J. T. Stapleton and others tamarins infected by intrahepatic injection resulted in self-limited infection, suggesting that the observed persis- tence was related to host genetic factors rather than a property of the specific GBV-B isolate (Jacob et al., 2004). The majority of immune competent individuals infected with GBV-C/HGV clear viraemia within 2 years of infection (Berg et al., 1999; Tanaka et al., 1998). Unlike HCV, which elicits antibodies to several viral proteins during viraemia that usually persist throughout infection (Baumert et al., 2000), GBV-C/HGV antibodies are not generally detected during viraemia, although some studies have reported the detection of anti-GBV-C/HGV peptide reactivity (Fernandez-Vidal et al., 2007; Gomara et al., 2010; Pilot-Matias et al., 1996b; Schwarze-Zander et al., 2006; Tan et al., 1999; Van der Bij et al., 2005; Xiang et al., 1998). Following clearance of GBV-C/HGV viraemia, most individuals develop conformation-dependent anti- bodies to the envelope glycoprotein E2, and thus E2 antibody serves as a marker of prior infection (Barnes et al., 2007; Gutierrez et al., 1997; McLinden et al., 2006; Nakatsuji et al., 1992; Pilot-Matias et al., 1996a; Tacke et al., 1997; Tanaka et al., 1998). Detection of anti-GBV-C/ HGV antibodies occurs coincidently with clearance of viraemia and appears to be restricted to E2, suggesting that this E2 antigenic site is immunodominant in humans (McLinden et al., 2006). In addition, HCV and GBV-C/ HGV particles contain high concentrations of lipids, and as a result have very low buoyant densities (,1.10 g cm23) (Agnello et al., 1999; Hijikata et al., 1993; Melvin et al., 1998; Monazahian et al., 1999, 2000; Thomssen et al., 1992, 1993; Wunschmann et al., 2000, 2006; Xiang et al., 1998). It is possible that these virus-associated lipids mask the HCV and GBV-C/HGV neutralization epitopes and contribute to viral persistence. However, this does not explain the failure of humans to develop antibodies to non-structural (NS) proteins in GBV-C/HGV infections, and suggests that the virus interacts with the humoral immune response. By comparing the number of healthy blood donors with either GBV-C/HGV viraemia or E2 antibody, it appears that approximately 80 % of healthy people spontaneously clear viraemia (Gutierrez et al., 1997; Nakatsuji et al., 1992; Pilot-Matias et al., 1996a; Tacke et al., 1997; Tanaka et al., 1998). Among HIV-infected subjects, the frequency of GBV-C/HGV clearance appears to be reduced, as the prevalence of viraemia is increased, while E2 antibody prevalence is generally the same or higher than in HIV- uninfected individuals (Dorrucci et al., 1995; Heringlake et al., 1998; Williams et al., 2004). Thus, the proportion of individuals with viraemia compared with those with E2 antibody is increased. GBV-C/HGV viraemia has been documented to persist for decades (Alter, 1997; Barnes et al., 2007), and by analogy with other viruses such as HBV, it is possible that higher frequencies of persistence may occur in individuals exposed very early in life. GBV-C/ HGV infection of chimpanzees (GBV-Ccpz or GBV-Ctro) may also persist in infected animals throughout 19 years of follow-up. However, like GBV-C/HGV in humans, it 236 appears that the majority of infections in chimpanzees are self limited (Mohr et al., 2010). Although HCV antibodies frequently persist in those who clear viraemia, HCV antibody titres wane over time, and longitudinal studies have revealed a substantial proportion of HCV-infected individuals without residual serological markers of infection (Takaki et al., 2000). Antibodies may prevent challenge with autologous virus (Farci et al., 1994; Tabor et al., 1980), but they do not prevent superinfection (Farci et al., 1992a). Nevertheless, neutralizing antibodies directed against conserved HCV epitopes have been identified, and are actively being studied for immunother- apy or as potential vaccine immunogens (Keck et al., 2004). To date, no antibodies to GBV-A have been detected, suggesting that GBV-A also somehow evades host recog- nition. However, there is a paucity of studies and reagents available for GBV-A, so humoral immunity in GBV-A cannot be conclusively described (Schaluder et al., 1995). In contrast, GBV-B antibodies are present following viraemia clearance and were thought to prevent or atten- uate experimental infection in marmosets (Schaluder et al., 1995). However, although a subsequent study found evidence of protection following GBV-B infection, this did not appear to involve humoral immunity (Bukh et al., 2008). Antibodies to GBV-B, HCV and GBV-C/HGV frequently decline following clearance of viraemia, some- times below the limit of detection. Thus, antibody detec- tion may underestimate the prevalence of prior infection. Information regarding GBV-D persistence or serological responses has not yet been described. Host range Despite the similarities in genome organization and existence of homologous proteins, specific host range differences exist among HCV, GBV-A, GBV-B, GBV-C/ HGV and GBV-D. HCV and GBV-C/HGV infect Old World primates, while GBV-A and GBV-B infect New World primates. Specifically, natural HCV infection is limited to humans, although experimental infection of chimpanzees is well documented (Farci et al., 1992b; Shimizu et al., 1990; Tabor et al., 1979). Natural infection of humans and chimpanzees with GBV-C/HGV is well documented (Adams et al., 1998; Birkenmeyer et al., 1998; Linnen et al., 1996; Simons et al., 1995a), and sequences of isolates obtained from chimpanzee (GBV-Ccpz or GBV- Ctro) form a separate phylogenetic group from human GBV-C/HGV (Adams et al., 1998; Birkenmeyer et al., 1998). The host range for experimental infection with HCV and human GBV-C/HGV infection appears to be restricted to humans and chimpanzees (Bukh et al., 1998, 1999, 2001b, 2008), although small studies suggest that HCV and GBV-C/ HGV may infect some Old World monkeys (Macaca) (Cheng et al., 2000; Krawczynski, 1997; Majerowicz et al., 2004; Ren et al., 2005; Vitral et al., 1997). This is controversial, as neither HCV nor GBV-C/HGV infection of macaques was reproduced by other laboratories (Bukh et al., Journal of General Virology 92