmitted by either heterosexual or homo-
sexual means (Sawayama et al., 1999). Intrafamilial trans-
mission of GBV-C has also been reported and analysis of
gene sequences suggested that both vertical and horizontal
transmission occurs (Seifried et al., 2004).
In a study of healthy individuals without risk factors for
GBV-C and with normal alanine transaminase (ALT) levels,
GBV-C RNA was reported in 1.9% of individuals whereas
GBV-C was seen in 6.8% of haemodialysis patients, 18.2%
of HIV infected individuals, 21.1% of multiple blood trans-
fusion recipients, 24.4% of HCV infected individuals, 28.8%
of intravenous drug users and 35.2% of haemophilia patients
(Feucht et al., 1997). Another study reported GBV-C RNA
in 18% of haemophiliacs (Mauser-Bunschoten et al., 1998).
Further to these studies, GBV-C was seen in 11% of non-drug
injecting homosexual and bisexual men and 35% of intra-
venous drug users (Stark et al., 1996). Actual prevalence of
GBV-C will obviously vary according to the particular pop-
ulation studied but what is clear is that carriage of GBV-C is
more common in groups with risk factors for percutaneous
and sexual transmission.
GBV-C viraemia was seen in 25.3% of patients present-
ing for liver transplantation with end stage liver disease due
to a viral cause. It was shown to have no influence on the
outcome of transplantation or recurrence of hepatitis in the
graft (Vargas et al., 1997). In addition, GBV-C acquired at
the time of transplantation was shown to have no impact on
the outcome of the graft including transplants performed for
reasons other than viral hepatitis (Fried et al., 1997).
3. Molecular biology and phylogenetics
GBV-C and its close relative HCV are unusual among
RNA viruses of humans in that they cause persistent infection
without a DNA intermediate or a known latent stage in their
replication cycle (Xiang et al., 2001). A diagram showing
the comparative genomic organisation of GBV-C and HCV,
potential differences as well as the various functions of HCV
genes is shown in Fig. 1.
The positive sense, single stranded RNA genome of GBV-
C is approximately 9400 nucleotides long. It contains a long
 M.D. Berzsenyi et al. / Journal of Clinical Virology 33 (2005) 257–266 259

Fig. 1. Comparative genomic organization of the GBV-C and HCV genomes showing open reading frames (ORF) and 5 and 3 untranslated regions (UTR).
Both genomes are composed of single stranded positive sense RNA (ss+RNA). The ORF of GBV-C has 29% amino acid sequence homology with HCV with
significant areas of conserved homology implying similar functions for these genes. One area of significant difference is a core/capsid gene for GBV-C is yet
to be identified. The proposed functions of HCV genes are shown. Genes shown are not to scale.

Open Reading Frame (ORF) predicted to encode a polypro-
tein of approximately 3000 amino acids (Leary et al., 1996;
Linnen et al., 1996; Polgreen et al., 2003). It contains an inter-
nal ribosomal entry site (IRES) in the 5 untranslated region
(UTR), two putative envelope proteins E1 and E2, NS3 with
RNA helicase and trypsin-like serine protease domains and
an RNA dependant RNA polymerase (NS5B). The ORF of
GBV-C has 29% amino acid sequence homology with HCV
and significantly conserved areas of homology exist implying
similar function of gene products. The similarities with HCV
are generally limited to specific enzymatic motifs in the NS3
and NS5B gene regions while there is little or no similarity in
the genes encoding the envelope genes between GBV-C and
HCV. Amongst GBV-C isolates there is limited variation in
the genes encoding the putative envelope glycoproteins un-
like HCV and HIV where variability has been linked to viral
persistence (Simmonds, 2001).
Important features remain to be determined with respect to
the genome of GBV-C. The coding region for the core protein
of GBV-C remains undefined, in contrast to the core gene for
HCV, which has been identified (Polgreen et al., 2003). It has
been suggested that the GBV-C core gene may utilize an alter-
native ORF or could be encoded by the negative sense RNA
(Xiang et al., 1999; Pavesi, 2000). However, this is somewhat
unlikely considering the availability of computer programs to
analyze ORFs in all three reading frames in both positive and
negative directions. One possible explanation is the forma-
tion of secondary structures within the RNA genome that has
made the detection of the core gene of GBV-C difficult.
Different isolates or genotypes of GBV-C show limited
variability with nucleotide sequences differing by a max-
imum of 13%. Comparison of epidemiologically distinct
isolates of GBV-C suggests that there are four major phy-
logenetic groupings or genotypes that are equally divergent
from primate GBV-C as determined from analysis of the
E2 gene. In addition, analysis of the E2 gene in certain
isolates from South Africa suggests there is a fifth genotype.
Thus, GBV-C is considered to have five genotypes based on
these sequence relationships (Smith et al., 2000; Mison et
al., 2000; Sathar et al., 1999; Muerhoff et al., 1996; Mukaide
et al., 1997). The world wide geographical distribution of
GBV-C variants and the non-pathogenic nature of the virus
suggests a long evolutionary history which parallels pre-
history human migration, implying the long term evolution
of this RNA virus has been extremely slow (Smith et al.,
2000). Recently, studies have shown that the five genotypes
of GBV-C can be determined accurately and inexpensively
by restriction fragment length polymorphism (Schleicher
and Flehmig, 2003). A Japanese study has shown that within
genotype 1 there are at least five subtypes. Interestingly
a majority of Japanese patients with haemophilia were
infected with GBV-C of a unique and newly discovered
subtype within genotype 1 (Liu et al., 2003).
4. Clinical significance
GBV-C has not been associated with any particular disease
entity despite numerous investigations. However, a number of
reports have shown GBV-C to have a profound “protective”
influence on HIV in the situation of co-infection. No role,
protective or otherwise, has been found with GBV-C and co-
infection with HCV or hepatitis B virus (HBV) infection to
this point.
260 M.D. Berzsenyi et al. / Journal of Clinical Virology 33 (2005) 257–266
4.1. Human immunodeficiency virus
Infection with HIV is associated with a wide range of
clinical scenarios ranging from preservation of the immune
system, particularly in the presence of highly active anti-
retroviral treatment (HAART), to asymptomatic and oppor-
tunistic infections leading all the way to established AIDS
(Pantaleo and Fauci, 1996). HIV infection has a particularly
high rate of co-infection with GBV-C. Studies have suggested
the rate of co-infection varies between 14% and 45% with
higher rates occurring in homosexual men and intravenous
drug users (Lau et al., 1999; Rey et al., 1999; Puig-Basagoiti
et al., 2000; Tillmann and Manns, 2001). However, the rate of
spontaneous clearance of GBV-C RNA and the development
of E2 antibodies in HIV/GBV-C co-infected patients occurs
at a slower rate than in the immunocomponent host. In some
instances GBV-C viraemia can be lost without the develop-
ment of E2 antibodies in the co-infected host (Alter, 1997;
Stapleton, 2003).
Reports initially started to appear in the late 1990s suggest-
ing that co-infection with HIV and GBV-C gave a more favor-
able outcome for patients with delayed development of AIDS
compared to those with HIV infection alone (Heringlake et
al., 1998; Lefrere et al., 1999b; Yeo et al., 2000; Tillmann
et al., 2001; Xiang et al., 2001; Williams et al., 2004). Sev-
eral key findings have been reported. Firstly, there is a higher
rate of GBV-C viraemia amongst those patients co-infected
with HIV. In HIV infected patients the mortality rate was
significantly lower among those with GBV-C viraemia, inde-
pendent of previous anti-retroviral treatment or prophylaxis
against pneumocystis carinii pneumonia, base-line CD4 posi-
tive T cell count, age, race, sex, or mode of HIV transmission.
In sub-group analysis, defined by CD4 positive cell counts,
all patients with GBV-C had a lower mortality rate than HIV
infected patients without GBV-C viraemia. Also shown was
that HIV replication was diminished in vitro by co-infection
with GBV-C (Xiang et al., 2001). This last fact is important
as it suggests that GBV-C directly affects HIV replication
rather than act via some other mechanism.
In another study, which may have relevance to the cur-
rent management of HIV patients in the post-HAART era,
197 HIV infected patients were screened for GBV-C and
their clinical status was then followed prospectively. Of the
patients who tested positive for GBV-C RNA, survival was
significantly longer and there was a slower progression to
AIDS than those patients who were GBV-C negative. Sur-
vival after the development of AIDS was also better in the
GBV-C positive patients. When the analysis was stratified
for age and CD4 positive cell count, GBV-C viraemia was
significantly associated with reduced mortality. Importantly,
in an analysis restricted to the post-HAART era, the pres-
ence of GBV-C RNA remained predictive of longer sur-
vival. HIV viral load was also lower in the GBV-C posi-
tive patients than in the GBV-C negative patients. An in-
verse correlation between the GBV-C viral load and the HIV
viral load was also shown. Of note, GBV-C viral load in-
creased in all patients who started HAART (Tillmann et al.,
2001).
More recently, samples collected in the pre-HAART era
from the Multicenter Acquired Immunodeficiency Syndrome
Cohort Study, an ongoing study in various centres in the
United States, have been analysed (Williams et al., 2004).
Individuals who had provided samples were then prospec-
tively followed up. The study showed that GBV-C viremia
was significantly associated with prolonged survival among
HIV positive men 5 to 6 years after HIV seroconversion, but
not at 12 to 18 months, and the loss of GBV-C RNA by 5 to
6 years after HIV seroconversion was associated with the
poorest prognosis. The authors of the study concluded that
there was a significant survival advantage associated with per-
sistence of GBV-C in the HIV co-infected patient (Williams
et al., 2004). Whether this data can be applied to the post-
HAART era remains to be determined. Further to this, a ret-
rospective study was performed on a cohort of HIV positive
patients with known GBV-C status who had answered ques-
tionnaires assessing quality of life. Patients with GBV-C vi-
raemia showed superior quality of life. This further supports
the favourable course of HIV disease in GBV-C viraemic
patients (Tillmann et al., 2004).
Not all studies of co-infection with HIV and GBV-C have
found a beneficial effect on HIV disease progression (Birk
et al., 2002; Brumme et al., 2002; Bjorkman et al., 2004;
Van der Bij et al., 2005). In a Swedish study of 157 HIV-1
infected individuals, no influence of GBV-C co-infection
could be seen on immunological or clinical outcomes of
HIV infection (Birk et al., 2002). However, patients in this
study had high CD4 positive T cell counts, which would
be expected early in the course of HIV infection. Many
of the studies describing a beneficial effect as previously
discussed, examined patients with a broader range of CD4
positive T cells counts (Heringlake et al., 1998; Lefrere et
al., 1999b; Yeo et al., 2000; Tillmann et al., 2001; Xiang et
al., 2001). Furthermore, it has been suggested that GBV-C
viraemia in HIV-1 infection may represent a phenomenon
secondary to HIV progression, rather than an independent
prognostic factor. However, an interaction between the two
viruses still appeared to exist, since loss of GBV-C viraemia
was associated with increased HIV progression. The study
found that GBV-C status at diagnosis did not predict disease
outcomes in their HIV cohort (Bjorkman et al., 2004). As
already discussed, long term persistence of GBV-C viraemia
is probably a key component of the beneficial outcome of
GBV-C/HIV co-infection. This may help explain discrepan-
cies in studies in which the follow-up has been shorter and
no apparent benefit has been shown (Williams et al., 2004).
A cohort of 326 homosexual males in the pre-HAART
era had GBV-C status determined shortly after HIV-1 sero-
conversion and again prior to widespread use of HAART in
1996. Median follow-up period was 8 years. Those who lost
GBV-C RNA between the two sample collections had nearly
a threefold increased risk of HIV disease progression com-
pared to those who never had GBV-C. This effect became
 M.D. Berzsenyi et al. / Journal of Clinical Virology 33 (2005) 257–266
much smaller following adjustment for time-updated CD4
positive T cell counts. The authors concluded that persis-
tence of GBV-C RNA depends on the presence of sufficient
numbers of CD4 positive cells and that a drop in CD4 cells
associated with HIV disease progression is a cause, not a
consequence, of GBV-C RNA loss (Van der Bij et al., 2005).
However, since the introduction of HAART, CD4 cell counts
have increased and HIV viral loads have decreased causing
a reduction in patient mortality from AIDS related illness
(Mocroft et al., 1998; Palella et al., 1998) and as already dis-
cussed GBV-C RNA remains predictive of longer survival in
the post-HAART era (Tillmann et al., 2001). Another study
found that GBV-C RNA was relatively common (20.4%) in
HIV infected individuals seeking treatment but the presence
of the virus had no effect on initial response to anti-retroviral
therapy (Brumme et al., 2002). In comparison, a further re-
port has shown that patients with concurrent GBV-C and HIV
infection exhibit a better response to HAART as indicated by
higher complete virological response rates (Rodriguez et al.,
2003).
4.2. Hepatitis C virus
Among newly diagnosed cases of blood-borne viral hep-
atitis in the United States, 18% were positive for GBV-C,
and 80% of these patients were also infected with HCV.
Other studies have reported the incidence of GBV-C amongst
patients with HCV infection varies from 11% to 24% (Di
Bisceglie, 1996; Tanaka et al., 1996; Feucht et al., 1997).
Does GBV-C have a role to play in HCV co-infection?
Histological evaluation of GBV-C infection in chronic HCV
has shown that GBV-C has no effect on severity of HCV re-
lated liver disease (Bralet et al., 1997). Hepatic inflammation
is thought to be predominantly as a result of HCV in the set-
ting of co-infection with GBV-C (Pereira et al., 2002) with no
statistical difference in the degree of inflammation between
liver biopsies from HCV mono-infected patients and GBV-
C/HCV co-infected patients. Of note, there was a trend to
a lesser degree of hepatic inflammation in the GBV-C co-
infected group (Strauss et al., 2002). GBV-C has been shown
to have no effect on the course of co-existent HCV infec-
tion or the clinical effectiveness of interferon-based treatment
regimens. Interferon-alfa has been shown to be effective in
the clearance of GBV-C viraemia in 20.7% of patients and
may potentate anti-E2 seroconversion in these individuals.
GBV-C viraemia has been shown to recur in 53% following
cessation of treatment (Oshita et al., 1998; Yu et al., 2001).
In a meta-analysis examining over 5300 patients, no role of
GBV-C in HCV infection was shown and no correlation was
observed between the response of HCV and GBV-C to inter-
feron. Overall, GBV-C is thought to have no adverse effect
on the course of HCV related chronic liver disease or the de-
velopment of chronicity from acute HCV infection. It does
not appear to have any influence on histology, transaminase-
levels or response of HCV to antiviral therapy (Rambusch
et al., 1998).
261
Does GBV-C infection in the setting of HCV and HIV
co-infection lead to any changes in outcome? This is an
important question as in urban intravenous drug using popu-
lations within the United States, HIV and HCV co-infection
has been reported in 60% to 80% of individuals, although
the prevalence of co-infection is highly variable and depen-
dent on the population’s risk factors for acquiring infection
(Sherman, 2004). Liver disease associated with HCV appears
to be accelerated in patients with HIV. There appears to be a
significant increase in fibrotic progression among those with
HCV and HIV co-infection (Benhamou et al., 1999). Anti-
retroviral therapy has been shown to have a positive impact
on progression of liver fibrosis in HCV and HIV co-infection
(Qurishi et al., 2003) although, drug-related hepatoxicity
makes use of these agents in the setting of chronic viral
hepatitis or cirrhosis a possible concern. Whether HCV
effects HIV disease progression seems less clear with some
reports suggesting more rapid progression to AIDS (Greub et
al., 2000) while others have shown no effect on CD4 counts,
recovery (Sherman et al., 2002) or survival (Macias et al.,
2002). Currently, little is known about the effect GBV-C has
in the setting of HCV and HIV co-infection. Interestingly,
patients infected with GBV-C, HCV, and HIV has been
shown to have an improved response to HAART (Voirin et
al., 2002). A recent abstract has reported GBV-C viraemia in
30% of patients co-infected with HCV and HIV, with GBV-C
viraemia being cleared in 45% of these patients following 24
weeks of combination therapy with interferon and ribivirin.
Sustained clearance of GBV-C RNA was seen in 18% of
patients while clearance of GBV-C RNA was not associated
with HIV-1 RNA levels becoming elevated (Zander et al.,
2003). The effect over time of GBV-C RNA clearance in this
situation is unknown including the possibility that the ben-
eficial effect of GBV-C maybe lost. To the present time, no
studies have addressed the long term effect GBV-C viraemia
has on chronic HCV related liver disease in the setting of HIV
co-infection.
Little work has been done in relation to HBV and GBV-
C co-infection. What has been shown is that there was no
significant effect of GBV-C on HBV DNA levels (Kao et al.,
1998).
5. Interactions of GBV-C and HIV with the host’s
cellular immune response
The identification of the mechanism by which GBV-C
inhibits the replication of HIV might lead to the development
of new treatments for HIV. The exact mechanism of the
beneficial effect of GBV-C on the course of HIV infection
remains obscure, although recent research has identified
a number of putative pathways. Fig. 2 summarises the
current postulated mechanisms by which GBV-C may exert
a protective effect against HIV.
Infection with both GBV-C and HIV has been shown to
lead to stable serum levels of T-helper 1 (Th1) cytokine pro-
262 M.D. Berzsenyi et al. / Journal of Clinical Virology 33 (2005) 257–266

Fig. 2. Multiple mechanisms have been postulated for the action GBV-C infection exerts on co-infected patients with HIV. Up regulation of Th1 cytokines
and down regulation of Th2 cytokines leads to a profile, which is associated with improved outcomes for HIV/AIDS. Another mechanism is via increased
chemokine production, which leads to inhibition of CCR5 and CXCR4 co-receptors for HIV entry. Central to this cascade is increased production of Regulated
on Activation, Normal T cell-Expressed and Secreted (RANTES) chemokine whose expression is also increased by the GBV-C E2 envelope protein interacting
with CD81 cell surface receptor. Other mechanisms that have been suggested include different strains of GBV-C having varying degrees of “protective effect”,
GBV-C augmenting innate immunity and GBV-C decreasing the efficiency of transcription from the integrated HIV pro-virus in the host genome. Whether
HCV and HBV have a clear role is in this scenario is yet to be determined.

files during follow-up compared to patients who are GBV-C
RNA negative in which Th1 cytokine profiles fall. In ad-
dition, T-helper 2 (Th2) cytokine profiles progressively in-
crease in the absence of GBV-C infection (Nunnari et al.,
2003). The importance of T-helper cell response against HIV
is supported by studies showing that progression of AIDS is
correlated with the inability of mononuclear cells to produce
Interleukin 2 (IL-2), Interleukin 12 (IL-12) and Interferon-␥
(INF-␥) cytokines (Th1 response) with increased production
of Interleukin 4 (IL-4) and Interleukin 10 (IL10) (Th2 re-
sponse) (Spellberg and Edwards, 2001). In an in vitro study,
GBV-C infection of peripheral blood mononuclear cells led to
lower replication of laboratory and clinical isolates of HIV
that use CCR5 or CXCR4 as co-receptors for T cell entry.
Certain strains of HIV (R5) use CCR5 while other strains of
HIV (X4) use CXCR4 to gain entry into cells. GBV-C induces
chemokines leading to decreased expression of these HIV
co-receptors. The chemokines implicated, as shown by their
higher levels of mRNA, include Regulated on Activation Nor-
mal T cell-Expressed and Secreted (RANTES), macrophage
inflammatory protein 1␣ (MIP-1␣), and macrophage inflam-
matory protein 1␤ (MIP-1␤) which are the natural ligands
for CCR5 and stromal-derived factor (SDF-1) which is the
only known ligand for CXCR4. Most importantly, the in-
hibitory effect of GBV-C on HIV was neutralized by an-
tibodies directed against these chemokines (Xiang et al.,
2004). In addition, GBV-C was not shown to cause cytotoxic
effects on lymphocytes in this study. Polymorphisms of these
chemokine receptors or SDF-1 do not appear to contribute to
the beneficial effect of GBV-C on HIV/AIDS (Tillmann et
al., 2002). Further to this, it has also been shown that GBV-C
E2 protein binds to CD81, a member of the tetraspanin fam-
ily, which is expressed on the cell surface of most nucleated
cells. GBV-C E2 envelope protein has been found to interact
with CD81 to increase RANTES and decrease CCR5 sur-
face expression thus also affecting entry of HIV to the cell
(Nattermann et al., 2003). Previously, ligation of CD81 with
HCV E2 has been shown to alter cellular functions of T cells
and natural killer cells (Tseng and Klimpel, 2002).
Studies have indicated that there is an innate immune
mechanism that inhibits HIV both early and late in the retro-
viral life cycle in various cells in humans and primates. It
has been suggested that GBV-C may augment this process
of intracellular inhibition of HIV internalization. GBV-C is
 M.D. Berzsenyi et al. / Journal of Clinical Virology 33 (2005) 257–266
also thought to decrease the efficiency of transcription of
HIV from the integrated provirus (Pomerantz and Nunnari,
2004). There is some limited evidence to suggest that differ-
ent genotypes of GBV-C offer different degrees of “protec-
tion” against HIV in the co-infected host. CD4 positive cell
counts tended to be lower in patients infected with GBV-C
genotype 2a. However, as the authors of the article stated,
further studies are required with larger cohorts from sep-
arate geographical areas to determine if a particular geno-
type is associated with reduced morbidity or mortality from
HIV (Muerhoff et al., 2003). Furthermore, clinical isolates of
GBV-C have been found to differ in their ability to replicate
and RNA sequence variability in key regulatory regions may
be the cause, at least in the in vitro model used in this study
(George et al., 2003).
6. Future directions
There remain many questions that need to be answered
before a full understanding of the impact of GBV-C co-
infection with HIV and other viruses can be determined.
One area, which requires further study is what happens to
GBV-C during the course of infection in terms of changes
in viral sequence and the effect these alterations may
have on the immune response to HIV. In addition, a better
understanding of any role different subtypes of GBV-C may
play in HIV/AIDS progression is required. Although GBV-C
has been shown to replicate within cells of the haemopoietic
lineage, clear evidence for replication within hepatocytes
has not yet been shown (Copra, 2004). Further, little work
has been done on co-infection of GBV-C with HBV.
Moreover, limited work has been performed in the rel-
atively common situation of GBV-C, HCV and HIV co-
infection. Specifically what effect does GBV-C have on the
natural history of chronic HCV infection in the HIV and HCV
co-infected host? Does GBV-C affect the severity of liver dis-
ease in HCV and HIV co-infection and are there any specific
alterations in pro-inflammatory, pro-fibrotic or pro-apoptotic
gene expression in this scenario?
Of significance in the GBV-C story is determination of
which molecular or cellular events are involved in its “protec-
tive” effect in the HIV infected person. Studies have already
started to delineate the mechanism of this beneficial effect, as
outlined in this review. This could lead to the development of
novel targets for anti-HIV drugs and vaccines. As these events
are occurring at the cellular level, it may be more difficult for
HIV to develop resistance to these effects (Xiang et al., 2004).
One way in which a better understanding of mechanism of the
GBV-C’s “protective” effect could be translated into a therapy
is by RNA interference. Using this approach the expression
of genes can be silenced by pathways that promote the degra-
dation of specific RNA molecules (Stevenson, 2004). These
pathways can be used in order to regulate gene expression in
a variety of biological systems. Currently work is under way
to harness RNA interference to interrupt the disease process
263
in HIV, hepatitis viruses, influenza virus as well as malignant
diseases, such as chronic myeloid leukaemia and its associ-
ated BCR-ABL transcript (Stevenson, 2004). In one possible
approach specific cellular RNA molecules, such as genes in-
volved in the Th2 response could be targeted to achieve the
effect GBV-C has on the HIV infected T cells without in-
fecting the individual with GBV-C. The silencing effect of
RNA interference is highly specific and potent and requires
only that the sequence of the target RNA be known. How-
ever, obstacles must be overcome before RNA interference
can live up to its potential as a therapeutic method (Stevenson,
2004).
7. Summary
GBV-C is a novel virus having a unique interaction with
HIV in the co-infected host. It is related to HCV, another
member of the Flaviviridae, but unlike HCV has no appar-
ent pathogenic role in liver disease. It has tropism for pe-
ripheral blood mononuclear cells including CD4 positive T
cells. Mysteries still remain about the genome of GBV-C
with the core gene still not identified. There is compelling
evidence to suggest that as long as GBV-C continues to repli-
cate in the HIV co-infected host it leads to an improvement
in HIV/AIDS related morbidity and mortality. This effect is
still seen following the introduction of HAART. Alteration
in the host’s cellular immune response to HIV seems to be
responsible for the “protective” effect of GBV-C. However,
the exact mechanism is still to be defined. In contrast, GBV-C
infection appears to have no affect on chronic liver disease
due to HCV or HBV. The influence of GBV-C on liver disease
in the situation of co-infection with HCV and HIV is yet to be
determined. The interaction between GBV-C and HIV may
lead to new therapeutic approaches that halt or slow the pro-
gression of HIV/AIDS without some of the current treatment
issues of drug resistance and toxicity.
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