Jpn. J･ Infect. Dis., 54, 55‑63, 2001

Review

GB VirusIC/Hepatitis G Virus
KenjiAbe*
Department of Pathology, National Institute of Infectious Diseases,

Toyama 1‑2311, Shinjuku‑ku, Tobo 16218640, Japan(Received January 25, 2001. Accepted April 23, 2001)

CONTENTS:
Summarylntroduction

History
Viral genome

Mutation rate of the viral genome
Diagnostic assay
Epidemiology and clinical significanceHepatotroplSm and extrahepatic replication of the virus
Relation to hepatocellular carcinoma occu汀enCe

Experimental infection in chimpanzees

C0‑infection in human immunodeficiency virus (HIV)‑infected patients
Existence of viral genotypes and its geographic distribution

Conclusion

SUMMARY: GB vims‑C (GBV‑C)仇epatitis G vims (HGV) is a positive, single‑strand RNA virus that has beenclassified in the family Flaviviridae. Interestlngly, GBVIC/HGV appears to have a truncated or absent coreprotein at the amino teminus of the polyprotein. GBV‑C/HGV is transmitted parenterally and probably sexually.
Most GBV‑C作iGV infections appear to be asymptomatiC, persistent, and no correlation between virus infection andliver dysfunction although the disease‑inducing activityof GBV‑C什IGV remains to be investigated. Furthermore,

there was no evidence ofpathogenesis in the liver by experiment with chimpanzees. From these results, GBV‑C/
HGV might be considered as a kind of …orphan" vims in search of a disease. EpidemiologlCal investlgation

demonstrated that GBVIC/HGV infection is present in about 1‑1.4% of the healthy population in developed
countries and in 8‑ 14.6% in developlng COuntries. The genome of GBV‑C/HGV exhibits a sequence variation
among different isolates. On the basis of this variation, it has been proposed that GBV‑C/HGV can be classified

into at least four major genotypes, consisting of type 1 (West Africa), type 2 (US/Europe), type 3 (Asia), andtype
4 (Southeast Asia).

ent isolates of the same vims. This article will provide a

Introd uction

review of the available infbmation concemlng GBVJC/HGV

After discovery of the hepatitis A and B viruses (HAV,
HBV) in the 1960s and 1970S, it became apparent that an

History

unidentified agent was responsible for hepatltlS ln a number

GBV‑C is the acronym for a virus onglnally derived froma surgeon (whose initials were G･B･) in whom hepatitis
developed in the 1960S (4)･ His plasma caused hepatitis. intamarins, and the 1 lth passage in tamarin serum was the clonlng

of patients suspected or having acute or chronic viral hepatitis.

The unknown pathogen was referred to as non‑A, non‑B
hepatitis until the hepatitis C virus (HCV) was identified in
1989 (1 ) and was found to a?count for hepatitis in the majprityof these patients. However, ln approximately lO% ofpatlentSsource of the virus. Three di飽rent GBV agents have been cloned

been suspected that additional hepatotroplC Viruses will bethus far; GBV‑A and GBVIB appear to be tamarin viruses,
and GBV‑C is a human vims (2,5). GBV‑C was discovered

discovered to account fわr some of these cases, especially slnCe

by gene amplification with prlmerS derived from sharedapproximately half of these patients have a history of bloodtransfusion. The cloning Ofthe HCV established that it issequences in GBVIA, GBVIB, and HCV (2). On the other hand,
the initial source from which HGV was cloned was a patientamong the most important human pathogens. ln 1 996, uslng

with community‑acquired chronic hepatitis (3 ). The sequences

similar methods, two new RNA viruses were independently
discovered in human serum and were named GB virus‑C

the two are considered to be closely related isolates of the(GBV‑C) and hepatitis G virus (HGV), respectively (2,3).

Same VlmS.

with liver diseases, no cause can be identified. lt has longof GBV‑C and HGV are more than 95% homologous, andDatabase screenlng indicated that these viruses had highsequence similarity, hence they are now regarded as independ‑

Viral genome*Corresponding author: Tel: +81‑3‑528511 I 1 I ext. 2624, Fax: +81

The genomic organization of GBV‑C/HGV is similar to

3 ‑5285‑1 189, E‑mail: kenjiabe@nih.go.jp

that ofHCV (Fig. 1). The GBVIC什IGV genome is a positive‑

55

YFV (10 kb)
NS4 (a+h)

HCV (9.6 kb)
NS4 (a+b)

111
FutLCtion

UTR?

ErLVelopeI

I

Protease

I

Protease/1
NS3

NS5(a+b)

I

I

RNA‑dependent

VTR

proteiTI Helicase Co factor RNA poJymerase

Fig. 1. Comparison ofgcnomc structure among yellow fcvcr virus (YFV), HCV, and GBVIC/HGV UTR, untranslatcd region;
C, core gcnc; EI and E2, Cnvclopc gcncs I and 2; NS2 through NS5b, non‑structural gcncs 2 through 5b.

strand RNA or about 9400 nucleotides (nt) and it contains adata also suggested that plasma samples from individuals

large open reading frame that encodes a polyprotein precursor

chronically infectedwith GBV‑C/HGV contained antibody

of about 2900 amiヮ0.acid (aa) residues･ Like HCV, GBV‑C/

to the GBV‑C/HGV core protein peptide. These data indicate

HGV has charactenstlCS Of a navivirusllike genome. The twothat GBV‑C/HGV has a nucleocapsid and that at least part ofviruses thus represent a new genus in the family Flaviviridae

the putative core reglOn Ofthe virus is expressed in vivo･ ln

includingflaviviruses and pestiviruses, Since the genetic distance
between GBV‑C/HGV and HCV is too great to consider GBV‑C/HGV as a different genotype ofHCV (2). Like HCV, thethe literature, infectious particles lacking such a core havegenome or GBVC/HGV is preceded by a 5'‑untranslated

entry site that is capable of directlng CAP‑independent trans‑

region (UTR), which is followed by a long open reading
frame. The genome terminates with a 3'UTR, but it has nolation of the polyprotein (9, 1 0)･ Multiple sequenc.e alignments
demonstrated that the 5'UTR and 3'UTR contalnS blocks ofpoly(A)‑tail･ ln contrast to HCV, the sequeヮce variability ofhighly conserved (>95%) sequences･ This cons?rvation has

envelope 2 (E2) is very low among different lSOlates collectedenabled the optlmization of RT‑PCR assays uslng PrlmerS

worldwide and no hypervariable reglOn exists in the envelope

from these conserved regions.

been generated artificially with the vesicular stomatitis virus
glycop.rotein (8)･ The 5'UTR coヮtains an intemal ribosome

reglOn･ The presumed polyprotein containsstructural envelope

1 (E 1 )and E2 glycoproteins at the amin0‑terminal end,followedby nonstmctural (NS) proteins (NS2, NS3, NS4, NS5) at the
carboxy‑terminal end. The E2 glycoprotein has three potential

Nakao et al. (1 1 ) reported that GBV‑C/HGV was estimatedglycosylation sites and 1 8 cysteine residues that might beto have a mutation rate of 3.9 × loヰ base substitutions per

involved in disulfide bonds. Interestlngly, the GBV‑C/HGV

putative core reglOn at the aa level in 54 GBV‑C什lGV isolates,site per year･ We also dete‑ined the mutation rate of GBV‑C/HGV For this purpose, we isolated and compared two
GBV‑C/HGV genomes (HGV‑IM68 isolate and HGV‑IM7 1
isolate) from the same Japanese patient. The IM68 isolate

they can be divided into four different groups (unpublished

had been obtained from the patient 12 years before the studydata). ln other words, 2 isolates with 107 aa (group 1) weretook place. The IM68 sequence differed from lM71 sequenceat 59 (1%) of the 5867 nt･ The differe.nces between those

Mutation rate or the viral genome

genome lacks a clearly identifiable core gene which encodes

a nucleocapsid protein. ln our study, from the size of thefound, 4 isolates with 84 aa (group 2), 9 isolates with 47 aa

isolates were exclusively nucleotide polnt mutations. Based(group 3), and 39 isolates with 16 aa (group 4). 1n addition,
one isolate lacked the core reglOn COmpletely. 1n contrast, theon these results, the mutation rate ofHGV‑lM7 I was estimatedcore reglOn OfHCV consists of 19l aa. The lack ofa core‑liketo be 0.8 × 10 3 base substitutions per site per year during aprotein at the N‑teminus of the viral polyprotein distinguishes
GBVIV/HGV from all other members of the Flaviviridae.
Thus, GBVIC/HGV appears to be distinct from enveloped

the GBV‑C什lGV genome is almost the same as that ofHCV

12‑year period. This result suggests that the mutation rate of(12‑14). However, unlike HCV; GBV‑C/HGV does not havevimses in general because they tend to encode a basic proteina hypeⅣariable reglOn in the entire gene. The highest rate ofthat mediates the packaging of the viral nucleic acid into themis‑sense mutation was found in the E2 region, Which wasvirion envelope. However, Schmolke et al. (6) reported that
GBV‑C/HGV builds classic viral particles displaylng E2

mi§‑sense mutation was seen in the core reglOn, nor in theenvelope protein on their outer surfaces by uslng a Panel ofNS5b reglOn. Moreover, no nucleotide mutation was obseⅣed

followed by the rate of mutations in El and NS4 reglOnS. No

eight monoclonal antibodies agalnSt the putative E2 proteinin the 5 ′‑UTR. Potential Asn‑linked glycosylation (N‑X‑T/S)

following DNA immunization. In addition, Xiang et al. (7)reported that GBV‑C/HGV particles included an extremely‑

motifs located within the El and E2 reg10nS Were foundto be conseⅣed entirely between the HGV‑lM71 and ‑lM68

low density virion particle (1.07 to 1.09 g/ml) and a nucleo‑

isolates.

capsid of〜日8 g/ml, as shown on a sucrose gradient. Their

56

GBV‑C/HGV RNA in serum reflects active viral infection,

Diagnostic assay

but the presence of anti‑E2 antibody has been reported tocorrelate with recovery from viral infection, because GBVIC/HGV E2 antibody was usually detected in individuals
without viral RNA and E2 antibody appeared in association

RT‑PCR is the only diagnostic tool to detect GBV‑C作iGVRNA. The nucleotide sequences in the 5'UTR and the 3′‑

UTR were highly conserved among different isolates ofGBV‑
C/HGV isolates (Fig. 2). Thus, these regions are the mostsuitable for RT‑PCRuse. An enzyme immunoassay for thedetection of antibodies to the E2 protein of GBV‑C/HGV has

with the cessation of viremia. These results suggest that thepresence of anti‑E2 of GBVIC/HGV indicates past infection･

been reported by several groups (15‑17). The presence ofa100
TAGCCACTATAG G TGGGTPNF21 61 (USA)GBC‑C(EA) (E. Africa)
GTl lOTAA(iAGAAG GTTAAGAT T CC TCTTG I 伝 CCT G CGG CGAGACCGCGCACG G T CCACAGGT 6 I TGGCCCTACCG GTGG GAATA‑‑‑6‑I‑‑‑‑I‑‑‑‑‑‑‑ll‑‑‑T‑‑一一一一一A‑‑‑一一一一一‑‑一一‑‑‑ll‑‑ll‑‑‑‑‑‑1(Japan)ClC

I

HGV‑lN71 (Japan)
GS l 93(Japan)GT230(Japan)

GBV‑C

一一GIG‑一一C一一C‑6‑C‑一一一C‑A‑AT‑AIGA‑AA‑‑‑‑‑‑一一‑一一(W. Afr i Ga)‑一一lG‑G‑‑‑ITIG‑C‑‑‑‑C‑Cl‑TIATA‑A‑AG‑AA‑一一一一一一一一

HGV‑GA128 (Ghana)120
PNF21 61
GBV‑C

140

(E.

Afr

呂去皿7.焼E::iica)一一一一一1‑‑‑‑‑‑‑‑‑‑A‑‑‑‑‑‑A‑AC一一一一一一一一一‑I‑‑‑‑‑‑‑‑

二二二二二二二二:!ヒ:二二二:二二:二二二i:二二:9二二二二二二二:二二二二::岩手主33 ‡霊g;:i :二::二:二二:二二::二:二二=二二二:二二二義‡=:二二:二::二二:こ:二二:
GBV‑C

(W.

HGV‑GA1

28

Af

200
TGTCTCTCTTGAC

160

AGGG CCCGACG T CAGGCTCGT CG TTAAACCGAGCCCG T TACCCACCT G G GCAAACGACGCCCACGT CGGTCCACG TCGCCCTT C

(USA)

(EA)

r

i

(Ghana)ca)‑‑‑C‑‑‑一一‑‑一一‑‑A一一一一6‑CT‑一一‑A‑lC‑‑‑‑一一一‑一一‑‑‑一一‑‑T‑C一一‑‑‑‑一一一‑‑I‑‑‑一一‑‑‑‑‑6‑CT‑‑‑‑A一一C‑‑一一‑一一一‑‑AH‑一一一C一一‑‑A‑‑‑一一一一一一一一一一Core
NF2. 6. (USA)
GBV‑C

(EA)

GTl 1 O(E.

CAATAGGCGT. AGCCGG訟GTTGACAAGGACCAG.G孟孟36ccGGGGGCT. ,GGAGA謡ACTCCAAG.CCCGCCCT琵gcGGTGGGCCGGGAAA73A
Afr(Japan)

HGV‑川71 (Japan)
GS l 93(Japan)GT230(Japan)GBV‑C(W. Afr i ca)

HGV‑GA128 (Ghana)ica)一一一一一‑I‑T‑.
一一一一一一lT

T‑

T‑‑‑‑‑‑一一‑I‑‑‑‑‑‑‑‑‑‑‑‑I‑‑‑‑6‑lGA‑‑AC‑CトTCAC‑‑T一一:T1‑‑‑‑‑I‑‑‑a‑‑‑‑‑‑‑‑ll‑‑‑‑‑‑‑I‑‑‑‑.

‑‑‑‑‑‑‑‑T‑.

‑‑‑‑‑‑‑‑‑‑‑‑‑‑C‑‑‑一一一一CIGC

一一一‑一一C‑

T‑T

G‑一一一一一一一一一一‑‑‑一一‑I‑‑‑‑‑‑‑T‑ll‑‑‑IT‑.一一一一‑‑‑‑‑‑‑‑‑‑‑6‑I‑‑I‑‑‑‑一一‑‑‑‑‑.
‑‑‑‑‑‑‑‑A.

‑/

GTl lO‑‑C.

T‑TG

T一一一一一一一一一一‑‑‑‑A‑6‑‑‑‑‑‑‑‑‑‑I‑‑C‑G

340

TCトT一一‑‑‑‑‑‑G‑G‑A‑‑C‑I

̲一一G一一A‑一一C‑‑T/‑‑‑‑‑‑一一一一一一一一一一一一一‑‑‑一一一C‑G320

PNF21 61 (USA)GBVIC(EA) (E. Africa)

T‑一一C‑C‑‑‑A‑‑‑‑‑一一‑‑‑Gl‑A‑‑‑C‑‑‑‑C‑‑T‑‑‑A‑‑‑‑lC‑‑‑‑‑‑‑I‑‑‑‑‑

̲一一6‑A…C

G

T

T

G

T

T‑一一‑一一

CA‑T‑‑‑一一一G

CG‑T一一一‑‑‑一一一AG

T‑‑‑‑‑‑

T‑一一一A‑‑GAG‑1G‑‑A‑‑C‑‑C‑CCGIT‑一一一‑‑GIA‑6‑‑‑‑‑‑‑‑

CAB‑lG‑‑A‑‑C‑‑T

GT

CG‑T‑T一一一‑‑6‑I‑G‑‑I‑‑‑‑360

TGGG GCCAC CCAG CT CCGCGGCGG CCTGCAGCCGGGG TAGCCCAAG仙TCCTT CGGGT GAGGGCGGGTG G 6‑‑‑‑‑‑‑‑‑‑‑‑‑‑一一‑‑‑‑‑‑‑一一一一一一‑一一一一一‑一一一一一GC/一一一1‑‑‑‑I‑I‑‑‑‑‑‑(Japan)

HGV一川71 (Japan)
GS1 93(Japan)GT230(Japan)

68V‑C(W. Afr i ca)

HGV‑GA1 28 (Ghana)b
1

PNF21 61(USA)

(9078)

20

40

60

80

1

00

TGAACT仙人TTCATCTGTTGCGGCAAG. GTCTGG‥ ‥ TGA. CT ‥ GATCATCACCGGAGGAGGTTCCCGCCCTCCCCGCCCCAG(iGGTCTCCCCGCTGG

GBC‑C(EA) (E. Africa)
GTl lO(Japan)HGV‑lH71 (Japan)
GS 1 93(Japan)GT230(Japan)GBV‑C

I‑1G‑C CCI T‑‑‑AA‑G G‑‑‑T TGA‑AC(W. Afr i ca)

140

PNF21 61

(USA)

160

180

200

GT仙人AAGGGCCCGGCCTTGGGAGGCATGGTGGTTACTAACCCCCTGGCAGGGTCAAAGCCTGATGGTGCTAATGCACTGCCACTTCGGTGGCGGGTCGC

G♭v‑C(EA) (E.Africa)
GT1 10(Japan)

HGV｣M71 (Japan)
GS1 93(Japan)GT230(Japan)PNF21 61

(USA)

220

240

260

280

G♭v‑C(EA) (E.Africa)
GTl lO(Japan)HGV‑LN71 (Japan)
GS柑3(Japan)GT230(Japan)PNF21 61

(USA)

320
CGGCCCGAAGGCCGGG T TCTACT

G♭v‑C(EA) (亡.Africa)
GTl lO(Japan)HGV‑lN71 (Japan)
GS柑3(Japan)GT230(Japan)300

TACCTTATAGCGTAATCCGTGACTACGGGCTGCTCGCAGAGCCCTCCCCGGATGGGGCACAGTGCACTGTGATCTGAAGGGGTGCACCCCGGGAAGAGCT

一一一一一A一一一一一一一一一一一一一一‑‑一一‑A‑‑一一1‑‑‑‑‑‑‑‑

Fig. 2.Alignment ofnucleotide sequcnccs inthc GBV‑C/HGV 5′UTR (a) and the 3'UTR (b)I Dashes indicate nuclcotides

identical to the top sequence. Sequences used for PCR primers are boxed･57

with hepatocellular carcinoma. On the other hand, GBV‑C/

Epidemiology and clinical significanceHGV RNA was also detected in 3 of 175 (1.7%) patients with
non‑viral liver diseases, including alcoholic liver disease, fatty

Retrospective studies in our laboratory have revealed that
GBV‑C/HGV RNA has been fわund in the semm or plasma ofliver, autoimmune hepatitis, prlmary biliary cirrhosis andvolunteer blood donors at afrequency of 1 ‑ I.4% in developed
countries and 8‑14･6% in developing countries (with the
exceptlOn Of l% in Nepal) (Table 1). GBV‑C/HGV has a highdmg‑induced hepatitis. We were unable to detect the GBV‑C/HGV genome within the livers of 54 patients with crypt0‑

genic liver diseases (26). Among 45 HGV‑positive patients,
GBV‑C/HGV coinfection withHBV and/or HCV were observedin 4 (8･9%) and 30 (66･7%), r?spectively, and in one (2･2%)

prevalence among patients receivlng hemodialysIS treatment(6.2‑26%), in patients who have received blood products, andin intravenous drug users (lVDU) (33‑75%). Thus it seems
likely that GBV‑C/HGV is transmitted parenterally･ ln addi‑

patient with a triple infection Involving these viruses (Tabletion, the virus is common in patients who are also infected

for GBVIC/HGV alone. However, there was no slgnificant

with other hepatitis viruses such as HBV (10%) and HCV

difference discovered among alanine aminotransferase levels(19%), perhaps because or similar modes of transmission･
Although GBV‑C/HGV RNA has been detected in 1‑1.4% of
healthy individuals and in 5‑52% of liver disease patients(ALT) in chronic hepatitis patients who were positive fわr2)I Ten (22･2%) of 45 HGV‑positive patients were positive

GBV‑C/HGV+HCV and HCV alone. Masuko et al. (21)reported that among GBV‑C/HGV‑positive blood donors and(3, 1 8120), the role ofGBVIC/HGV infection in liver diseases

hemodialysIS patients, there was no co汀elation between GBV‑

is not well understood. It appears that persistent infection withthis virus is common, but the data do not support an associa‑

C/HGV RNA levels and elevation in serum ALT. Furthermore,
no evidence has demonstrated that GBV‑C/HGV acquiredtion with significant liver injuries (2 1‑23). GBVIC/HGV has

during liver transplantation contributes to post‑Operative liver

also been seen in 7‑50% of patients with non‑A‑E acute orfunction test abnormalities or has any Impact On Clinicalfulminant hepatitis (1 8,22,24,25), but its Causal role has not

RNA was detected in 45 of 663 (6.8%) serum samples fromprogress. Neither age nor sex of patients was comlated tothe prevalence of GBV‑C/HGV infection in our study･ Only
14 of45 (3 1%) patients infected with GBVIC/HGV had apatients with liver disease (Table 2), and it was found in 2 ofhistory ofblood transfusions (18). The remaining 31 of45

been established. In the Japanese populatlOn, GBV‑C/HGV

145 (1.4%) healthy individuals (1 8). Among the liver disease(69%) GBV‑C/HGV‑positive patients had no history of blood

patients, GBV‑C/HGV RNA was present in 4 of 58 (6･9%)
with acute hepatitis, 1 6 of229 (7%) with chronic hepatitis, 5transfusions nor intravenous drug abuse. Mother‑to‑infanttransmission or GBV‑C/HGV does occur and the rate oftransmission is much higher than that ofHCV (27‑29)･ GBVIof58 (8.6%) with liver ci汀hosis, and in 17 of 139 (12.2%)

C/HGV infection in newboms induce persistent viremia, but
the infection is not accompanied by any symptoms of liverdisease.

Table 1. Prevalence ofGBV‑C/HGV among healthy
populations in various countries

Countryn

Positive fわr

HepatotropISm and extrahepatic replication of the virus

GBV‑C/HGV RNA (%)

1 1 1 1 3 2 2 54 2 0 0 0ノ 1 4 7 0 3 5 0 2 4 7 3 2 4 2 02(I.4)

ln order to understand the pathogenesis in the liver, it2(1.2)

is important to clarify whether or not GBV‑C/HGV is a1(I)hepatotroplC Virus. GBVC/HGV genome organization was
found to be similar to that ofHCV. Considering this genomic
resemblance, it can be assumed that GBV‑C/HGV replicates

1(1)

4(1)

similarly to HCV i.e., through negative‑strand RNA, the17 (8)

84 (14.6)

presence of which could be regarded as direct evidence ofviral replication. Based on this theory, Laskus et al. (30) have9(ll)shown that all livers obtained from 10 patients who were28 (12)seropositive fわr GBV‑C/HGV were negative fわr the presence3(10)Table 2. Prevalence ofHGV infection in paticntswith various liver diseases in Japan (1 985‑1996)
Co‑infcctcd with (%)

No. or HGV total HGV alone
subj

Acute hepatitis
Fulminant hepatitis

Chronic hepatitis
Liver ci汀hosis

HepatoccHular carcinoma

Alcoholic liver discasc

(%)

58

4 (6.9)

4

229

0

16

(7.0)

58

5 (8.6)17 (12.2)

50
21

Primary biliary cirrhosis

27

Fatty liver67

Drug‑induced

10

663

2 (4)
0

4/4 (loo)0

HCV

HBV+HCV

0

0

0

0

0

3/16(18.8)

13/16(81.2)

0l/5 (20)

I/5 (20)

2/5 (40)

2/17(ll.8)

0

15/17

2/2 (loo)

00000(88.2)

00000

O
1/5 (20)
0

00000

0

0

1

HBV

(%)

0

139

Autoimmunc hepatitis

Tota1

ects

(1.5)
0

45 (6.8)

0

1/1

(loo)

0

IO/45 (22.2)

4/45 (8.9)

30/45 (66.7)

l/45 (2.2)(ref. 18)58

of the GBV‑C/HGV‑RNA negative strand and only six wereExperimental infection in chimpanz:ees

positive fわr the presence of the positive strand. In striking

contrast, negative and positive strands of HCV RNA weredetected in the liver specimens from HCV‑seropositive patients.

lt is known that chimpanzees are susceptible to GBV‑C/
HGV infection. Bukh et al. (37) reported that the infection of

We also obtained the same results by PCR uslng liver tissue

GBVIC/HGV in experimentally infected chimpanzees was(data not shown). These findings imply that the liver is notcharacterized by the late appearance (weeks 10 and 1 1 a洗er

the prlmary replication site fわr GBV‑C/HGV Absence of

inoculation) of viremia that persisted throughout a 1 20‑Week

replication in liver tissue may explain the lack of influence

follow‑up･ However, desplte the relatively high titer of viremia,of GBV‑C/HGV on the progression toward liver disease. In

none of the chimpanzees developed hepatitis. This result

contrast, Madejon et al. (3 I) and Saito et al. (32) have shownindirectly that GBV‑C/HGV can replicate in the liver. The

suggests that persistence of GBV‑C/HGV and HCV mightoccur by different mechanisms. HCV has a hypervariable

genomic GBV‑C/HGV strand has been detected in peripheral

reglOn in the E2 protein that may circumvent the immune

blood mononuclear cells (PBMC)Jn addition, Fogeda et al.

system and permit viral persistence. On the other hand, a
hypervariable reglOn in GBV‑C/HGV was not identified.

(33) have shown the in vitro infection ofPBMC by GBV‑C/
HGV･ Recently, they reported the heterogeneityand quasispecies
composition of GBV‑C/HGV isolated from in vitro‑infected

Co‑infection in human immunoderICiency
virus (HIV)‑infected patients

PBMC and from sera, livers, and PBMC from chronicallyinfected patients. Their report showed the existence ofHighfrequency of exposure to HBV and HCV is seen indifferent GBV‑C/HGV variants with various levels of tissue
tropism (34)･ As regards diseases associated with viral infec‑

HIV‑infected subjects. To clarify the infection rate of GBV‑C/HGV in HIV‑infected patients, we investigated the preva‑
lence ofGBVIC/HGV, HBV, and HCV infections among 258

t10n･ Ellenrieder et all (35) have demons.trated an increased
prevalence ofGBV‑C什lGV ( 1 6･3%) in patlentS With low一grade

non‑Hodgkin's lymphoma. Further studies to evaluate theclinical and pathological significance of GBV‑C/HGV infec‑

patients who were seropositive for anti‑HIV antibody. The

serum samples were collected from patients in SoutheastAsia

tion in PBMC will be needed in order to clinically usefuland in the United States (U.S.). The results revealed that GBV‑

conclusions.

C/HGV RNA was detected in 74 (29%) of258 patients (Table3). On the other hand, 66 (26%) and 29 (11%) patients werepositive fわr HCV RNA and HBsAg, respectively. Among these

Relation to hepatocellularcarcinoma occurrence

patients, sexual contact was a more slgnificant predictor of

Hepatocarcinogeniclty lS another important key questionrisk of GBVIC/HGV than HCV infection (Table 4). Lefrere
et al. (38) and Yeo et al. (39) reported that patients with GBV‑C/HGV infection have higher CD4 T cell counts and camageof this vims is associated with a slower progression ofHIV

with regard to this virus. Tb elucidate the prevalence andassociation of GBV‑C/HGV infection among hepatocellular
carcinoma patients, we ca汀ied out a retrospective study byin situ detection ofHBV, HCV, and GBV‑C/HGV genome indisease in coinfected patients. Further careful studies are

265 hepatocellular carcinoma tissues from various countries

required to confirmthese results.

(36). HBV DNA and HCV RNA were detected舟equently in

carcinoma tissues. However, GBV‑C/HGV RNA was un‑

Existence ofviraJ genotypes and its geographic
distribution

detected in all tested specimens, desplte the inclusion of liver

specimens from 5 GBV‑C/HGV‑seropositive patients. Thissuggests that GBV‑C/HGV does not play an important role

Based on variation in nucleotide sequence of 5'‑UTR,
GBV‑C/HGV can be classified into three major genOtyPeS.

in hepatocarcinogenesis.

Table 3. Prcvalcncc ofHGV, HCV, and HBV in HIV‑infected patients

country nT::ebde, HGVRNA HCVRNA HBsAg G･C G･B
Vietnam

Myanmar62

89

Cambodia19(31)

25(28)

9

4

26

3

(12)

U.S.

72

23

(32)

258

74

(29)

(27)

29(33)(44)

Thailand

Tbtaト

17

6

15(17)

0

1

0

20

66

(10)

(1

3

(28)

(26)

4

29

5

fJHu 3 3 r一J ltJ I ヽ/ ー 一l

(8)

円川t川u

19(ll)
1)

O

(12)

0

2‑

0
0

4

(6)

1

(1)

(1

19

(7)

7

(3)

1(1)
2

(0.7)

Number in parenthesis indicate perccntages.

Table 4. Risk categorywithHCV, HGV, and HBV infections among HIV‑infcctcd

paticnts in SoutheastAsia
Risk categoryHCV(n‑46)

Heterosexual transmission
Commercial sex workers
Intravenous drug users

U nkn own

HGV
(n‑5

I

)

4 (9%)

13 (25%)

4

18

(9%)

(35%)

37 (80%)16 (31%)

I (2%)

4 (10%)

59

0

ー

(6)

I)

0

O2000

2 つJ 1 0

HBV(n‑25)

6 (24%)
5(20%)

10 (40%)4 (16%)

】

(0.4)

Type
1

Fig. 3. Phylogram generated by neighborJoining analysis orgcnctic distallCeS in the 5'UTR or HGV/GBV‑C isolates. Databasc‑derived GBV‑C/HGV isolates are presented in thin lettcrlng. The percentage of bootstrap rcplicatcs supportlngthcsc branches
is shown by the number glVen.

ln addition to this classification, we recently identified a novel

different countries: Ghana, U.S., Spain, Egypt, Nepal, Thailand,

genotype of GBV‑C/HGV in Southeast Asia and designatedMyanmar, Ⅵetnam, Cambodia, Japan, the PhilipplneS, andit as type 4 (Fig. 3) (40,41). In order to allow for the determina‑

Bolivia. The results revealed that type 1 was detected in 28 oftiop ofgenotypes 1 , 2, 3, and 4 ofGBV‑C/HGV, We developed

251 (1 1%) serum samples, mainly these from Ghana (Table 5).

a slmple and precise genotyplng System based on PCR uslng

Type 2 was distributed in 1 0 out of 1 2 countries investlgated,

type‑specific primers (42). The type‑Specific primers werebut mainly in the U.S., Spain, Egypt, Nepal, and Myanmar.

designed on the basis of the conserved nature of thoseType 3 was also distributed in various countries, but it wassequences within a genotype, and of their poor homology

mainly in Japan and Bolivia. Type 4 was prevalent mainly inwith the sequences derived from other GBV‑C/HGV genotypes.

Ⅵetnam, Myanmar, and Cambodia. Four of the 25 1 samples

The alignment of the sequences of PCR primers used in our( 1 ･6%) did not yield any specific products by PCR genotypipg,

PCR genotyplng System is shown in Fig. 4. By this newhence the samples were considered unclassified. ln Bolivla,

method, the frequency of infection with the four classified

our epidemiologlCal study revealed that GBV‑C/HGV RNA

major genOtyPeS Of GBV‑C/HGV was investlgated in 25 1

was present in 79 out of574 (13.8%) blood donors, whereas
HBsAg was detected in only 2 (0.3%), and no individuals

infected individuals and/or patients from the following I 260

Type‑spccirlC Sense primers (genotype)tlGl (sense)

Type
Isolate (Country)
OY lfrICa)

G38 (type 1)

66TCGTAAATCCCGGTCACC‑

GGGTCTTA16AGAIGGTT人IGA^V〇‑‑‑‑T‑‑(Ghana)一一‑‑一一1‑1㌻屯一一一C‑一一6(Ghana)‑‑‑‑‑‑G+‑C‑一一一G(Ghana)一一一‑‑‑‑ら‑6‑‑Cl‑C‑G(Ghan8)
PNF2161(U S A )RIO291(U

S

A‑‑‑‑‑‑‑‑‑‑GG‑‑一一一位.一一一一A‑TC‑‑‑‑‑一一‑)‑(JDpan)

C88

一一GG‑

‑

‑T一

TH24

(Tha i I and)

NE256

(Nep8 1 )(Ky8mar)

GBV‑C(El)(E AfrlGa)

CB9(Canbod l a)(lyarrFIa r )VT58(V I etnaql)(Japan)(Japan)N71

GS l 85(Japan)NE184(N叩81)

K 1 789
VT2‑
一一

PH1 19
BL249‑‑‑‑‑一一‑‑I‑‑‑G

G‑‑A‑TC

一1‑G‑‑一一6‑‑‑‑A‑TC‑

1‑6‑‑‑‑‑‑‑‑‑I‑‑‑‑‑‑‑‑‑T一‑‑‑一一‑‑一一一T一‑‑一一‑‑‑‑‑‑‑T1

Sl)(Ph‖岬p川eS)(一yarTnar )(NyBrqar )‑‑‑G‑‑‑‑‑A‑ITC

A‑‑‑‑‑ATT‑‑一一6

A‑‑‑T‑‑hT‑‑T

A‑‑‑‑‑‑‑ATT‑‑‑‑8トMT‑‑AIT‑一一一T

A‑‑一一一一ATT‑‑‑‑6A‑lCT‑A‑T‑一一一T

A‑‑C‑一一ATT‑‑‑一一G

A‑‑‑T‑A‑T‑‑‑T

A‑‑‑ATT

A‑‑‑T‑A‑T‑‑Tl

A一一T‑A‑T‑lT

l

A一一

1

A‑T‑‑T

ATT‑‑

‑ATT

$

T一一一‑‑TC‑‑ぺ6
T‑‑‑‑I‑TC‑‑‑GG

T‑

T‑‑‑TC‑‑lGG‑

1‑‑6‑I‑+A‑TC‑‑‑I‑‑6‑T…‑G‑

一一一6‑‑‑一冬一一‑A‑TC‑‑‑‑16‑I‑‑‑‑6‑‑A‑‑TC‑‑‑‑‑I‑‑TG一一一C一一一6‑‑ら‑‑‑‑G‑lA‑TC‑‑‑‑‑‑‑‑T‑TG‑‑‑‑6

一一一G一一1‑I‑‑ら‑‑A‑TC‑‑‑‑‑‑‑‑6‑T6‑‑‑C‑‑‑G‑‑ぺ一一‑一一一G‑A‑TC

一一1‑‑‑‑‑6‑T6‑‑‑‑G(V I etnam)‑

一一一6‑‑‑‑‑8‑‑A‑lTC‑(V 1 8tnan)‑

1‑‑G‑‑一一1‑‑6‑A‑TC‑‑一一一一一6‑T61‑‑‑‑6‑‑G‑TG1

TC‑166‑‑‑‑‑1‑‑I‑1‑‑‑C‑

T‑‑‑‑一一一TC‑‑ぺ6

一一

61‑‑‑CA‑一丁1‑

6‑‑‑CA‑‑T
6｣トTG一一C一一G

一一一一‑一一G‑TG‑‑C‑‑6‑

T‑‑‑‑TC‑‑づG

GITG‑ぺ‑G‑‑‑‑‑‑C‑‑‑‑‑‑‑‑‑‑‑一一‑‑‑一一‑‑Hl‑‑TC‑li6

TC‑1iG

一一一一一一一一6‑T6‑‑C一一一6

T‑‑6

TC‑lGG‑GIT‑C‑a

‑‑‑‑

6

‑lTT

T

‑6‑TT‑‑C‑一一6

一一一‑6‑‑

一‑一一‑‑‑‑ATT‑‑‑GT

一一6‑‑‑‑‑tト一一一1‑TC(V letnan)

A‑‑‑T‑‑AIT‑‑T

T‑‑6‑‑‑‑‑‑‑6‑‑A‑TC‑‑6‑‑‑‑‑ぺ‑‑A‑TC

T‑一一一G

ATT‑‑一一GA‑‑‑‑‑‑‑1トTT‑C‑6‑‑‑‑‑‑‑‑6‑TT一一一C‑‑G

一一

A

T

A‑‑‑A‑T一一‑T‑G‑TT‑C‑‑6

一(lyarm r)

A‑‑‑‑AT

A‑T‑A‑TG‑TT一一一七一‑6‑‑‑(LlyBrYn8 ( )A‑Cl‑C‑lTC‑‑‑‑CGA‑‑T‑A‑T‑‑‑T‑‑‑‑‑‑6‑T6‑‑‑0‑‑‑G(恥8†¶a r )A‑C‑TC‑一一一CG‑‑一一6‑‑‑‑‑‑‑(ト一一‑A‑TC(V l etnan)lC

A‑‑CA‑a‑I‑‑‑も一‑T‑‑‑‑‑‑(V I etnanl)

A‑C‑‑‑TC‑I‑‑瑠A一一CT1‑

一一‑‑T‑‑‑‑一‑‑6‑‑‑‑‑6‑IA‑lTC‑1(V柑tnyFl)

A一一CT‑‑一一T

一一一一T‑‑‑‑‑‑‑6‑‑‑‑‑1ト一一一A‑TC‑1

A‑C‑‑TC‑一七I‑

一一‑a‑‑‑‑･6‑‑A一一TC‑

A‑CT‑‑‑‑‑T

一一一一T一一一‑一一一一一‑

A=

A一一一一1‑‑TC‑‑CG‑‑‑‑1‑‑‑G‑TT一一一1‑‑a‑a‑‑‑6‑‑A‑TC

lGTTGACAAGGACCAGTGGG

一一C‑T‑‑‑‑‑

A‑‑6一一七一TC‑‑‑i

一C‑I‑‑‑‑‑‑8‑TT‑‑‑‑6‑‑‑6‑‑‑‑‑‑6‑‑‑A‑ITC

GGTCCACGTCGCCCTTCAATGGGTYAIGGCICCTCTTA‑T‑‑‑一一一6‑TT‑‑‑‑‑a‑

HGIR (antiseTtSe)

TGGTClAGGI∝CTCTG

一一16‑‑‑‑‑‑8‑‑A‑TC

T1

HG2R (antisense)

A‑‑‑T一丁一‑‑‑‑‑‑‑6‑‑‑A一一TC‑6‑TT一一‑‑‑‑6Gヰo (type 4)

A‑CT‑

一一･･6‑‑‑‑+‑‑A一一TC‑一一6‑‑‑‑6‑‑A‑TC(lyaTYna r )(Ky8rTna r)

トー1‑TC‑‑1(Bol川Ia)

NY 1 O7

一66‑小一1‑TC

一‑‑I‑(J叩Jln)(U‑‑‑8‑‑‑‑‑‑6‑‑‑A‑‑TC

一‑‑‑T一(V i etnirb)

U130

一一6‑‑‑‑‑6‑‑A‑TC‑‑IG一一‑‑8‑‑‑ll‑‑TC

NY108

l

‑‑‑一一一一一一‑‑‑‑一‑‑I一l‑‑‑I‑‑‑‑‑

NY293

S一一一一A‑TC
一一一6‑I‑‑‑6‑‑A‑lTC‑I‑8‑‑‑‑‑‑6‑‑A‑‑TC(C都bod J a)

GT230

‡一一七16‑8‑6‑‑‑‑TIC‑‑‑‑‑‑‑GJi一一lC‑‑G(6hana)GTl lOG41 (type 3)

G35 (type 2)

CA‑‑T

G‑

CA‑‑T

‑‑‑‑ A‑‑I ‑‑ A‑‑‑伝‑‑‑‑C1‑‑TG‑

CA一一一T

6‑‑‑‑‑‑‑T‑‑T
6‑‑一丁一一一一丁一一一T
G‑‑‑‑‑‑T一一一一T

6‑‑ド‑‑‑一丁

‑G

a‑T‑

‑T

G‑‑‑T‑‑‑T1‑T‑一一‑‑

TT‑1‑‑‑‑‑‑‑‑TT‑‑‑‑‑‑I‑TT‑‑‑
‑

TC‑‑‑

‑I‑‑TC‑‑一一‑‑‑‑‑‑‑TT‑‑

Fig. 4. Alignment ofnuclcotidc sequences inthe 5'UTR ofGBV‑C/HGV isolates andthc positions of universal andtype‑specific pnmers. A total of 39 isolates kom databases were compared to design the sequence of the PCR primers. Conserved

sequenceswithin each genotype are boxed. Dashes indicate nucleotides identical tothe top sequence used forthe PCRprimers. Conserved sequcnceswithin each genotype are shown in boxes.

(ref. 42)

positive for HCV RNA were found (43). Interestingly, We
found that the major genotype of GBV‑C/HGV in infected

Conclusion

Bolivians istype 3, i.e., theAsian type, followed bytype 2.
migrants Who mlgratedfromAsia to South America, including

An understanding of the biology and clinical significanceor GBV‑C/HGV is evolving. Increaslng evidence suggeststhat GBV‑C/HGV is not a slgnificant cause of liver disease,

Bolivia, a long tlme ago. ln fact, people ofMongoloid descentalthough it may be capable of inducing hepatitis in a subset

account for more than half of the general population in

orpatients. GBV‑C/HGV is probably "ha‑less" to its host,

Bolivia. Similar genotypic distributions are seen in thedue to a long history of mutual adaptation. Followlng themolecular epidemiology of human T‑cell leukemia virus (44).

discovery of the GBV‑C/HGV, the genome of a novel DNA
virus, designated as the TT virus (TTV), was discovered

This result may be correlated to the translocation of Mongoloid

Table 5. Gcnotypic distribution ofGBV‑C/HGV in different countries, as dctcrmined by PCR using
thc genotype‑Specific pr)mcrs
G en otypc
Coun

try

n
1

Ghana

22

U.S.

14

Spain

16

22

(100)

0

2

(14)

ll

0

Egypt

39

3

Ncpa1

7

0

Thailand

2

(8)

3

3

(79)

l

16(100)

0

2+3

0

(7)

36

(92)

0

4

(57)

3

3

(loo)

0

0

4

0

(43)

000000210

3+4

0 0 O 0 0 0 O一1 0 0

0

0

0

0

0

O

0

0

27

(58)

5

(ll)

11

(23)

Victnam

28

0

5

(18)

4

(14)

17

(60)

Cambodia

4

0

3

(75)

Japan

20

1

0

1

ヽ ー ヽ13llU 4 421000

PhilipplnCS

2

Bolivia

49

Tbta1

251

28

0

(70)

0

0

(1

14

18(37)

1)

124

(49)

2

55

0

2

(loo)

26(53)(22)

Number in parenthesis indicate perccntages. *Unclassified

61

(10)

0

0

29

円Ju fJu

4 4 ー ヽ1

(25)
nlu

(5)

*

0

0

47

l

UC

0

O

Myanmar(5)2+4000000000100

円川川u

ヽノ

5

0

4(8)

(12)

5‑

9

1 (2)

(4)

(ref. 42)recently from a patient with post‑transfusion non‑B, non‑C

Characterization of hepatitis G virus (GB‑C virus)

acute hepatitis by reprePentational difference analysis (45)･particles: evidence for a nucleocapsid and expression of

It appears to be a ubiqultOuS Virus. The TTV infection does

sequences upstream of the El protein. J. Ⅵro1., 72, 2738‑

not appear to have a slgnificant effect on liver disease and2744.

therefore it also could be considered as an "orphan virus".

8. Rolls, M. M., Webster, P., Balba, N. H. and Rose, J. K.

However, Continued study of these novel vimses in non‑liver( 1 994): Novel infectious particles generated by expres‑related clinical settlngS Will help to determine whether thesion of the vesicular stomatitis virus glycoprotein froma self‑replicatlng RNA. Cell, 79, 497‑506.

virus contributes to other human diseases with unknown
etiology.

9. Simons, ∫. N., Desai, S. M., Schultz, D. E., Lemon, S.

M. and Mushahwar, 1. K. (1996): Translation initiationin GB viruses A and C: evidence f♭r intemal ribosome

ACKNOWLEDGMENTS

entry and implications f♭r genome organization. ∫. Ⅵro1. ,I thank Dr. Takeshi Kurata (Deputy Director‑General) and
Dr. Tetsutaro Sata (Director of Pathology) of the National96, 6126‑6135.

10. Rijnbrand, R.,Abell, G. and Lemon, S. M. (2000): Muta‑

Institute of Infectious Diseases for their continuous encourage‑
ment during this study. Drs. Hideo Naito, Tamiko Saito, Namitional analysts Ofthe GB virus B intemal ribosome entry

Konomi, Tomoko lnami, Naoto Aiba, Shigeki Hayashi, Yutaka

日. Nakao, H., Okamoto, H., Fukuda, M., Tsuda, F., Mitsui,

Takebe, Koichi lshikawa, Khim Maung Win, Vo Xuan Ouang,

T･, Masuko, K., Iizuka, H., Miyakawa, Y. and Mayumi, M.

and David Y Zhang are to be thanked fわr their kind collabora‑(1997): Mutation rate of GB virus C/hepatitis G virus

site. ∫. Viro1., 74, 773‑783.

over the entire genome and in subgenomic reglOnS. Vi‑

tion.

rology, 233, 43‑50.
12. Ogata, N., Alter, H. ∫., Miller, R. H. and Purcell, 良. H.

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