The GB Viruses: An Update of Their Biology, Molecular Virology and Significance

Abstract

In the quest to identify further viruses associated with hepatitis, three new viruses were cloned and assigned to the Flaviviridae family in the mid‐1990s. These were named the GB virus A (GBV‐A), GBV‐B and GBV‐C/hepatitis G virus (HGV). A more recent member is GBV‐D. Of these, GBV‐B, which is not a human pathogen, is associated with hepatitis in tamarins (Saguinus sp). GBV‐A, ‐C/HGV and ‐D, in turn, infect primates, humans and frugivorous bats. These three viruses, unlike GBV‐B, are characterised by the lack of an identifiable core protein and do not appear to be associated with any signs and symptoms of disease. Moreover, the liver does not appear to be the primary site of replication for GBV‐A and GBV‐C/HGV. Instead, the lymphoid system seems to be their primary target. The current review deals with what is known of the natural history, virology and molecular biology of these viruses.

Key Concepts:

  • GBV‐A, GBV‐B, GBV‐C/HGV and GBV‐D are members of the Flaviviridae family.

  • GBV‐B causes hepatitis only in tamarins (Saguinus sp).

  • GBV‐A, ‐C/HGV and ‐D are not associated with hepatitis.

  • GBV‐A and ‐C/HGV appear to replicate primarily in lymphocytes.

  • GBV‐A, ‐C/HGV and ‐D do not have an identifiable core‐encoding region in their genome.

  • GBV‐A and ‐C/HGV cause persistent infection.

  • Loss of GBV‐C/HGV viraemia is associated with the development of anti‐E2 antibodies.

Keywords: GB virus; GB inoculum; Flaviviridae; molecular biology; tamarins; experimental animals; RNA genome

Figure 1.

Genomic organisation of the GB viruses in comparison with HCV, showing the 5′ and 3′ NCRs flanking the polyprotein‐encoding ORF. The structural and NS proteins are labelled accordingly, whereas the cleavage sites are indicated with arrows; host signalase cleavages are shown in green and orange arrows, and those by virally encoded enzymes in blue (NS2/NS3) and brown (NS3/NS4A). Undefined or unspecified region/proteins are denoted with a question mark.

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References

Beames B, Chavez D, Guerra B et al. (2000) Development of a primary tamarin hepatocyte culture system for GB virus‐B: a surrogate model for hepatitis C virus. Journal of Virology 74: 11764–11772.

Belyaev AS, Chong S, Novikov A et al. (1998) Hepatitis G virus encodes protease activities which can effect processing of the virus putative non‐structural proteins. Journal of Virology 72: 868–872.

Benureau Y, Warter L, Malcolm BA and Martin A (2010) A comparative analysis of the substrate permissiveness of HCV and GBV‐B NS3/4A proteases reveals genetic evidence for an interaction with NS4B protein during genome replication. Virology 406: 228–240.

Berg T, Müller AR, Platz KP et al. (1999) Dynamics of GB virus C viremia early after orthotopic liver transplantation indicates extrahepatic tissues as the predominant site of GB virus C replication. Hepatology 29: 245–249.

Bukh J, Apgar CL and Yanagi M (1999) Toward a surrogate model for hepatitis C virus: an infectious molecular clone of the GB virus‐B hepatitis agent. Virology 262: 470–478.

Bukh J and Apgar CL (1997) Five new or recently discovered (GBV‐A) virus species are indigenous to New World monkeys and may constitute a separate genus of the Flaviviridae. Virology 229: 429–436.

Choo Q‐L, Kuo G, Weiner AJ et al. (1989) Isolation of a cDNA clone derived from a blood‐borne non‐A, non‐B viral hepatitis genome. Science 244: 359–364.

Epstein JH, Quan PL, Briese T et al. (2010) Identification of GBV‐D, a novel GB‐like flavivirus from old world frugivorous bats (Pteropus giganteus) in Bangladesh. PLoS Pathogens 6: e1000972.

Fogeda M, Navas S, Martín J et al. (1999) In vitro infection of human peripheral blood mononuclear cells by GB virus C/Hepatitis G virus. Journal of Virology 73: 4052–4061.

George SL, Varmaz D and Stapleton JT (2006) GB virus C replicates in primary T and B lymphocytes. Journal of Infectious Diseases 193: 451–454.

Ghibaudo D, Cohen L, Penin F and Martin A (2004) Characterization of GB virus B polyprotein processing reveals the existence of a novel 13‐kDa protein with partial homology to hepatitis C virus p7 protein. Journal of Biological Chemistry 279: 24965–24975.

Grace K, Gartland M, Karayiannis P et al. (1999) The 5′ untranslated region of GBV‐B shows functional similarity to the internal ribosome entry site of hepatitis C virus. Journal of General Virology 80: 2337–2341.

Jacob JR, Lin KC, Tennant BC and Mansfield KG (2004) GB virus B infection of the common marmoset (Callithrix jacchus) and associated liver pathology. Journal of General Virology 85: 2525–2533.

Karayiannis P, Hadziyannis SJ, Kim J et al. (1997a) Hepatitis G virus infection: clinical characteristics and response to interferon. Journal of Viral Hepatitis 4: 37–44.

Karayiannis P and McGarvey MJ (1995) The GB hepatitis viruses. Journal of Viral Hepatitis 2: 221–226.

Karayiannis P, Petrovic LM, Fry M et al. (1989) Studies of GB hepatitis agent in tamarins. Hepatology 9: 186–192.

Karayiannis P, Pickering J, Chiaramonte M and Thomas HC (1997b) Hepatitis G virus infection. Lancet 359: 954.

Kim JP, Linnen J, Wages J et al. (1997) Molecular cloning and characterisation of hepatitis G virus (HGV). In: Rizzetto M, Purcell RH, Gerin JL and Verme G (eds) Viral Hepatitis and Liver Disease, pp. 340–346. Turin: Edizione Minerva Medica.

Laskus T, Radkowski M, Wang LF, Vargas H and Rakela J (1997) Lack of evidence for hepatitis G virus replication in the liver of patients co‐infected with hepatitis C and G viruses. Journal of Virology 71: 7804–7806.

Laskus T, Radkowski M, Wang LF, Vargas H and Rakela J (1998) Detection of hepatitis G virus replication sites using highly strand‐specific Tth‐based reverse transcriptase PCR. Journal of Virology 72: 3072–3075.

Laxton CD, McMillan D, Sullivan V and Ackrill AM (1998) Expression and characterisation of the hepatitis G virus helicase. Journal of Viral Hepatitis 5: 21–26.

Leary TP, Muerhoff AS, Simons JN et al. (1996) Sequence and genomic organisation of GBV‐C: a novel member of the Flaviviridae associated with human non‐A‐E hepatitis. Journal of Medical Virology 48: 60–67.

Linnen J, Wages J, Zhang‐Keck ZY et al. (1996) Molecular cloning and disease association of hepatitis G virus: A transfusion transmissible agent. Science 271: 505–508.

Linnen JM, Fung K, Fry KE et al. (1997) Sequence variation and phylogenetic analysis of the 5′ terminus of hepatitis G virus. Journal of Viral Hepatitis 4: 293–302.

Martin A, Bodola F, Sangar DV et al. (2003) Chronic hepatitis associated with GB virus B persistence in a tamarin after intrahepatic inoculation of synthetic viral RNA. Proceedings of the National Academy of Sciences of the USA 100: 9962–9967.

McGarvey MJ, Iqbal M, Nastos T and Karayiannis P (2008) Restricted quasispecies variation following infection with the GB virus B. Virus Research 135: 181–186.

McLinden JH, Kaufman TM, Xiang J et al. (2006) Characterization of an immunodominant antigenic site on GB virus C glycoprotein E2 that is involved in cell binding. Journal of Virology 80: 12131–12140.

Muerhoff AS, Dawson GJ and Desai SM (2006) A previously unrecognized sixth genotype of GB virus C revealed by analysis of 5′‐untranslated region sequences. Journal of Medical Virology 78: 105–111.

Muerhoff AS, Leary TP, Simons JN et al. (1995) Genomic organisation of GB viruses A and B: two new members of the Flaviviridae associated with GB agent hepatitis. Journal of Virology 69: 5621–5630.

Nam JH, Faulk K, Engle RE et al. (2004) In vivo analysis of the 3′ untranslated region of GB virus B after in vitro mutagenesis of an infectious cDNA clone: persistent infection in a transfected tamarin. Journal of Virology 78: 9389–9399.

Parks WP, Melnick JL, Voss WR et al. (1969) Characterisation of marmoset hepatitis. The Journal of Infectious Diseases 120: 548–559.

Pessoa MG, Terrault NA, Detmer J et al. (1998) Quantitation of hepatitis G and C viruses in the liver: evidence that hepatitis G virus is not hepatotropic. Hepatology 27: 877–880.

Pickering JM, Thomas HC and Karayiannis P (1997) Predicted secondary structure at the 3′ end of the HGV 5′ UTR consistent with an IRES. Journal of Viral Hepatitis 4: 175–114.

Prati D, Zanella A, Bosoni P et al. (1998) The incidence and natural course of transfusion‐associated GB virus C/hepatitis G virus infection in a cohort of thalassaemic patients. Blood 91: 774–777.

Radkowski M, Wang LF, Cianciara J, Rakela J and Laskus T (1999) Analysis of hepatitis G virus/GB virus C quasispecies and replication sites in human subjects. Biochemical and Biophysical Research Communications 258: 296–299.

Ross RS, Viazov S, Schmitt U et al. (1998) Distinct prevalence of antibodies to the E2 protein of GB virus C/hepatitis G virus in different parts of the world. Journal of Medical Virology 54: 103–106.

Sbardellati A, Scarselli E, Verschoor E et al. (2001) Generation of infectious and transmissible virions from a GB virus B full‐length consensus clone in tamarins. Journal of General Virology 82: 2437–2448.

Scarselli E, Urbani A, Sbardellati A et al. (1997) GB virus B and hepatitis C virus NS3 serine proteases share substrate specificity. Journal of Virology 71: 4985–4989.

Schlauder GG, Dawson GJ, Simons JN et al. (1995) Molecular and serologic analysis in the transmission of the GB hepatitis agent. Journal of Medical Virology 46: 81–90.

Schlueter V, Schmolke S, Stark K et al. (1996) Reverse transcription‐PCR detection of hepatitis G virus. Journal of Clinical Microbiology 34: 2660–2664.

Semprini AE, Persico T, Thiers V et al. (1998) Absence of hepatitis C virus and detection of Hepatitis G virus/GB virus C RNA sequences in the semen of infected men. Journal of Infectious Diseases 177: 848–854.

Sheng L, Soumillion A, Peerlinck K et al. (1998) Anti‐hepatitis G E2 antibody detection and its relation to serum HGV‐RNA in patients with clotting disorders: high prevalence of HGV infection and spontaneous remission. Thrombosis and Haemostasis 79: 752–755.

Simons JN, Desai SM, Schultz DE et al. (1996) Translation initiation in GB viruses A and C: Evidence for internal ribosome entry and implications for genome organisation. Journal of Virology 70: 6126–6135.

Simons JN, Leary TP, Dawson GJ et al. (1995b) Isolation of novel virus‐like sequences associated with human hepatitis. Nature Medicine 1: 564–569.

Simons JN, Pilot‐Matias TJ, Leary TP et al. (1995a) Identification of two flavivirus‐like genomes in the GB hepatitis agent. Proceedings of the National Academy of Sciences of the USA 92: 3401–3405.

Stapleton JT, Chaloner K, Martenson JA et al. (2012) GB virus C infection is associated with altered lymphocyte subset distribution and reduced T cell activation and proliferation in HIV‐infected individuals. PLoS One 7: e50563.

Stapleton JT, Foung S, Muerhoff AS et al. (2011) The GB viruses: a review and proposed classification of GBV‐A, GBV‐C (HGV), and GBV‐D in genus Pegivirus within the family Flaviviridae. Journal of General Virology 92: 233–246.

Takikawa S, Engle RE, Emerson SU et al. (2006) Functional analyses of GB virus B p13 protein: development of a recombinant GB virus B hepatitis virus with a p7 protein. Proceedings of the National Academy of Sciences of the USA 103: 3345–3350.

Targett‐Adams P, Schaller T, Hope G et al. (2006) Signal peptide peptidase cleavage of GB virus B core protein is required for productive infection in vivo. Journal of Biological Chemistry 281: 29221–29227.

Thomas DL, Vlahov D, Alter HJ et al. (1998) Association of antibody to GB virus C (hepatitis G virus) with viral clearance and protection from re‐infection. Journal of Infectious Diseases 177: 539–542.

Xiang J, Klinzman D, McLinden J, Jordan EL and Stapleton JT (1998) Characterisation of hepatitis G virus (GBV‐C) particles: evidence for a nucleocapsid and expression of sequences upstream of the E1 protein. Journal of Virology 72: 2738–2744.

Xiang J, Wunschmann S, Schmidt W, Shao J and Stapleton JT (2000) Full‐length GB virus C (Hepatitis G virus) RNA transcripts are infectious in primary CD4‐positive T cells. Journal of Virology 74: 9125–9133.

Zampino R, Pickering J, Iqbal M et al. (1999) Hepatitis G virus/GBV‐C persistence: absence of hypervariable E2 region and genetic analysis of viral quasispecies in serum and lymphocytes. Journal of Viral Hepatitis 6: 209–218.

Zhang W, Chaloner K, Tillmann H, Willams CF and Stapleton JT (2006) Effect of early and late GB virus C viraemia on survival of HIV‐infected individuals: a meta‐analysis. HIV Medicine 7: 173–180.

Further Reading

Bhattarai N and Stapleton JT (2012) GB virus C: the good boy virus? Trends in Microbiology 20: 124–130.

Lemon SM, Walker CM, Alter MJ and Yi MK (2012) Hepatitis C virus. In: Fields BN, Knipe DM and Howley PM (eds) Fields Virology, 5th edn, pp. 1253–1304. Philadelphia: Lippincott Williams & Wilkins.

Lindenbach BD, Thiel HJ and Rice CM (2007) Flaviviridae. In: Fields BN, Knipe DM and Howley PM (eds) Fields Virology, 5th edn, pp. 1101–1152. Philadelphia: Lippincott Williams & Wilkins.

Mohr EL and Stapleton JT (2009) GB virus type C interactions with HIV: the role of envelope glycoproteins. Journal of Viral Hepatitis 16: 757–768.

Reshetnyak VI, Karlovich TI and Ilchenko LU (2008) Hepatitis G virus. World Journal of Gastroenterology 14: 4725–4734.

Simmonds P (2001) The origin and evolution of hepatitis viruses in humans. Journal of General Virology 82: 693–712.

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Karayiannis, P(Apr 2013) The GB Viruses: An Update of Their Biology, Molecular Virology and Significance. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023614]