healthy blood donors in most developed countries are viraemic at the time of blood donation, and another 5– 13 % have anti-E2 antibodies, indicating prior infection (Blair et al., 1998; Gutierrez et al., 1997; Pilot-Matias et al., 1996a; Tacke et al., 1997). In developing countries, blood donor viraemia prevalence is higher, approaching 20 % in some regions of the world (reviewed by Mohr & Stapleton, 2009; Polgreen et al., 2003). Among people with blood-borne or sexually transmitted infections, GBV-C/HGV is more prevalent (Scallan et al., 1998), and in one study of human immunodeficiency virus (HIV)-infected homosexual men, 39.6 % had viraemia and 46 % had E2 antibody detected for a total exposure rate of 85.6 % (Williams et al., 2004). These data, in combination with the blood donor studies, suggest that at least one quarter of the world’s population has been infected with GBV-C/HGV. In contrast, sexual transmission of HCV is inefficient, and most transmission occurs through exposure to blood or from mother to child during birth (Lauer & Walker, 2001). Of the non-human GB viruses, GBV-A and GBV-B can be experimentally transmitted to different species of New World monkeys via the blood-borne route. It is not clear if sexual, vertical or other modes of transmission occur for these two viruses. Following identification, GBV-D RNA was detected using real-time PCR methods in 5 of 98 (5 %) P. giganteus (bat) serum samples in a population of wild bats in Bangladesh. No further epidemiological studies have been reported. Although there are no data to indicate the mode of GBV-D transmission, viral RNA was identified in the saliva in one of the five bats with viraemia, suggesting horizontal and potentially zoonotic transmis- sion, and none of the viraemic bats had GBV-D RNA detected in urine (Epstein et al., 2010). Pathogenesis and cellular tropism HCV and GBV-B viruses are primarily detected in the liver of naturally infected humans and experimentally infected New World monkeys, respectively, although viral genomes can be found in peripheral blood mononuclear cells (PBMCs) in some infected hosts (Beames et al., 2000; Bright et al., 2004; Bukh et al., 2001a; Fong et al., 1991; Ishii et al., 2007; Jacob et al., 2004; Laskus et al., 1997b; Simons et al., 1995b). GBV-B has not been identified in New World primates except in experimentally infected animals. High levels of virus are present in the blood, typically between 1–10 million genome equivalents ml21 for HCV and 102100 million genome equivalents ml21 for GBV-B. GBV-A and GBV-A-like agents, and GBV-C/HGV viruses are present in low or non-detectable levels in the liver of infected hosts, and the viruses are more readily detected in circulating lymphocytes, suggesting that GBV-A and GBV- C could be lymphotropic, and not hepatotropic (Kobayashi et al., 1999; Laskus et al., 1997a, 1998; Pessoa et al., 1998; Radkowski et al., 1999, 2000; Simons et al., 2000; Tucker http://vir.sgmjournals.org The GB viruses et al., 2000). Although replication of HCV and GBV-C/ HGV in hepatocyte and lymphocyte cell culture has been described, HCV and GBV-B replication is optimal in cultured cells of hepatocyte origin (Beames et al., 2000; Lanford et al., 1994; Lindenbach et al., 2005a; Wakita et al., 2005; Zhong et al., 2005). In contrast, GBV-C/HGV replication is most frequently accomplished in PBMCs, including the CD4 and CD8 T lymphocyte subsets, and B lymphocytes (Fogeda et al., 1999; George et al., 2003, 2006; Xiang et al., 2000). Cell culture replication of GBV-A or GBV-D has not been described. Serum concentrations of GBV-D RNA ranged from 350 to 70 000 genome copies ml21 (Epstein et al., 2010), but bat liver, PBMCs or other cell types have not been assessed for evidence of viral replication. Viral RNA transcripts and/or serum are infectious in animal models for HCV and GBV-B (Beames et al., 2001; Bukh et al., 1999, 2001a; Jacob et al., 2004; Kolykhalov et al., 1997; Lanford et al., 2001, 2003; Martin et al., 2003; Nam et al., 2004; Sbardellati et al., 2001; Yanagi et al., 1997), and for cell culture models for HCV, GBV-B and GBV-C/HGV (Beames et al., 2000; Lindenbach et al., 2005a, 2006; Wakita et al., 2005; Xiang et al., 2000; Zhong et al., 2005). Consistent with the tropism of these viruses, both HCV and GBV-B are associated with hepatitis (Bukh et al., 2001a; Hoofnagle, 1997; Simons et al., 1995b), but GBV-A and GBV-C/HGV are not associated with hepatitis in clinical and experimental studies (Alter et al., 1997a, b; Schlauder et al., 1995; Simons et al., 1995b). No experimental transmission studies of GBV-D have been reported; however, no difference in liver enzyme values in serum was identified in bats with GBV-D viraemia (Epstein et al., 2010). Persistence and humoral immunity HCV and GBV-A infection frequently leads to persistent viraemia, with approximately 80 % of HCV infections and all GBV-A infections studied longitudinally, resulting in life-long infection (Hoofnagle, 1997; Lauer & Walker, 2001; Simons et al., 1995b). Neutralizing antibodies are detect- able against HCV in at least 95 % of persistently viraemic individuals (Lauer & Walker, 2001; Owsianka et al., 2008). Their role in chronic HCV hepatitis remains poorly defined. Although antibodies to GBV-A were not identified during acute or chronic infection, this may relate to the paucity of reagents available for GBV-A (Simons et al., 1995b). GBV-B is usually cleared by the host 1–6 months after experimental infection of tamarins (Bukh et al., 2001a; Jacob et al., 2004; Simons et al., 1995b), and no persistent infection has been observed in animals infected with virus particles. However, infection was present at the time of sacrifice in two animals (90 weeks and 2 years, respec- tively) that were injected intrahepatically with full-length, synthetically transcribed GBV-B RNA (Martin et al., 2003; Nam et al., 2004). Further passage of GBV-B derived from 235