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ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2008 August 14; 14(30): 4725-4734

 EDITORIAL

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; 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 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 hepatiti[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 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.

 

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 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 13610 blood donors described in 30 reports revealed viral RNA in 649 (4.8%) of cases. These included Caucasians (4.5%), Asians (3.4%), and Africans (17.2%)[42]. The authors propose to test blood samples due to the high risk of infection with GBV-C[42,43].

   An investigation of the prevalence of HGV among north-eastern Thai blood donors carrying HBsAg and anti-HCV revealed the high frequency of GBV-C RNA (10% and 11%, respectively) in the co-infected as compared with the controls (0%)[44].

   The development of an anti-E2 detection method has promoted a complete definition of the prevalence of GBV-C. E2 antibodies are several times more frequently detectable than RNA in blood donors (Table 2)[8,33,38,40,41,45].

   GBV-C is a parenterally transmitted infection[28-30]. The first verification of this fact were the experiments dealing with inoculation of primates with the blood of the surgeon who fell ill in 1966[2]. Cases of acute posttransfusion hepatitis along with the enhanced activity of serum aminotransferases and the detection of blood GBV-C RNA in the absence of other markers of viral hepatitides has been documented[3,31,32]. Indirect evidence that HGB is parenterally transmitted lies in its more frequent detection in the groups at higher risk for infection with hepatitis viruses by similar routes of transmission (Table 3)[8,11,34,36,38,41,46-51], as well as the increased risk for infection in patients treated with multiple hemodialysis procedures and higher units of transfused blood products[33-35].

   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 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, but also genetic predisposition to prolonged viral circulation is suggested. 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 , and 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 activities[87]. GBV-C-associated hepatitis runs with normal 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 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 -glutamyl transpeptidase (-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 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 with HBV and/or HCV as compared in those with HBV+GBV-C and/or HCV+GBV-C[104-106]. Patients with CHC alone and in combination with HGV have been meticulously examined. By examining 420 patients, Tanaka et al revealed a higher ALT activity in the group 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 -interferon (-IFN) to patients at a dose of 3000000 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 -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 -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 termination, 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. 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-1, MIP-1), 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.

 

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                                                                                           S- Editor  Zhong XY    L- Editor  Lalor PF    E- Editor  Yin DH

 


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